Modeling leaf dispersal in mixed hardwood forests using a ballistic approach.
In mixed-species stands, modeling leaf litter dispersal is important to predict the physical and chemical characteristics of the forest floor, which plays a major role in nutrient cycling and in plant population dynamics. In this study, a spatially explicit model of leaf litterfall was developed and compared with two other models. These three models were calibrated for a mixed forest of oak and beech using litterfall data from mapped forest plots. All models assumed that an allometric equation described individual leaf litter production, but they strongly differed in the modeling of the probability density of leaf shedding with distance from source trees. Two models used a negative exponential function to account for leaf dispersal with distance, and this function was allowed to vary according to wind direction in one of them. In contrast, our approach was based on a simple ballistic equation considering release height, wind speed, wind direction, and leaf fall velocity; the distributions of wind speeds and wind directions were modeled according to a Weibull and a Von Mises distribution, respectively. Using an independent validation data set, all three models provided predictions well correlated to measurements (r > 0.83); however, the two models with a direction-dependent component were slightly more accurate. In addition, parameter estimates of the ballistic model were in close agreement with a foliar litter production equation derived from the literature for beech and with wind characteristics measured during leaf litterfall for both species. Because of its mechanistic background, such a spatially explicit model might be incorporated as a litterfall module in larger models (nutrient cycling, plant population dynamics) or used to determine the manner in which patch size in mixed-species stands influences litter mixture.


PCR, in-situ hybridization, and phylogenetic analysis suggest that 'big belly' disease in barramundi, Lates calcarifer (Bloch), is caused by a novel Vibrio species.
'Big belly' disease is a chronic, granulomatous bacterial enteritis and peritonitis, first reported in 3- to 4-week-old Asian seabass or barramundi, Lates calcarifer Bloch fry. Affected fry are emaciated and have a swollen abdomen, and the condition is referred to as 'skinny pot-belly' or 'big belly' disease. In this study, histopathological examinations of diseased fish from a batch of 2-month-old, 6- to 8-cm L. calcarifer fingerlings, kept in seawater recirculating aquaculture systems, showed pathology resembling 'big belly' disease. Ethanol-fixed tissues were tested positive using specific PCR primers based on 16S rRNA genes. In situ hybridization using dioxygenin-labelled positive PCR products on formalin-fixed paraffin-embedded tissues showed positive reactions with intralesional, clusters of the large, 'big belly' coccobacilli. A phylogenetic tree constructed based on analyses of these 16S rRNA gene PCR products from five positive fish suggests that the 'big belly' bacterium is most likely a novel Vibrio species.


Abnormal trunk control determines postural abnormalities in Amyotrophic Lateral Sclerosis.
Postural instability in Amyotrophic Lateral Sclerosis (ALS) occurs at an early stage of the disease and often results in falls. As ALS is considered a multisystem neurodegenerative disorder, postural instability may result from motor, sensory and central processing deficits. We analysed postural control of 12 ALS patients and 12 healthy age-matched control subjects. Postural control was characterised by spontaneous sway measures and measures of postural reactions to pseudorandom anterior-posterior platform tilts, which were then correlated with clinical test scores. Spontaneous sway amplitudes and velocities were significantly larger and sway frequencies higher in ALS patients than in control subjects. ALS patients' body excursions following platform tilts were smaller, with relatively higher upper body excursions. We found high correlations between abnormal postural reactions and clinical tests representing motor or balance deficits. We conclude that ALS patients' postural abnormalities are mainly determined by an abnormal axial control and abnormally small body excursions as a function of support surface tilts, seemingly indicating better postural stabilization than control subjects. The latter contradicts the hypothesis that muscle weakness is the main source for this deficit. Instead, we suggest an altered central control strategy.


Speciation studies of diorganotin(IV) complexes with 3,3-bis(1-methylimidazol-2-yl)propionate--displacement reaction by DNA constituents.
The interaction of 3,3-bis(1-methylimidazol-2-yl)propionate (BIMP) with dimethyltin(IV) dichloride (DMT), dibutyltin(IV) dichloride (DBT), and diphenyltin(IV) dichloride (DPT) is investigated at 25°C and 0.1 M ionic strength in water for dimethyltin(IV), and in a 50% dioxane-water mixture for dibutyltin(IV) and diphenyltin(IV). The stepwise formation constants of the 1 : 1 and 1 : 2 complexes formed in solution are calculated from potentiometric measurements using the nonlinear least-square program MINIQUAD-75. The concentration distribution of the various complex species is evaluated as a function of pH. Displacement reactions of the coordinated 3,3-bis(1-methylimidazol-2-yl)propionate by inosine and inosine-5'-monophosphate are investigated from calculations based upon equilibrium properties.


ATP is dispensable for both miRNA- and Smaug-mediated deadenylation reactions.
MicroRNAs (miRNAs), as well as the RNA-binding protein Smaug, recruit the CCR4-NOT deadenylase complex for shortening of the poly(A) tail. It has been believed that ATP is required for deadenylation induced by miRNAs or Smaug, based on the fact that the deadenylation reaction is blocked by ATP depletion. However, when isolated, neither of the two deadenylases in the CCR4-NOT complex requires ATP by itself. Thus, it remains unknown why ATP is required for deadenylation by ribonucleoprotein complexes like miRNAs and Smaug. Herein we found that, in the absence of the ATP-regenerating system, ATP is rapidly consumed into AMP, a strong deadenylase inhibitor, in Drosophila cell lysate. Importantly, hydrolysis of AMP was sufficient to reactivate deadenylation by miRNAs or Smaug, suggesting that AMP accumulation, rather than ATP depletion, caused the inhibition of the deadenylation reaction. Our results indicate that ATP is dispensable for deadenylation induced by miRNAs or Smaug and emphasize caution in the use of ATP depletion methods.


Pharmacokinetics in clinical practice. I. Concepts.
Important concepts of pharmacokinetics, such as the biologic half-life, clearance, and bioavailability of drugs, can be utilized to describe and predict the time course of drug concentrations in plasma as a function of dose and frequency of drug administration. In quantitative terms, they can serve to characterize the individuality of the patient, including the effects of disease, with respect to drug absorption, distribution, excretion, and metabolism.


RPNI, TMR, and Reset Neurectomy/Relocation Nerve Grafting after Nerve Transection in Headache Surgery.
In the context of headache surgery, greater occipital nerve (GON) transection is performed when the nerve appears severely damaged, if symptoms are recurrent or persistent, and when neuromas are excised. Lesser occipital nerve (LON) excision is commonly performed during the primary decompression surgery. Advanced techniques to address the proximal nerve stump after nerve transection such as regenerative peripheral nerve interface (RPNI), targeted muscle reinnervation (TMR), relocation nerve grafting, and reset neurectomy have been shown to improve chronic pain and neuroma formation. These techniques have not been described in the head and neck region. This article describes RPNI, TMR, and reset neurectomy with GON autograft relocation to prevent chronic pain and neuroma formation after GON/LON transection. RPNI and TMR are feasible options in patients undergoing GON/LON transection. Further, relocation nerve grafting with GON autograft relocation is a method that is beneficial in patients with diffuse nerve injury requiring proximal nerve division. Advanced nerve reconstruction techniques should be considered in headache surgery following GON/LON transection.


Realizing Compact Lithium Deposition via Elaborative Nucleation and Growth Regulation for Stable Lithium-Metal Batteries.
Metallic lithium (Li) has been regarded as an ideal candidate for anode materials in next-generation high-energy-density batteries. However, a ubiquitous spongy Li deposition results in low reversibility, huge interfacial impedance, and even safety issues, hindering its practical application. Herein, we proposed a bifunctional electrolyte (BiFE) to avoid the spongy Li deposition, in which lithium nitrate (LiNO3) facilitates a uniform granular Li nucleation via forming a kinetically favorable solid electrolyte interphase and silicon dioxide (SiO2) adsorbs anions to stabilize the electric field distribution near the electrode surface. Such a BiFE provides an even Li+ ion flux for the subsequent growth of electrochemical Li deposition, which was verified by ζ potential, Raman spectra, and specific capacitance characterizations, thus realizing a compact and uniform Li deposition via elaborative nucleation and growth regulation. An improved Li Coulombic efficiency of 99.1% can be achieved within BiFE. When used in Cu∥Li half-cells and Li∥Li symmetric cells, the high Li utilization prolonged the cycling life span to above 300 cycles and 1200 h, respectively. The compact Li deposition also resisted the corrosion of polysulfides to enhance the cycling performance of Li∥S full cells.


Loss of the tumour suppressor gene AIP mediates the browning of human brown fat tumours.
Human brown fat tumours (hibernomas) show concomitant loss of the tumour suppressor genes MEN1 and AIP. We hypothesized that the brown fat phenotype is attributable to these mutations. Accordingly, in this study, we demonstrate that silencing of AIP in human brown preadipocytic and white fat cell lines results in the induction of the brown fat marker UCP1. In human adipocytic tumours, loss of MEN1 was found both in white (one of 51 lipomas) and in brown fat tumours. In contrast, concurrent loss of AIP was always accompanied by a brown fat morphology. We conclude that this white-to-brown phenotype switch in brown fat tumours is mediated by the loss of AIP. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Seasonal weight regulation of the raccoon dog (Nyctereutes procyonoides): interactions between melatonin, leptin, ghrelin, and growth hormone.
The raccoon dog (Nyctereutes procyonoides, Canidae, Carnivora) is a middle-sized omnivore with excessive autumnal fattening and winter sleep. We studied seasonal weight regulation of the species by following the plasma leptin, ghrelin, and growth hormone (GH) levels of farm-bred raccoon dogs (n = 32) for 6 months. In August, half of the raccoon dogs received continuous-release melatonin implants, and in November, half of the animals of both the sham-operated and melatonin-treated groups were fasted for 2 months. In the autumn, the plasma leptin and GH levels were low, but the ghrelin levels were relatively high and correlated positively with energy intake. This represents the period of energy storage. Leptin and GH levels peaked simultaneously in late October, and melatonin advanced the peaks by 1 week. Thereafter, the levels rapidly declined, representing the transition period from autumnal anabolism to wintertime catabolism. In the winter, the leptin and GH levels rose to high levels, but the ghrelin-leptin ratio was very low. This is the period of winter sleep, with fat accumulated in the autumn as the principal metabolic fuel. In the winter, leptin, ghrelin, and GH may work in synergy to increase lipolysis. GH may also induce winter sleep to the raccoon dog. Fasting had no effect on the hormone levels, unlike in humans and rodents. Instead of the amount of fat in the body, the main regulators of the levels of these hormones in the raccoon dog are presumably seasonal rhythms entrained by melatonin.


Successful use of partial aneurysmectomy and repair approach for managing complications of arteriovenous fistulas and grafts.
Arteriovenous fistulas and grafts may often be associated with localized complications related to aneurysms/pseudoaneurysms, buttonholes, or structural defects that require proper management to ensure continued access functionality for hemodialysis. Partial aneurysmectomy and repair (PAR) is a targeted surgical approach specifically designed for managing these complications. The basic concepts of PAR include resecting unhealthy or excessive tissue over an access, reconstructing the vascular access lumen using in situ vascular wall or tissue when possible, and closing overlying skin with healthy margins to promote reliable healing. This report analyzes the clinical outcomes of PAR in a large clinical series. The demographic and outcome data of patients who underwent PARs at an ambulatory surgery center from 2009 to 2016 were collected and analyzed. A total of 220 PAR operations were performed in 209 patients, of which 185 had fistulas and 24 had grafts. In the fistula group, 11 patients underwent subsequent staged aneurysm repairs. Comparing the fistula group (n = 185) vs the graft group (n = 24): men were 63% vs 29%, the mean age was 60.1 ± 14.8 vs 63.9 ± 16.0 years, diabetic patients were 54% vs 75%, the mean age of the accesses at the time of repair was 5.3 ± 3.2 vs 5.0 ± 4.0 years, the upper arm accesses were 69% vs 88%, the forearm accesses were 31% vs 12%, and the mean follow-up was 27.9 ± 21.9 vs 14.0 ± 11.6 months. A pneumatic tourniquet was used during 81% of the fistula and 42% of the graft operations. Dialysis catheters were required in 2% of the patients in the fistula group and 4% in the graft group to continue hemodialysis. After repair operations, the primary patency, assisted primary patency, and secondary patency rates of the whole access conduit for the fistula group were 45%, 96%, and 98% at 1 year; 28%, 91%, and 96% at 2 years; and 19%, 87%, and 95% at 3 years, respectively. The same patency rates of the graft group were 31%, 70%, and 96% at 6 months and 10%, 57%, and 96% at 1 year, respectively. Two fistulas and one graft were lost ≤30 days postoperatively. PAR is a reliable approach for managing localized arteriovenous access complications related to aneurysms/pseudoaneurysms, buttonholes, or structural defects. Given its simplicity and reliability, we recommend PAR as a first-line choice for managing these complications of arteriovenous fistulas and a choice in selected arteriovenous graft patients.


High-sensitivity Cardiac Troponin T Is a Useful Biomarker for Predicting the Prognosis of Patients with Systemic Sarcoidosis Regardless of Cardiac Involvement.
Objective Cardiac involvement defines the prognosis for patients with systemic sarcoidosis. Despite advancements in techniques for diagnosing cardiac lesions, there remains significant room for improvement in cardiac screening and prognostic prediction. The present study therefore assessed the prognostic factors associated with cardiovascular events in patients with sarcoidosis. Methods We retrospectively studied 132 patients with systemic sarcoidosis and evaluated the clinical data obtained between 2009 and 2022. A Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the associations between cardiovascular events and prognostic factors. Results The median age of the patients at the diagnosis was 64.0 (55.0-71.0) years old. During a mean follow-up period of 6.3±3.2 years, 28 patients suffered from cardiovascular events. Patients in the event group had more severe heart failure symptoms, more frequent ventricular tachycardia, higher serum high-sensitivity cardiac troponin T (hs-cTnT) values [0.025 (0.017-0.044) vs. 0.011 (0.007-0.019) ng/mL, p<0.001], and lower left ventricular ejection fraction values than those in the non-event group. These trends were observed even if the patients were not diagnosed with cardiac involvement at the time of enrollment. A multivariate analysis revealed that hs-cTnT was an independent biomarker for the prediction of cardiac events (hs-cTnT >0.014 ng/mL: HR: 7.31, 95% confidence interval: 2.20 to 24.28, p<0.001). Conclusion Hs-cTnT is a useful biomarker for predicting cardiovascular events in patients with sarcoidosis, even if cardiac involvement is not detected at the initial evaluation.


Expression of CD34-positive sinusoidal endothelial cells in patients with HBV-associated chronic liver diseases.
It has been demonstrated that CD34-positive cells isolated from human peripheral blood differentiate into endothelial cells and contribute to neoangiogenesis in adults. We investigated the role of CD34-positive endothelial cells in liver samples from patients with hepatitis B virus (HBV)-associated chronic liver diseases. Tissue sections were obtained by liver biopsy from 25 patients with HBV-associated chronic liver diseases and were examined by immunohistochemistry using anti-CD34, anti-von Willebrand factor (vWF), and anti-vascular endothelial growth factor (VEGF) antibodies. CD34-positive, but vWF-negative endothelial cells were observed, particularly in the sinusoids and vascular endothelial cells. We counted these cells and expressed the results as a CD34-labeling index (LI). The CD34 LI did not correlate with VEGF expression and the CD34 LI of patients who progressed to hepatocellular carcinoma (HCC) tended to increase compared to those that did not progress to HCC. CD34 LI was an independent risk factor for development of HCC (relative risk, 35.689; P = 0.033). We conclude that CD34-positive endothelial cells in patients with HBV-associated chronic liver diseases might play a role in hepatocarcinogenesis.


Efficient Non-Invasive Plasmid-DNA Administration into Tibialis Cranialis Muscle of "Little" Mice.
An alternative treatment for growth hormone deficiency based on hGH-DNA administration, followed by electro gene transfer, was investigated by injecting the plasmid into surgically exposed or non-exposed quadriceps or tibialis muscle of immunodeficient "little" mice. An optimization of electrotransfer conditions via a new combination of high/low voltage pulses is presented. After 3 days, serum hGH was determined and in a 28-day assay, the relative growth parameters were compared. Both groups exhibited similar results: 5.0 ± 2.2 (SD) and 3.5 ± 0.9 ng hGH/ml (P>0.05; n=7) for the exposed quadriceps and non-exposed tibialis treatments, respectively. The final body weight increases were 16.1% for the quadriceps and 18.9% for the tibialis group. The tail and nose-to-tail length increases were 4.5% and 7.1% for the quadriceps and 4.8 and 4.6% for the tibialis group. The right and left femur length increases, obtained from radiographic measurements, were 16.9% and 12.7% for the quadriceps and 19.4% and 12.3% for the tibialis, respectively. A non-significant difference between exposed quadriceps and non-exposed tibialis treatments (P=0.48) was confirmed via a completely integrated statistical analysis. Circulating mIGF-1 levels were 126 ± 47, 106 ± 93 (P>0.05) and 38 ± 15 ng/ml for the quadriceps, tibialis and saline treatments, respectively. These results show that hGH-DNA administration into non-exposed tibialis muscle followed by the new HV/LV electrotransfer protocol was an equally efficient, less traumatic treatment, much more suitable for pre-clinical testing than administration into exposed quadriceps.


Evaluation of the protective effectiveness of gloves from occupational exposure to 2-methoxyethanol using the biomarkers of 2-methoxyacetic acid levels in the urine and plasma.
To evaluate the protective effectiveness of gloves from occupational exposure to 2-methoxyethanol (2-ME); and to examine the association of 2-methoxyacetic acid (MAA) in urine and plasma collected simultaneously from low 2-ME exposure and high 2-ME exposure workers in a semiconductor copper laminate circuit board manufacturing plant. Eight hour time weighted breathing zone monitoring was performed to verify the 2-ME exposure classification between workers in regular and special operations. Urine and plasma samples were simultaneously collected from 74 exposed and 80 non-exposed workers. MAA concentrations in the urine (UMAA) and plasma (PMAA) were measured using previously published methods. Three types of gloves worn by workers (cotton, rubber, and no gloves) were recorded by direct observations in the workplace and validated by person-to-person interview. Protective effectiveness indices (PEI) were used to evaluate the glove effectiveness. There was no detectable 2-ME/MAA in the air, or in urine and plasma samples in non-exposed workers. The average UMAA and PMAA in special operations were 72.63 mg/g Cr. and 29.72 mg/l, significantly higher than values in regular operations (5.44 mg/g Cr. and 2.58 mg/l, respectively). PMAA showed satisfactory correlation to UMAA in all participants from both regular and special operations. The rubber gloves provided significant reduction in 2-ME uptake, whereas cotton gloves provided little protection with fluctuating effectiveness, based on PEI estimates. PMAA, similar to UMAA, could serve as a specific biomarker for 2-ME exposure. Wearing impermeable rubber gloves during high risk tasks can reduce major 2-ME exposure. Other improvements, including engineering control, should be provided to diminish worker exposure to 2-ME in occupational environments.


Evaluation of image-guidance strategies in the treatment of localized prostate cancer.
To compare different image-guidance strategies in the alignment of prostate cancer patients. Using data from patients treated using daily image guidance, the remaining setup errors for several different strategies were retrospectively calculated. The alignment data from 74 patients treated with helical tomotherapy were analyzed, resulting in a data set of 2,252 fractions during which a megavoltage computed tomography image was used for image guidance with intraprostatic metallic fiducials. Given the daily positional adjustments, a variety of protocols, differing in imaging frequency and method, were retrospectively studied. The residual setup errors were determined for each protocol. As expected, the systematic errors were effectively reduced with imaging. However, the random errors were unaffected. Even when image guidance was performed every other day with a running mean of the previous displacements, residual setup errors>5 mm occurred in 24% of all fractions. This frequency increased to about 40% if setup errors>3 mm were scored. Setup errors increased with decreasing frequency of image guidance. However, residual errors were still significant at the 5-mm level, even with imaging was performed every other day. This suggests that localizations must be performed daily in the set up of prostate cancer patients during a course of external beam radiotherapy.


The ultimate speed limit to protein folding is conformational searching.
More than a dozen proteins are known to be ultrafast folders. In addition to being fast, their kinetics is unusual. Like traditional rate processes, fast folding proteins have activation barriers at low temperatures, but unlike traditional processes, they have negative activation energies at high temperatures. We develop a model of ultrafast folders that joins a macroscopic mass-action model with a microscopic energy landscape description; we call it the Thruway Search Model. We find good agreement with experimental rates and equilibria on 13 ultrafast folders. The observed folding rates are found to be proportional to the number of microscopic folding routes: fast-folding proteins have more parallel microscopic routes on energy landscapes. At high temperatures, where traditional barriers are small, the remaining bottleneck is a search through denatured conformations to find thruway routes to the native state. Negative activation arises because increasing temperature expands the denatured ensemble, broadening the search, slowing the folding to the native state. We find that the upper estimate of the free energy barriers are positive but small, as little as 0.5 kT.


Quality of life of hemodialysis patients in Togo: A single-center study on 64 hemodialysis patients at the Sylvanus Olympio University Hospital in Lomé, Togo.
This study aims at assessing patients' quality of life during hemodialysis (HD) and determining influencing factors. This prospective study was conducted over a three-month period (December 1, 2012-February 28, 2013) at the Sylvanus Olympio University Hospital (CHU-SO) HD unit, the only center to provide such services in Togo. Respondents used the standard Medical Outcome Survey-Short Form 36 questionnaire. This study was conducted on 64 patients (44 males and 20 females = M/F ratio 2.2). Mean patient age was 45.51 ± 14.00 years old with the vast majority in the 16-44-year-old group (90.82%), and mean dialysis vintage was 2.84 ± 2.37 years (1 month to 9.5 years). The mean global quality of life score was 35.58 (standard deviation ± 15). Quality of life physical score and mental score were, respectively, 31.84 and 40.64. Physical limitation scores were 15.23, followed by general ill-health score 37.38 and poor physical function score 47.37. Mental limitation score was 30.20 and vitality score was 43.75. The quality of life was inversely proportional to patient age and the dialysis vintage, with female quality of life scores worse than male in all questionnaire parameters. Togolese dialysis patients suffer from poor quality of life. Factors underlying such poor quality of life include advanced age, female gender, long-standing history of dialysis, and patient profession.


Investigation of the influence of pressurized CO2 on the crystal growth of poly(l-lactic acid) by using an in situ high-pressure optical system.
Since CO2 is a kind of nontoxic, non-flammable and biocompatible fluid, introducing CO2 in the PLLA formation process has been regarded as a green way to the manufacture of biological products or medical supplies. However, it is still a challenge to understand the influence of CO2 on the crystal growth behavior of PLLA. Here, we developed an in situ high-pressure observation system, composed of optics, polarization optics and a small angle laser scattering system, to record the growth process of PLLA crystals in a pressurized CO2 environment. It is found that, at a low temperature (near Tg), low pressure CO2 (0.5 MPa in this work) can still induce the formation of numerous micron-sized spherulites of PLLA. Therefore, the introduction of CO2 can significantly enhance the crystallization ability of PLLA and decrease the crystallization temperature, which is helpful in improving the mechanical properties of PLLA products. We also found that a snowflake-shaped crystal was assembled by rhombic lamellae under pressurized CO2. There is a melt accumulation zone surrounding the growth front of the snowflake-shaped crystal, indicating that the growth front nucleation is limited by the pressurized CO2. This melt accumulation zone is quite different from the melt depletion zone existing ahead of the reported dendritic crystal front. Interestingly, in a high-pressure CO2 environment, a kind of bamboo-like branch is formed in a rhythmic growth mode. The repeating unit of the bamboo-like branch is constructed by an asymmetric terrace crystal originated from screw dislocation in the melt accumulation zone. These results demonstrated that CO2 has a remarkable tunability on the polymer crystal morphology.


Measuring the quality of exercises.
This work explores the problem of exercise quality measurement since it is essential for effective management of diseases like cerebral palsy (CP). This work examines the assessment of quality of large amplitude movement (LAM) exercises designed to treat CP in an automated fashion. Exercise data was collected by trained participants to generate ideal examples to use as a positive samples for machine learning. Following that, subjects were asked to deliberately make subtle errors during the exercise, such as restricting movements, as is commonly seen in cases of patients suffering from CP. The quality measurement problem was then posed as a classification to determine whether an example exercise was either "good" or "bad". Popular machine learning techniques for classification, including support vector machines (SVM), single and double-layered neural networks (NN), boosted decision trees, and dynamic time warping (DTW), were compared. The AdaBoosted tree performed best with an accuracy of 94.68% demonstrating the feasibility of assessing exercise quality.


Histochemistry of bone marrow aspirations.
The accuracy of diagnosis of hematological diseases from bone marrow aspirates and peripheral blood smears is considerably improved by use of histochemical stains. As hematopoietic cells differentiate and mature from the pluripotent stem cell and are committed to a particular cell line, the committed cell lines produce different substances, particularly enzymes, which can be identified by various histochemical stains. Histochemical stains are not diagnostic, but are aids in diagnosis, because various cell lines may produce similar substances and because the stains lack absolute specificity. A discussion of the use of histochemical stains for the diagnosis of leukemias is presented. Complete procedures for Prussian blue stain for iron, peroxidase, Sudan black B, naphthol AS-D chloroacetate esterase, nonspecific esterase, periodic acid Schiff (PAS), acid phosphatase, toluidine blue and alkaline phosphatase stains are given in the appendix.


Clinicopathological consultation. Lymphoepithelial carcinoma of the larynx hypopharynx, and trachea.
Lymphoepithelial carcinoma of the larynx, hypopharynx, and trachea is a rare neoplasm composed of large, poorly differentiated, nonkeratinized cells intermingled with small nonneoplastic lymphocytes and plasma cells. It is histologically similar to its more common counterpart occurring in the nasopharynx. In contrast to nasopharyngeal carcinoma, most cases have not been associated with Epstein-Barr virus (EBV), although rare cases have been reported to be EBV-positive. The diagnosis often requires immunohistochemistry or electron microscopy for confirmation. The neoplasm seems to behave in a fashion reminiscent of nasopharyngeal carcinoma. Lymph node metastasis occurs in the majority of patients, and eventual visceral dissemination occurs in one fourth. Radiotherapy is the main treatment for the primary tumor and regional metastases, but chemotherapy is indicated for more advanced disease. The initial stage is the primary determinant of prognosis. Death from disease occurs in about one third of patients.


Advances in the generalized entropy theory of glass-formation in polymer melts.
The generalized entropy theory (GET) of polymeric glass-forming liquids is reformulated into a computationally simpler and more natural formalism than the original version of this theory. The new theoretical framework greatly facilitates establishing essential trends in the dependence of the segmental relaxation time τ, fragility, characteristic temperatures of glass-formation, etc., on the combined influences of monomer molecular structure, chain rigidity, and cohesive interaction strength. Special attention is placed on the estimating the parameters of the phenomenological Vogel-Fulcher-Tammann relations for describing segmental relaxation in diverse liquids in the low temperature range of glass-formation, Tg > T > Tc (or Tg < T < Tg + 100 K), where Tg and Tc are, respectively, the glass transition temperature and the crossover temperature separating the high and low temperature regimes of glass-formation. Finally, we discuss how the molecular energetic interaction parameters of the GET can be estimated from experimental data. Illustrative calculations are performed for the stiffness factor σ and the cohesive energy density u as a first step in this direction.


Simulations of molecular photodynamics in long timescales.
Nonadiabatic dynamics simulations in the long timescale (much longer than 10 ps) are the next challenge in computational photochemistry. This paper delimits the scope of what we expect from methods to run such simulations: they should work in full nuclear dimensionality, be general enough to tackle any type of molecule and not require unrealistic computational resources. We examine the main methodological challenges we should venture to advance the field, including the computational costs of the electronic structure calculations, stability of the integration methods, accuracy of the nonadiabatic dynamics algorithms and software optimization. Based on simulations designed to shed light on each of these issues, we show how machine learning may be a crucial element for long time-scale dynamics, either as a surrogate for electronic structure calculations or aiding the parameterization of model Hamiltonians. We show that conventional methods for integrating classical equations should be adequate to extended simulations up to 1 ns and that surface hopping agrees semiquantitatively with wave packet propagation in the weak-coupling regime. We also describe our optimization of the Newton-X program to reduce computational overheads in data processing and storage. This article is part of the theme issue 'Chemistry without the Born-Oppenheimer approximation'.


Durability of fiber post-to-composite bonds achieved by physical vapor deposition and tribochemical silica coating.
To evaluate post-to-composite bonds in terms of their durability, achieved either by physical vapor deposition (PVD) or tribochemical silica coating (TSC) compared to coupling strategies for fiber posts at chairside. Thirty uncoated fiber posts (DT Light) each were either left untreated (control) or silanized with a one-bottle (Monobond Plus) or a two-bottle (Clearfil SE Bond/Porcelain Bond Activator) silane at the chairside. Thirty coated fiber posts each had already been silica coated and silanized by the manufacturer using PVD (DT Light SL) or TSC (DentinPost Coated) deposition techniques. Surface analysis was carried out by profilometry and x-ray microanalysis. All the posts were surrounded by 2-mm-thick disks of a dual-curing composite resin (MultiCore Flow). After water storage for 24 h at 37°C, the specimens in each group were randomly divided into three subgroups (n=10) and subjected to 0, 1500, and 20,000 thermocycles (5°C to 55°C) prior to push-out testing. Failure modes were evaluated by optical and scanning electron microscopy. The statistical significance was determined with two-way ANOVA, the Student-Newman-Keuls test, and Fisher's exact test. The conditioned posts had significantly higher interfacial bond strengths than the control posts after thermocycling (p<0.05). Extended thermocycling significantly reduced the interfacial strength of chairside silanized posts (p<0.05). This effect was not significant with industrially coated posts (p>0.05). Coatings deposited by TSC reached the highest bond values (p<0.05) and showed predominantly adhesive failures in the form of coating delamination (p<0.0001). In contrast, the other coupling strategies showed significantly lower values and adhesive failures between the post and the composite. PVD and TSC techniques enhanced the bond durability of fiber posts. TSC led to a superior post-tocomposite bond, probably based on more effective micromechanical adhesion due to the higher surface roughness.


Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting αvβ3 Integrin and VEGF Receptors.
A dual-action ligand targeting both integrin αVβ3 and vascular endothelial growth factor receptors (VEGFRs), was synthesized via conjugation of a cyclic peptidomimetic αVβ3 Arg-Gly-Asp (RGD) ligand with a decapentapeptide. The latter was obtained from a known VEGFR antagonist by acetylation at the Lys13 side chain. Functionalization of the precursor ligands was carried out in solution and in the solid phase, affording two fragments: an alkyne VEGFR ligand and the azide integrin αVβ3 ligand, which were conjugated by click chemistry. Circular dichroism studies confirmed that both the RGD and VEGFR ligand portions of the dual-action compound substantially adopt the biologically active conformation. In vitro binding assays on isolated integrin αVβ3 and VEGFR-1 showed that the dual-action conjugate retains a good level of affinity for both its target receptors, although with one order of magnitude (10/20 times) decrease in potency. The dual-action ligand strongly inhibited the VEGF-induced morphogenesis in Human Umbilical Vein Endothelial Cells (HUVECs). Remarkably, its efficiency in preventing the formation of new blood vessels was similar to that of the original individual ligands, despite the worse affinity towards integrin αVβ3 and VEGFR-1.


Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis.
Metastasis is directly linked to poor prognosis of cancer patients and warrants search for effective anti-metastatic drugs. MACC1 is a causal key molecule for metastasis. High MACC1 expression is prognostic for metastasis and poor survival. Here, we developed novel small molecule inhibitors targeting MACC1 expression to impede metastasis formation. We performed a human MACC1 promoter-driven luciferase reporter-based high-throughput screen (HTS; 118.500 compound library) to identify MACC1 transcriptional inhibitors. HTS revealed 1,2,3,4-tetrazolo[1,5-b]pyridazine-based compounds as efficient transcriptional inhibitors of MACC1 expression, able to decrease MACC1-induced cancer cell motility in vitro. Structure-activity relationships identified the essential inhibitory core structure. Best candidates were evaluated for metastasis inhibition in xenografted mouse models demonstrating metastasis restriction. ADMET showed high drug-likeness of these new candidates for cancer therapy. The NFκB pathway was identified as one mode of action targeted by these compounds. Taken together, 1,2,3,4-tetrazolo[1,5-b]pyridazine-based compounds are effective MACC1 inhibitors and pose promising candidates for anti-metastatic therapies particularly for patients with MACC1-overexpressing cancers, that are at high risk to develop metastases. Although further preclinical and clinical development is necessary, these compounds represent important building blocks for an individualized anti-metastatic therapy for solid cancers.


Evaluating communication with parents in paediatric patient encounters: a systematic review protocol.
Breaking bad news and dealing with difficult patient encounters is a skill that medical residents must learn during their curriculum. Many different tools are available to measure communication quality, but their development and validation processes are often missing. In this paper, we present the protocol of a systematic review aiming to identify the validated tools for measuring communication skills or communication effectiveness with parents in a paediatrics setting in general, including for difficult patient encounters. We will conduct our systematic review in accordance with the methodology suggested by COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) and will report this paper following the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analyses. We will include the studies in which authors developed and/or validated tools for assessing the quality of communication with families by residents and/or physicians during patient encounters in paediatric settings. Studies assessing communication in telemedicine and studies that use the tool to measure a different outcome than its validation will be excluded. Our search strategy will be developed by a scientific librarian and validated using the Peer Review of Electronic Search Strategy (PRESS) tool. Two reviewers will independently screen the studies for selection, extract data of the ones included and assess their level of risk of bias using the COSMIN Risk of Bias checklist. We will perform a narrative synthesis on the study selection process, the characteristics of studies and study population, the characteristics of tools identified, their process of development and/or validation and their psychometric properties. If sufficient data are available, we will do quantitative analyses for each psychometric property. Approval from an ethics committee is not required, as there is no primary data collection. Our findings will be disseminated through a peer-reviewed publication and at local, national and international conferences. CRD42020151642.


Association of Autoimmune Encephalitis With Combined Immune Checkpoint Inhibitor Treatment for Metastatic Cancer.
Paraneoplastic encephalitides usually precede a diagnosis of cancer and are often refractory to immunosuppressive therapy. Conversely, autoimmune encephalitides are reversible conditions that can occur in the presence or absence of cancer. To report the induction of autoimmune encephalitis in 2 patients after treatment of metastatic cancer with a combination of the immune checkpoint inhibitors nivolumab and ipilimumab. A retrospective case study was conducted of the clinical and management course of 2 patients with progressive, treatment-refractory metastatic cancer who were treated with a single dose each (concomitantly) of the immune checkpoint inhibitors nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg. Nivolumab and ipilimumab. The clinical response to immunosuppressive therapy in suspected autoimmune encephalitis in the setting of immune checkpoint inhibitor use. Autoantibody testing confirmed identification of anti-N-methyl-D-aspartate receptor antibodies in the cerebrospinal fluid of 1 patient. Withdrawal of immune checkpoint inhibitors and initiation of immunosuppressive therapy, consisting of intravenous methylprednisolone sodium succinate equivalent to 1000 mg of methylprednisolone for 5 days, 0.4 mg/kg/d of intravenous immunoglobulin for 5 days, and 2 doses of rituximab, 1000 mg, in 1 patient and oral prednisone, 60 mg/d, in the other patient, resulted in improved neurologic symptoms. Immune checkpoint inhibition may favor the development of immune responses against neuronal antigens, leading to autoimmune encephalitis. Early recognition and treatment of autoimmune encephalitis in patients receiving immune checkpoint blockade therapy will likely be essential for maximizing clinical recovery and minimizing the effect of drug-related toxic effects. The mechanisms by which immune checkpoint inhibition may contribute to autoimmune encephalitis require further study.


Relationship between the vertical craniofacial disproportions and the cervicovertebral morphology in adult subjects.
Orthodontic diagnosis includes the interpretation of the relations between the craniofacial and cervical system, given the potential impact of the irregularities from one system to another. The aim of this study was to examine morphological characteristics of the cervical spine, depending on the parameters of the vertical craniofacial growth and gender in adult subjects. The sample comprised lateral cephalograms of 120 subjects with different vertical facial growth, aged 17.5-35 years. Measured parameters were the following: anterior and posterior vertebral body height (ABHC2-C5, PBHC2-C5), anterior and posterior intervertebral space (AISC2-C5, PISC2-C5), distance between vertebrae and point sella (SC2, SC3, SC4), pterygomaxillare (PmC2), gonion (GoC2) and basion (BaC4); cervical spine angulation (OPT/CVT) and inclination (OPT/HOR, CVT/HOR). Results showed that subjects with anterior facial growth rotation have greater values for BaC4, OPT/HOR, CVT/HOR, OPT/CVT, anterior and posterior vertebral body heights and intervertebral spaces, and lower values for GoC2 and PmC2. Higher values in males were found for anterior and posterior vertebral body heights, distances SC2, SC3, SC4, and BaC4. In females, the greater values were found for GoC2 and OPT/CVT. Subjects with anterior facial growth rotation have greater cervical spine inclination and angulation, higher cervical vertebrae and intervertebral spaces, longer upper cervical spines and shorter distances GoC2 and PmC2. Males show smaller cervical column curvature, but higher cervical vertebrae and greater length of the upper cervical spine.


Transcriptome profiling of venom gland from wasp species: de novo assembly, functional annotation, and discovery of molecular markers.
Vespa velutina, one of the most aggressive and fearful wasps in China, can cause grievous allergies and toxic reactions, leading to organ failure and even death. However, there is little evidence on molecular data regarding wasps. Therefore, we aimed to provide an insight into the transcripts expressed in the venom gland of wasps. In our study, high-throughput RNA sequencing was performed using the venom glands of four wasp species. First, the mitochondrial cytochrome C oxidase submit I (COI) barcoding and the neighbor joining (NJ) tree were used to validate the unique identity and lineage of each individual species. After sequencing, a total of 127,630 contigs were generated and 98,716 coding domain sequences (CDS) were predicted from the four species. The Gene ontology (GO) enrichment analysis of unigenes revealed their functional role in important biological processes (BP), molecular functions (MF) and cellular components (CC). In addition, c-type, p1 type, p2 type and p3 type were the most commonly found simple sequence repeat (SSR) types in the four species of wasp transcriptome. There were differences in the distribution of SSRs and single nucleotide polymorphisms (SNPs) among the four wasp species. The transcriptome data generated in this study will improve our understanding on bioactive proteins and venom-related genes in wasp venom gland and provide a basis for pests control and other applications. To our knowledge, this is the first study on the identification of large-scale genomic data and the discovery of microsatellite markers from V. tropica ducalis and V. analis fabricius.


Vagal afferents and EEG rhythms in the Sl area in anesthetized cats: similarities between responses to electrical and chemical (phenyldiguanide) stimulations.
In anesthetized, artificially ventilated cats with open chest, bilateral stimulation of all afferent vagal fibres (pulse duration: 800 microseconds, 30 Hz, train duration 30 to 40 s) produced marked changes in the spontaneous EEG activities in the primary somatosensory cortex (Sl area). They were characterized by depressed background rhythms, with a tendency to desynchronization, decreased amplitude and number of spindles, with altered pattern, and/or evoked sustained fast rhythmic activities. These effects occurred within 1 to 5 sec during vagal stimulation. On the contrary, the EEG response was weaker or absent when only myelinated vagal afferents were stimulated (100 microseconds). I.v. injection of phenyldiguanide (PDG), used for stimulation of unmyelinated vagal sensory fibres and mainly of pulmonary afferents, induced EEG changes within the first 30 s, similar to those observed during electrical vagal stimulation. These EEG responses were unrelated to the induced hypotension. Cervical bivagotomy produced persistent changes in EEG activity, with enhancement of the magnitude, duration and number of spindles, which resembled the delayed effects induced by PDG. The present results obtained with three test agents (electrical or chemical vagal stimulation and bivagotomy) demonstrated that, in cats, vagal afferent information interacted with the spontaneous EEG rhythms in the Sl area.


Active learning in capstone design courses.
There is a growing trend to encourage students to take a more active role in their own education. Many schools are moving away from the sage on the stage to the guide on the side model where the instructor is a facilitator of learning. In this model, the emphasis is more on learning and less on teaching, and it requires instructors to incorporate more active and student-centered learning methods into their courses. These methods include collaborative, cooperative, problem-based, and project-based learning.


Comparison of polycyclic aromatic hydrocarbons in sediments from the Songhuajiang River (China) during different sampling seasons.
The Songhuajiang River watershed is the important industrial and foodstuff base in the northeast part of China. However, the increasing population, industrial and agricultural activities around the Songhuajiang River lead to the introduction of contaminants and the possibility of polluting the river. This investigation represents an extensive study of the spatial and temporal distribution of polycyclic aromatic hydrocarbons (PAHs) in the sediment samples collected from the Songhuajing River in flood season (August, 2005) and icebound season (December, 2005) by using the gas chromatography-mass spectrometry (GC/MS) analyses. In flood season, the total PAHs concentrations in sediments ranged from 84.44 ng g-1 to 14938.73 ng g-1, with average concentration of 2430.37 ng g-1. In icebound season, the total PAHs concentrations in sediments ranged from 23.61 ng g-1 to 15310.25 ng g-1, with average concentration of 1825.60 ng g-1. Compared to the concentration of PAHs between central sediment and riverbank-exposed sediment at some stations, the concentration in exposed sediment was higher than that in the central sediment in the upstream of river. It was also observed that the concentration of PAHs in flood season was higher than that in icebound season. The level of PAHs in the sediments of Songhua River was higher in comparison with values reported from other river and marine systems in the world. The most contaminated sediment samples were found in the upstream area of Songhuajiang River located near Jilin petrochemical industrial company for both flood and icebound seasons. The 4-6 ring PAHs were dominated in sediments due to their higher persistence. There was positive correlation between total PAHs concentration in sediment samples and TOC or LOI (r = 0.62 and r = 0.58, P < 0.01, n = 31). The calculated ratio of selected PAH and principal component analysis (PCA) suggests the contamination source of PAHs were combined inputs of pyrolytic and petrogenic contamination, due to the discharge from municipal and industrial wastewater runoff and atmospheric fallout.


Treatment of Parkinson's disease using cell transplantation.
The clinical trials with intrastriatal transplantation of human fetal mesencephalic tissue, rich in dopaminergic neurons, in Parkinson's disease (PD) patients show that cell replacement can work and in some cases induce major, long-lasting improvement. However, owing to poor tissue availability, this approach can only be applied in very few patients, and standardization is difficult, leading to wide variation in functional outcome. Stem cells and reprogrammed cells could potentially be used to produce dopaminergic neurons for transplantation. Importantly, dopaminergic neurons of the correct substantia nigra phenotype can now be generated from human embryonic stem cells in large numbers and standardized preparations, and will soon be ready for application in patients. Also, human induced pluripotent stem cell-derived dopaminergic neurons are being considered for clinical translation. Available data justify moving forward in a responsible way with these dopaminergic neurons, which should be tested, using optimal patient selection, cell preparation and transplantation procedures, in controlled clinical studies.


A near analytic solution of a stochastic immune response model considering variability in virus and T-cell dynamics.
Biological processes at the cellular level are stochastic in nature, and the immune response system is no different. Therefore, models that attempt to explain this system need to also incorporate noise or fluctuations that can account for the observed variability. In this work, a stochastic model of the immune response system is presented in terms of the dynamics of T cells and virus particles. Making use of the Green's function and the Wilemski-Fixman approximation, this model is then solved to obtain the analytical expression for the joint probability density function of these variables in the early and late stages of infection. This is then also used to calculate the average level of virus particles in the system. Upon comparing the theoretically predicted average virus levels to those of COVID-19 patients, it is hypothesized that the long-lived dynamics that are characteristics of such viral infections are due to the long range correlations in the temporal fluctuations of the virions. This model, therefore, provides an insight into the effects of noise on viral dynamics.


Regulation by cAMP of STAT1 activation in hepatic stellate cells.
Previously we reported that dibutyryl cAMP and phosphodiesterase inhibitor methylxanthines block rat stellate cell proliferation. To analyze the underlying mechanism, modulation by these agents of platelet-derived growth factor (PDGF)/BB-stimulating signal pathway was studied. Without reducing STAT1 protein level, these agents were found to attenuate STAT1 activation in stellate cells stimulated with PDGF/BB as revealed by an electrophoretic mobility shift assay. Inhibitory effect started 12 h after exposure of the cells to these agents at concentrations of more than 100 microM. These agents had no effects on DNA binding activity of STAT1 that had already been activated. Treatment with these agents failed to affect the function of PDGF receptors except for partial attenuation of phospholipase C activation under PDGF/BB stimulation. The present results indicate that inhibition of STAT1 activation may be one of factors involved in the cAMP-dependent stellate cell growth arrest.


[The epidemiological study of hepatolithiasis in the Kamigoto district, Nagasaki where hepatolithiasis is high incidence].
Regional distribution, age, sex, type of disease and history of surgery of the biliary tract were examined in 134 patients with hepatolithiasis in the Kamigoto district. The ratio of patient to population was 1:126 in the region showing the highest incidence. When classified by age at establishment of the diagnosis, patient in their sixties comprised the largest portion in both sexes. The ratio of men to women was 1:1.2. When classified in accordance with the draft by Research Group for the Study of Hepatolithiasis, 103 cases (76.9%) were of the intrahepatic type, and 31 cases (23.1%) were of the intra-extrahepatic type. The stones were found in the right lobe in 58 patients (43.3%), the left lobe in 59 patients (44.0%) and the both lobes in 17 patients (12.7%). Forty-four patients (32.8%) had a history of surgery of the biliary tract. Ultrasonographic examination of the abdomen in junior high school students revealed hepatolithiasis in one. As a result, the intrahepatic type and the right lobe type are high frequency in this district, and epidemiological survey of the family history and the food habit in this district is necessary.


Perspective on Melatonin Use for Sleep Problems in Autism and Attention-Deficit Hyperactivity Disorder: A Systematic Review of Randomized Clinical Trials.
Melatonin is a hormone produced by the pineal gland and is available over the counter for treating sleep problems in the pediatric population. We conducted a systematic review of randomized clinical trials (RCTs) on MEDLINE and included six studies that met our inclusion criteria. RCTs were conducted in patients from two to 18 years of age with a diagnostic and statistical manual of mental disorders (DSM)-IV diagnosis of autism spectrum disease (ASD) and/or attention-deficit hyperactivity disorder (ADHD) in both short-term and long-term RCTs ranging from eight-week to 52-week studies. The mean difference in the children's sleep disorder showed statistically significant improvement in sleep duration and sleep latency onset compared to the placebo. Overall, a high response rate was observed in the melatonin group compared to the placebo in treating sleep problems in children. Melatonin is a well-tolerated and safe medication in the dose range of 2-10 mg/day in the child and adolescent population.


Delayed diagnosis of nasal natural killer/t-cell lymphoma.
Midline destructive lesions of the face have multiple possible etiologies. The majority of these cases are found to be due to an extranodal lymphoma of natural killer/T-cell-type non-Hodgkins lymphoma (NKTL). Unfortunately, diagnosis is often delayed. With variable presenting complaints, including nonspecific issues like chronic rhinosinusitis or nasal congestion, initial treatments are aimed at these presumed diagnoses. Only as the lesion progresses do overt signs of destruction occur. As with our patient, who was initially treated for presumed infection and abscess, final diagnosis often does not occur until several months, and several antibiotic courses, from initial presentation. As such, it is important for this rare entity to remain in the clinician's differential diagnosis for nasal lesion.


[The research advances in the relationship between visfatin and cancer].
Visfatin is a cytokine secreted by visceral adipose tissue, which plays an important role in obesity, diabetes, insulin resistance, atherosclerosis and polycystic ovarian syndrome. Additionally, visfatin is also involved in the metabolic syndrome-associated malignancies such as breast, colon, gastric and endometrial cancers. Visfatin inhibitor might be a potential antitumor therapeutic strategy for inhibiting the growth of many cancers.


Microfluidic Brain-on-a-Chip: Perspectives for Mimicking Neural System Disorders.
Neurodegenerative diseases (NDDs) include more than 600 types of nervous system disorders in humans that impact tens of millions of people worldwide. Estimates by the World Health Organization (WHO) suggest NDDs will increase by nearly 50% by 2030. Hence, development of advanced models for research on NDDs is needed to explore new therapeutic strategies and explore the pathogenesis of these disorders. Different approaches have been deployed in order to investigate nervous system disorders, including two-and three-dimensional (2D and 3D) cell cultures and animal models. However, these models have limitations, such as lacking cellular tension, fluid shear stress, and compression analysis; thus, studying the biochemical effects of therapeutic molecules on the biophysiological interactions of cells, tissues, and organs is problematic. The microfluidic "organ-on-a-chip" is an inexpensive and rapid analytical technology to create an effective tool for manipulation, monitoring, and assessment of cells, and investigating drug discovery, which enables the culture of various cells in a small amount of fluid (10-9 to 10-18 L). Thus, these chips have the ability to overcome the mentioned restrictions of 2D and 3D cell cultures, as well as animal models. Stem cells (SCs), particularly neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs) have the capability to give rise to various neural system cells. Hence, microfluidic organ-on-a-chip and SCs can be used as potential research tools to study the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders. Accordingly, in the present review, we discuss the latest progress in microfluidic brain-on-a-chip as a powerful and advanced technology that can be used in basic studies to investigate normal and abnormal functions of the nervous system.


WNT signalling supported by MEK/ERK inhibition is essential to maintain pluripotency in bovine preimplantation embryo.
Capturing stable embryonic stem cell (ESC) lines from domesticated animals still remains one of the challenges of non-rodent embryology. The stake is high, as stable ESCs derived from species such as cattle present high economic and scientific value. Understanding of the processes leading to the embryonic lineage segregation is crucial to provide species-orientated molecular environment capable of supporting self-renewal and pluripotency. Therefore, the aim of this study was to validate the action of the two core regulatory pathways (WNT and MEK/ERK) during bovine embryo development. In vitro produced bovine embryos were obtained in the presence of inhibitors (i), which enable activation of the WNT pathway (via GSK3i, CHIR99021) and suppression of MEK signalling by PD0325901 in the 2i system and PD184325 and SU5402 in the 3i system. We have followed the changes in the distribution of the key lineage specific markers both at the transcript and protein level. Our results showed that WNT signalling promotes the expression of key inner cell mass (ICM) specific markers in bovine embryos, regardless of the MEK/ERK inhibitor cocktail used. MEK/ERK downregulation is crucial to maintain OCT4 and NANOG expression within the ICM and to prevent their exclusion from the trophectoderm (TE). At the same time, the classical TE marker (CDX2) was downregulated at the mRNA and protein level. As a follow up for the observed pluripotency stimulating effect of the inhibitors, we have tested the potential of the 2i and the 3i culture conditions (supported by LIF) to derive primary bovine ESC lines. As a result, we propose a model in which all of the primary signalling pathways determining embryonic cell fate are active in bovine embryos, yet the requirement for pluripotency maintenance in cattle may differ from the described standards. WNT activation leads to the formation (and stabilisation of the ICM) and MEK/ERK signalling is maintained at low levels. Unlike in the mouse, GATA6 is expressed in both ICM and TE. MEK/ERK signalling affects HP formation in cattle, but this process is activated at the post-blastocyst stage. With regard to self-renewal, 2i is preferable, as 3i also blocks the FGF receptor, what may prevent PI3K signalling, important for pluripotency and self-renewal.


Integrating publicly available information to screen potential candidates for chemical prioritization under the Toxic Substances Control Act: A proof of concept case study using genotoxicity and carcinogenicity.
The Toxic Substances Control Act (TSCA) became law in the U.S. in 1976 and was amended in 2016. The amended law requires the U.S. EPA to perform risk-based evaluations of existing chemicals. Here, we developed a tiered approach to screen potential candidates based on their genotoxicity and carcinogenicity information to inform the selection of candidate chemicals for prioritization under TSCA. The approach was underpinned by a large database of carcinogenicity and genotoxicity information that had been compiled from various public sources. Carcinogenicity data included weight-of-evidence human carcinogenicity evaluations and animal cancer data. Genotoxicity data included bacterial gene mutation data from the Salmonella (Ames) and Escherichia coli WP2 assays and chromosomal mutation (clastogenicity) data. Additionally, Ames and clastogenicity outcomes were predicted using the alert schemes within the OECD QSAR Toolbox and the Toxicity Estimation Software Tool (TEST). The evaluation workflows for carcinogenicity and genotoxicity were developed along with associated scoring schemes to make an overall outcome determination. For this case study, two sets of chemicals, the TSCA Active Inventory non-confidential portion list available on the EPA CompTox Chemicals Dashboard (33,364 chemicals, 'TSCA Active List') and a representative proof-of-concept (POC) set of 238 chemicals were profiled through the two workflows to make determinations of carcinogenicity and genotoxicity potential. Of the 33,364 substances on the 'TSCA Active List', overall calls could be made for 20,371 substances. Here 46.67%% (9507) of substances were non-genotoxic, 0.5% (103) were scored as inconclusive, 43.93% (8949) were predicted genotoxic and 8.9% (1812) were genotoxic. Overall calls for genotoxicity could be made for 225 of the 238 POC chemicals. Of these, 40.44% (91) were non-genotoxic, 2.67% (6) were inconclusive, 6.22% (14) were predicted genotoxic, and 50.67% (114) genotoxic. The approach shows promise as a means to identify potential candidates for prioritization from a genotoxicity and carcinogenicity perspective.


Early Cosmetic Results and Midterm Follow-up Findings of Rhinophyma Patients Treated With High-Frequency Electrosurgery and a Discussion on the Severity Assessment of the Disease.
Different methods can be used in the surgical treatment of patients with rhinophyma. There are limited numbers of reports on high-frequency electrosurgery treatment. In addition, an efficient scoring system is required to evaluate severity of the disease in clinical progress and recurrence after treatment. We evaluated patients with rhinophyma who were treated with high-frequency electrosurgery and discussed the methods used to assess severity of the disease. Data and photos of 13 patients were retrospectively evaluated and scored via 2 different forms of the rhinophyma severity index. Median rhinophyma severity index scores of patients at first visits were significantly higher than those at second and third visits ( P = .002 and P = .002, respectively). Likewise, median modified rhinophyma severity scores of patients at first visits were significantly higher than those at second and third visits ( P = .001 and P = .001, respectively). Also, there was a strong positive correlation between these 2 assessment methods ( r = 0.838, P < .001). The rhinophyma severity assessment methods used in this study are positively correlated. High-frequency electrosurgery seems to be a procedure that is safe, effective, and relatively cost-effective in the treatment of rhinophyma lesions.


Effect of High-Anisotropic Co2+ Substitution for Ni2+ on the Structural, Magnetic, and Magnetostrictive Properties of NiFe2O4: Implications for Sensor Applications.
This work reports on the effect of substituting a low-anisotropic and low-magnetic cation (Ni2+, 2μB) by a high-anisotropic and high-magnetic cation (Co2+, 3μB) on the crystal structure, phase, microstructure, magnetic properties, and magnetostrictive properties of NiFe2O4 (NFO). Co-substituted NFO (Ni1-xCoxFe2O4, NCFO, 0 ≤ x ≤ 1) nanomaterials were synthesized using glycine-nitrate autocombustion followed by postsynthesis annealing at 1200 °C. The X-ray diffraction measurements coupled with Rietveld refinement analyses indicate the significant effect of Co-substitution for Ni, where the lattice constant (a) exhibits a functional dependence on composition (x). The a-value increases from 8.3268 to 8.3751 Å (±0.0002 Å) with increasing the "x" value from 0 to 1 in NCFO. The a-x functional dependence is derived from the ionic-size difference between Co2+ and Ni2+, which also induces grain agglomeration, as evidenced in electron microscopy imaging. The chemical bonding of NCFO, as probed by Raman spectroscopy, reveals that Co(x)-substitution induced a red shift of the T2g(2) and A1g(1) modes, and it is attributed to the changes in the metal-oxygen bond length in the octahedral and tetrahedral sites in NCFO. X-ray photoelectron spectroscopy confirms the presence of Co2+, Ni2+, and Fe3+ chemical states in addition to the cation distribution upon Co-substitution in NFO. Chemical homogeneity and uniform distribution of Co, Ni, Fe, and O are confirmed by EDS. The magnetic parameters, saturation magnetization (MS), remnant magnetization (Mr), coercivity (HC), and anisotropy constant (K1) increased with increasing Co-content "x" in NCFO. The magnetostriction (λ) also follows a similar behavior and almost linearly varies from -33 ppm (x = 0) to -227 ppm (x = 1), which is primarily due to the high magnetocrystalline anisotropy contribution from Co2+ ions at the octahedral sites. The magnetic and magnetostriction measurements and analyses indicate the potential of NCFO for torque sensor applications. Efforts to optimize materials for sensor applications indicate that, among all of the NCFO materials, Co-substitution with x = 0.5 demonstrates high strain sensitivity (-2.3 × 10-9 m/A), which is nearly 2.5 times higher than that obtained for their intrinsic counterparts, namely, NiFe2O4 (x = 0) and CoFe2O4 (x = 1).


[Expression of monocarboxylate transporter 8 mRNA in the brain tissue of rats with cerebral ischemia].
To investigate the mRNA expression of monocarboxylate transporter 8 (MCT8), a thyroid hormone transport protein, in the lateral ventricle of rats with cerebral ischemia. Immunofluorescence staining was used to observe the expression of MCT8 in the lateral ventricle of 5 normal SD rats. Another 20 adult male SD rats were randomized into 4 groups and subject to permanent ligation of both the common carotid arteries (2-vessel occlusion, 2VO) for 3 days, 2 weeks, or 5 weeks, or no ligation (control). At the end of the experiment, the transcriptional level of MCT8 in the brain tissue of the rats were detected using fluorescent quantitative PCR. MCT8 mRNA levels in 3-day and 2-week 2VO groups were comparable with that in the control group (P=0.909; P=0.694), but increased significantly in 5-week 2VO group compared with that in the control and 3-day 2VO groups (P=0.029; P=0.023). No significance was found in MCT8 mRNA between the 2-week and 5-week 2VO groups (P=0.065). Prolonged cerebral ischemia causes compensatory increase of MCT8 mRNA expression on the capillary endothelial cell membranes in the lateral ventricle of rats.


18F-GP1, a Novel PET Tracer Designed for High-Sensitivity, Low-Background Detection of Thrombi.
Thromboembolic diseases such as myocardial infarction, stroke, transient ischemic attacks, and pulmonary embolism are major causes of morbidity and mortality worldwide. Glycoprotein IIb/IIIa (GPIIb/IIIa) is the key receptor involved in platelet aggregation and is a validated target for therapeutic approaches and diagnostic imaging. The aim of this study was to develop and characterize a specific small-molecule tracer for PET imaging that binds with high affinity to GPIIb/IIIa receptors and has suitable pharmacokinetic properties to overcome limitations of previous approaches. Methods: Binding of 18F-GP1 to GPIIb/IIIa receptors was investigated in competition binding assays and autoradiography using a fresh cardiac thrombus from an explanted human heart. The clot-to-blood ratio for 18F-GP1 was investigated by an in vitro blood flow model. Biodistribution and thrombus detection was investigated in cynomolgus monkeys after insertion of a roughened catheter into either the vena cava or the aorta. Results:18F-GP1 is an 18F-labeled small molecule for PET imaging of thrombi. The half maximal inhibitory concentration of 18F-GP1 to GPIIb/IIIa was 20 nM. 18F-GP1 bound to thrombi with a mean clot-to-blood ratio of 95. Binding was specific and can be displaced by excess nonradioactive derivative. Binding was not affected by anticoagulants such as aspirin or heparin. 18F-GP1 showed rapid blood clearance and a low background after intravenous injection in cynomolgus monkeys. Small arterial, venous thrombi, thrombotic depositions on damaged endothelial surface, and small cerebral emboli were detected in vivo by PET imaging. Conclusions:18F-GP1 binds specifically with high affinity to the GPIIb/IIIa receptor involved in platelet aggregation. Because of its favorable preclinical characteristics, 18F-GP1 is currently being investigated in a human clinical study.


Robotic Versus Conventional Unicompartmental Knee Surgery: A Comprehensive Systematic Review and Meta-Analysis.
Robotic-assisted surgery is a computer-controlled technique that may improve the accuracy and outcomes of unicompartmental total knee arthroplasty (TKA), a partial knee replacement surgery. The purpose of a meta-analysis about robotic-assisted versus conventional surgery for unicompartmental TKA is to compare the effectiveness of these two methods based on the current evidence. Our meta-analysis can help inform clinical decisions and guidelines for surgeons and patients who are considering unicompartmental TKA as a treatment option. We searched four online databases for studies that compared the two methods until March 2023. We used RevMan software to combine the data from the studies. We calculated the mean difference (MD) and the 95% confidence interval (CI) for each outcome, which are statistical measures of the difference and the uncertainty between the two methods. We included 16 studies in our analysis. We found that robotic-assisted surgery had a better hip-knee-ankle angle, which is a measure of how well the knee is aligned, than conventional surgery (MD = 0.86, 95% CI = 0.16-1.56). We also found that robotic-assisted surgery had a better Oxford Knee score, which is a measure of how well the knee functions, than conventional surgery (MD = 3.03, 95% CI = 0.96-5.110). This study compared the results of conventional and robotic-assisted unicompartmental knee arthroplasty in 12 studies. We concluded that robotic-assisted surgery may have some benefits over conventional surgery in terms of alignment and function of the knee. However, we did not find any significant difference between the two methods in terms of other outcomes, such as pain, range of motion, health status, and joint awareness. Therefore, we suggest that more research is needed to confirm these results and evaluate the long-term effects and cost-effectiveness of robotic-assisted surgery.


Natural RNA circles function as efficient microRNA sponges.
MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.


Age-associated defect in human TLR-1/2 function.
The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21-30 and >65 years of age, using a multivariable mixed effect model. Using flow cytometry to assess TLR-induced cytokine production, we observed a substantial, highly significant defect in TLR1/2-induced TNF-alpha (p = 0.0003) and IL-6 (p < 0.0001) production, in older adults compared with young controls. In contrast to findings in aged mice, other TLR (including TLR2/6)-induced cytokine production appeared largely intact. These differences were highly significant even after correcting for covariates including gender, race, medications, and comorbidities. This defect in TLR1/2 signaling may result from alterations in baseline TLR1 surface expression, which was decreased by 36% in older adults (p < 0.0001), whereas TLR2 surface expression was unaffected by aging. Production of IL-6 (p < 0.0001) and TNF-alpha (p = 0.003) after stimulation by N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Ser1-[S]-Lys(4) trihydrochloride was strongly associated with TLR1 surface expression. Diminished TLR1/2 signaling may contribute to the increased infection-related morbidity and mortality and the impaired vaccine responses observed in aging humans.


Mode-resolved dual-comb spectroscopy using error correction based on single optical intermedium.
Dual-comb spectroscopy (DCS) is an emerging and promising spectrometric technique with high resolution, high sensitivity, broad spectral range, and fast acquisition speed. For the recovery of the information encoded on comb modes without resolution loss, two continuous wave lasers are commonly utilized as optical intermedia to track the real-time jitter of dual-comb interferograms. This paper presents a simplified error correction method based on single optical intermedium for quasi-free-running fiber DCS. This method combines the strengths of conventional optical referencing and self-referencing error correction. We acquired whole P branch H13C14N transmittance spectra in the near infrared as a demonstration. In contrast to that of conventional dual intermedium error correction, the standard deviation of our method was merely 0.01 over the 4 THz spectral range. Our method provides a balanced and practical postprocessing routine for high-performance mode-resolved DCS applications.


Single-Nanowire Fuse for Ionization Gas Detection.
Local electric field enhancement is crucial to detect gases for an ionization gas sensor. Nanowires grown collectively along the identical lattice orientation have been claimed to show a strong tip effect in many previous studies. Herein, we propose a novel ionization gas detector structure by using a single crystalline silicon nanowire as one electrode that is placed above the prepatterned nanotips. A significant improvement of the local electric field in its radical direction was obtained leading to an ultralow operation voltage for gas breakdown. Different from the tip of the nanowire in the reported ionization gas sensors, the gaseous discharge current in this device flows towards the sidewall in the case of a trace amount of gas environment change. Technically, this discharge current brings about a sudden temperature rise followed by a fusion of the silicon nanowire. Such unique fusibility of a single nanowire in this gas detection device suggests a novel architecture that is portable and in-site executable and can be used as an integrated gas environmental monitor.


Avian cholera in a southern giant petrel (Macronectes giganteus) from Antarctica.
A southern giant petrel (Macronectes giganteus) was found dead at Potter Peninsula, King George Island, South Shetland, Antarctica. The adult male was discovered approximately 48 hr after death. Macroscopic and microscopic lesions were compatible with avian cholera and the bacterium Pasteurella multocida subsp. gallicida, serotype A1 was isolated from lung, heart, liver, pericardial sac, and air sacs. In addition, Escherichia coli was isolated from pericardial sac and air sacs. This is the first known report of avian cholera in a southern giant petrel in Antarctica.


Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance.
Ubiquitin-conjugating enzyme E2 C (UBE2C) plays a carcinogenic role in gastric cancer (GC); yet, its role in cisplatin (DDP) resistance in GC is enigmatic. This study sought to probe into the impact of UBE2C on DDP resistance in GC and its concrete molecular mechanism in GC progression. Bioinformatics analysis was used to analyze differentially expressed mRNAs and predict upstream regulatory molecules in GC. Real-time quantitative reverse transcriptase polymerase chain reaction and western blot were used to detect the expression of UBE2C and MYB proto-oncogene like 2 (MYBL2). Dual luciferase and chromatin immunoprecipitation (ChIP) assays were used to verify the binding relationship. Cell counting kit-8 was used to detect cell viability and calculate IC50 values. Flow cytometry was used to detect the cell cycle. Comet assay was used to detect DNA damage. Western blot was used to detect the expression of DNA loss-related proteins (γ-H2AX, ATM/p-ATM). The knockdown of highly expressed UBE2C in GC cell lines could reduce cell viability, induce G2/M arrest, induce apoptosis, and promote DNA damage and DDP sensitivity. Bioinformatics analysis predicted that the substantially upregulated MYBL2 was an upstream transcription factor in UBE2C. The binding relationship between the UBE2C promoter region and MYBL2 was verified by dual luciferase and ChIP. Overexpression of UBE2C in the rescue experiment was found to reverse the inhibited GC progression and promoted DDP sensitivity brought by the knockdown of MYBL2. In conclusion, the MYBL2/UBE2C regulatory axis may be a potential way to overcome DDP resistance in GC.


[Prevision of the hazard of acute carbon monoxide poisoning. A nomogram for calculating blood HbCO on the basis of the carbon monoxide concentration in air, the length of exposure and the lung ventilation (author's transl)].
The kinetics of carbon monoxide absorption was studied by the authors. An equation is proposed which enables to define the percentage of blood HbCO on the basis of the CO concentration in the air, the length of exposure, and the lung ventilation. The results proved to be satisfactory and were found to be comparable to the experimental data reported in the literature. A set of nomograms is reported which enables to define the blood HbCO saturation on the basis of the parameters which it depends on, therefore appearing to be very profitable to the physician in order to foresee and then prevent the hazard of acute carbon monoxide poisoning.


Pharmacological studies of human erectile tissue: characteristics of spontaneous contractions and alterations in alpha-adrenoceptor responsiveness with age and disease in isolated tissues.
1. The pathophysiology of impotence related to vascular smooth muscle dysfunction in the male corpus cavernosum was studied on human isolated erectile tissue (HET). Studies were conducted on 140 sections of HET obtained from 38 male patients undergoing surgery for implantation of penile prostheses to correct underlying erectile dysfunction. 2. Spontaneous myotonic oscillations were characteristic of greater than 90% of all HET preparations at 37 degrees C. These spontaneous oscillations were markedly attenuated by indomethacin, BW755C, nifedipine, removal of extracellular Ca2+, or lower temperatures (less than or equal to 32 degrees C), but were not sensitive to inhibition by atropine, phentolamine or tetrodotoxin. Our data suggest that the oscillations may, at least in part, result from the generation and/or release of a stable cyclo-oxygenase product and a consequent increase in transmembrane Ca2+ influx. 3. The phenylephrine-induced contractions in HET may be reliably assayed up to 24 h after surgical removal, without significant alterations in the EC50, maximum response (Emax) or slope index of the steady-state concentration-response curve to phenylephrine. 4. The competitive and surmountable nature of the antagonism of phenylephrine-induced contractions by prazosin and yohimbine allowed calculation of antagonist dissociation constants. The calculated pKb values for prazosin and yohimbine, respectively, were 9.47 +/- 0.49 and 5.54 +/- 0.22. The rank order of agonist potency in HET was: noradrenaline = phenylephrine much greater than clonidine. These data indicate the presence of a population of membrane receptors that are predominantly of the alpha 1-adrenoceptor subtype. 5. The entire patient population was stratified on a decennial basis into five age groups, and each age group was subsequently subdivided into diabetic and nondiabetic diagnostic categories. With respect to the steady-state phenylephrine concentration-response curves, a Winer two-factor analysis of variance revealed a significant effect of age on the calculated pEC50 value, as well as a significant age-diagnosis interaction. A post hoc statistical analysis for unpaired samples yielded significant differences between pEC50 values for diabetic and nondiabetic patients in age groups 41-50 and 61-70 years. In addition, a Winer two-factor analysis of variance also detected a significant effect of age on the calculated E.., value. 6. In conclusion, our studies demonstrate that spontaneous contractions in HET are likely to be mediated by the generation and release of a stable cyclo-oxygenase product. Furthermore, the results of both agonist and antagonist studies are consistent with the presence of a homogeneous alpha x-adrenoceptor population. Lastly, the responsiveness of isolated HET to phenylephrine was shown to be altered by both age and disease.


[Drug delivery system of anti-inflammatory and anti-rheumatic drugs].
Anti-rheumatic drugs such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and disease modifying anti-rheumatic drugs are valuable medications for patients with rheumatoid arthritis available for physicians now. This review provides a practical approach for increasing efficacy and minimizing adverse response of some of these drugs by the development of drug delivery system.


[Evaluation of Antihypertensive Efficacy and Patient Adherence to Treatment With the New Formulation Perindopril Arginine (Orally Disintegrating Tablet) in General Clinical Practice: OPTIMUM Program].
The purpose of this study was to evaluate the antihypertensive efficacy of perindopril arginine in the oral dispersible form of tablets, in clinical practice. Post-marketing observational open program OPTIMUM was carried out from october 2014 to march 2015 year in 48 cities of the Russian Federation, 197 doctors. The observation included 957 patients. Prematurely retired from the study 17patients completed the observation in accordance with the protocol of 940 people. Of the patients included men was 40.8%, 28.1% smokers , obese patients were 32.2% , cholesterol >5.0 mmol/l - 54.1%, diabetes - 13.3% . Angina was at 19.5% of patients had previous myocardial infarction, 5.3%, 3.7% of stroke, heart failure, was at 26.5% . Previously treated with 16% of patients , 53% had received monotherapy 2-koponentnuyu - 35% 3-component therapy and more 13% of patients. Angiotensin converting enzyme obtained 50.9% of the patients, 20.2% Sartana, diuretics - 22.9%, -blockers - 25.8%, calcium antagonists - 13.6% other drugs - 2.2%. With the inclusion in the program every fifth patient had BP Stage I level and included patients had hypertension II degree. The mean duration of disease was 7.0+/-6.2 years (median 5 years). When replacing the previously used ACE inhibitors or sartans on mouth-dispersible form of perindopril arginine BP decreased from 140,9+/-12.7/84.2+/-7.6 to 127.0+/-8.4/78.1+/-5.8 mm Hg. Target BP <140/90 mm Hg 91.4% of patients reached after 3 months of treatment. Adherence to the treatment of patients improved significantly and the total score increased from an average of 2.76+/-1.25 to 3.57+/-0.89 points (p<0.00001). When filling out a special questionnaire >2/3 of patients agreed or strongly agreed with the statements that orodispersible form is more easy to use, dissolves quickly and easily swallowed, is more convenient for the reception is at home or traveling. It can be expected that the extension of the possibility of using perindopril arginine, including through the appointment of a new form for the reception, can lead to increased adherence to treatment, improve blood pressure control and reduce the incidence of adverse events in patients with hypertension.


Potent inhibitors of human LAT1 (SLC7A5) transporter based on dithiazole and dithiazine compounds for development of anticancer drugs.
The LAT1 transporter is acknowledged as a pharmacological target of tumours since it is strongly overexpressed in many human cancers. The purpose of this work was to find novel compounds exhibiting potent and prolonged inhibition of the transporter. To this aim, compounds based on dithiazole and dithiazine scaffold have been screened in the proteoliposome experimental model. Inhibition was tested on the antiport catalysed by hLAT1 as transport of extraliposomal [3H]histidine in exchange with intraliposomal histidine. Out of 59 compounds tested, 8 compounds, showing an inhibition higher than 90% at 100µM concentration, were subjected to dose-response analysis. Two of them exhibited IC50 lower than 1µM. Inhibition kinetics, performed on the two best inhibitors, indicated a mixed type of inhibition with respect to the substrate. Furthermore, inhibition of the transporter was still present after removal of the compounds from the reaction mixture, but was reversed on addition of dithioerythritol, a S-S reducing agent, indicating the formation of disulfide(s) between the compounds and the protein. Molecular docking of the two best inhibitors on the hLAT1 homology structural model, highlighted interaction with the substrate binding site and formation of a covalent bond with the residue C407. Indeed, the inhibition was impaired in the hLAT1 mutant C407A confirming the involvement of that Cys residue. Treatment of SiHa cells expressing hLAT1 at relatively high level, with the two most potent inhibitors led to cell death which was not observed after treatment with a compound exhibiting very poor inhibitory effect.


Expression of macrophage migration inhibitory factor in rat skin during embryonic development.
We have previously shown that human epidermal keratinocytes express macrophage migration inhibitory factor (MIF) mRNA, and immunohistochemical studies showed that MIF is expressed in human epidermis. To explore the possible pathophysiological roles of MIF in skin during rat fetal development, we examined the expression patterns of MIF during rat epidermal development using Northern blot analysis and in situ hybridization. Expression of MIF mRNA was first detected by in situ hybridization in the developing epidermis and hair germ cells from embryonic day (ED) 16. From ED 19, moderate levels of MIF expression were detected in the epidermis and epithelial sheath cells of growing hair follicles. In postnatal rat skin, higher MIF expression was detected in the epidermis and hair follicles on postnatal day 3. These observations were also confirmed by Northern blot analysis. Immunohistochemical analysis with an anti-MIF antibody showed a similar distribution to that of the mRNA. Our results suggest that MIF is associated with epidermal and hair follicle development.


A comparison of diagnostic imaging ordering patterns between advanced practice clinicians and primary care physicians following office-based evaluation and management visits.
Little is known about the use of diagnostic testing, such as medical imaging, by advanced practice clinicians (APCs), specifically, nurse practitioners and physician assistants. To examine the use of diagnostic imaging ordered by APCs relative to that of primary care physicians (PCPs) following office-based encounters. Using 2010-2011 Medicare claims for a 5% sample of beneficiaries, we compared diagnostic imaging ordering between APC and PCP episodes of care, controlling for geographic variation, patient demographics, and Charlson Comorbidity Index scores. Provider specialty codes were used to identify PCPs and APCs (general practice, family practice, or internal medicine for PCP; nurse practitioner or physician assistant for APC). Episodes were constructed using evaluation and management (E&M) office visits without any claims 30 days prior to the index visit and (1) no claims at all within the subsequent 30 days; (2) no claims within the subsequent 30 days other than a single imaging event; or (3) claims for any nonimaging services in that subsequent 30-day period. The primary outcome was whether an imaging event followed a qualifying E&M visit. Advanced practice clinicians and PCPs ordered imaging in 2.8% and 1.9% episodes of care, respectively. In adjusted estimates and across all patient groups and imaging services, APCs were associated with more imaging than PCPs (odds ratio [OR], 1.34 [95% CI, 1.27-1.42]), ordering 0.3% more images per episode. Advanced practice clinicians were associated with increased radiography orders on both new (OR, 1.36 [95% CI, 1.13-1.66]) and established (OR, 1.33 [95% CI, 1.24-1.43]) patients, ordering 0.3% and 0.2% more images per episode of care, respectively. For advanced imaging, APCs were associated with increased imaging on established patients (OR, 1.28 [95% CI, 1.14-1.44]), ordering 0.1% more images, but were not significantly different from PCPs ordering imaging on new patients. Advanced practice clinicians are associated with more imaging services than PCPs for similar patients during E&M office visits. Expanding the use of APCs may alleviate PCP shortages. While increased use of imaging appears modest for individual patients, this increase may have ramifications on care and overall costs at the population level.


A practical concept for preoperative identification of patients with impaired primary hemostasis.
The findings of a large prospective study designed to identify primary and/or secondary hemostatic disorders before surgical interventions are presented. A total of 5649 unselected adult patients were enrolled to identify impaired hemostasis before surgical interventions. Each patient was asked to answer a standardized questionnaire concerning bleeding history. Activated partial thromboplastin time (aPTT), prothrombin time (PT), and platelet counts (PC) including PFA-100 (platelet function analyzer): collagen-epinephrine (C/E), and collagen-ADP (C/ADP) were routinely done in all patients. Additional tests, bleeding time (BT), and von Willebrand factor (vWF: Ag) were performed only in patients with a positive bleeding history and/or evidence of impaired hemostasis; e.g., drug ingestion. The bleeding history was negative in 5021 patients (88.8%) but positive in the remaining 628 (11.2%). Impaired hemostasis could be verified only in 256 (40.8%) of these patients. The vast majority were identified with PFA-100: C/E (n=250; 97.7%). The other six patients with impaired hemostasis were identifiable solely based on the PT (n=2), PFA-100: C/ADP (n=2), and vWF: Ag (n=2). The PFA-100: C/ADP detected 199 patients (77.7%). The only abnormality found among patients with a negative bleeding history was a prolonged aPTT due to lupus anticoagulant in nine patients (0.2%). The sensitivity of the PFA-100: collagen-epinephrine was the highest (90.8%) in comparison to the other screening tests (BT, aPTT, PT, vWF: Ag). The positive predictive value of the PFA-100: collagen-epinephrine was high (81.8%), but the negative predictive value was higher (93.4%). The use of a standardized questionnaire and, if indicated, the PFA-100: C/E and/or other specific tests not only ensure the detection of impaired hemostasis in almost every case but also a significant reduction of the cost.


Protection against aflatoxin B1-induced hepatocarcinogenesis in F344 rats by 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz): predictive role for short-term molecular dosimetry.
Previous studies have demonstrated that dietary administration of the schistosomicidal drug 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz) ameliorates the hepatotoxicity of aflatoxin B1 (AFB1). Notably, mortality, altered hepatic function, hepatic AFB1-DNA adduct levels, and expression of hepatic enzyme-altered foci were markedly reduced in the rat by concurrent feeding of oltipraz during exposures to AFB1. Collectively, these studies prompted us to evaluate the chemoprotective properties of oltipraz against AFB1-induced liver cancer. In addition, preliminary molecular dosimetry studies were undertaken to determine the utility of measurements of urinary aflatoxin-N7-guanine excretion as a marker of relative risk for hepatocarcinogenesis in AFB1-exposed rats. For the carcinogenesis studies, 5-wk-old male F344 rats were randomly divided into two groups. One group (55 rats) received the AIN-76A diet, and the other group (56 rats) received the AIN-76A diet supplemented with 0.075% oltipraz. The oltipraz-supplemented diet was fed for 4 wk. Beginning 1 wk after starting the experimental diets, all rats in both groups received 25 micrograms of AFB1/rat/day by gavage for 5 days per wk over the next 2 wk. One wk following cessation of dosing with AFB1, oltipraz was removed from the diet, and all rats were fed the AIN-76A diet for the remainder of the experiment. At 3 mo after dosing, livers of ten sentinel rats from each group were analyzed for the burden of gamma-glutamyltranspeptidase-positive foci. In accord with previous findings, rats fed the oltipraz-supplemented diet exhibited substantial reductions in the focal burden (97% reduction; P less than 0.05) of these AFB1-induced lesions. The remaining rats were maintained for the cancer study until they became moribund or the termination of the experiment at 23 mo. Gross liver lesions were identified at autopsy and confirmed by microscopic evaluation. An 11% incidence of hepatocellular carcinoma was observed in the AFB1-treated, control diet-fed rats. An additional 9% of this group had hepatocellular adenomas. Oltipraz afforded complete protection against both AFB1-induced hepatocellular neoplasms. Using Kaplan-Meier survival analyses, rats in the oltipraz group had a significantly (P less than 0.02) longer life span and an increased survival free of liver tumors (P less than 0.0002). Molecular dosimetry studies used rats fed either the oltipraz-supplemented or control diet for 1 wk and then challenged with a single dose of AFB1 to examine the initial rates of 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 excreted in the urine.(ABSTRACT TRUNCATED AT 400 WORDS)