Salinomycin exhibits anti-angiogenic activity against human glioma in vitro and in vivo by suppressing the VEGF-VEGFR2-AKT/FAK signaling axis.
Tumor angiogenesis plays a crucial role in tumor growth, progression and metastasis, and suppression of tumor angiogenesis has been considered as a promising anticancer strategy. Salinomycin (SAL), an antibiotic, displays novel anticancer potential against several human cancer cells in vitro and in vivo. However, little information concerning its anti-angiogenic properties is available. Therefore, the anti‑angiogenic effect of SAL and the underlying mechanism in human glioma were evaluated in the present study. The results indicated that SAL treatment significantly inhibited human umbilical vein endothelial cell (HUVEC) proliferation, migration, invasion and capillary-like tube formation. Further investigation on intracellular mechanisms showed that SAL markedly suppressed FAK and AKT phosphorylation, and downregulated vascular endothelial growth factor (VEGF) expression in HUVECs. Pretreatment of cells with a PI3K inhibitor (LY294002) and FAK inhibitor (PF562271) markedly enhanced SAL-induced inhibition of HUVEC proliferation and migration, respectively. Moreover, U251 human glioma xenograft growth was also effectively blocked by SAL treatment in vivo via inhibition of angiogenesis involving FAK and AKT depho-sphorylation. Taken together, our findings validated that SAL inhibits angiogenesis and human glioma growth through suppression of the VEGF-VEGFR2-AKT/FAK signaling axis, indicating the potential application of SAL for the treatment of human glioma.


Regulating the Crystallization Growth of Sn-Pb Mixed Perovskites Using the 2D Perovskite (4-AMP)PbI4 Substrate for High-Efficiency and Stable Solar Cells.
Sn-Pb mixed perovskite solar cells (PSCs) are developing rapidly and making great progress due to their environmentally friendly advantages. High-crystalline quality perovskite films are essential for obtaining high-efficiency and -stability PSCs. Here, the DJ-phase two-dimensional (2D) perovskite (4-AMP)PbI4 (4-AMP is 4-(aminomethyl) piperidine) was used as a substrate to regulate the crystallization growth of the Sn-Pb mixed perovskite for preparing high-quality perovskite films, and the regulation mechanism was analyzed in detail. The results indicate that the suitable amount of the 2D perovskite substrate is favorable for the formation of PbI2/SnI2 films with wide intergranular gaps and vertical distribution grain boundaries. Moreover, the suitable hydrophobicity of the PbI2/SnI2 film made on the 2D perovskite substrate also provides a better template for regulating the formation and dissolution of prophase perovskite capping. In addition, the 4-AMP cations from the collapsed 2D perovskite substrate can diffuse into PbI2/SnI2 films and interact with PbI2 to form the intermediate (4-AMP)-PbI2-(4-AMP) and with SnI2 to form the 2D perovskite (4-AMP)SnI4. All of these promote the diffusion of FAI/MAI molecules and decrease the crystallization growth rate of the Sn-Pb perovskite and thus increase the conversion levels of the perovskite phase and improve the crystallization orientation and quality of the perovskite, which helps mitigate the erosion of water and oxygen. In addition, the 2D perovskite used as a substrate can passivate the buried interface defects and improve the interfacial contact. Moreover, the diffusion behavior of 4-AMP cations regulates the perovskite energy levels, which match more with those of the electron transport layer. As a result, the champion device made on the (4-AMP)PbI4 substrate acquires a power conversion efficiency (PCE) of 17.7% with an open-circuit voltage (Voc) of 0.806 V, a short-circuit current density (Jsc) of 28.97 mA cm-2, and a fill factor (FF) of 75.86%, far exceeding those of the control device. Meanwhile, the unencapsulated PSCs modified with 4-AH retain above 70% of the initial efficiency value after storage for 1200 h in N2 at room temperature and about 25% of its initial efficiency after exposure to air for nearly 300 h with RH = 30 ± 10% at room temperature, while the control device has only 30% of the initial efficiency and near-zero efficiency at the same conditions.


Migration of Schwann cells and axons into developing chick forelimb muscles following removal of either the neural tube or the neural crest.
A study has been made of the effects of neural crest and neural tube removal at the brachial level on the migration of Schwann cells and axons into the flexor digitorum profundus (fdp) and flexor carpi ulnaris (fcu) muscles of the avian forelimb. The identification of Schwann cells was based on the assumption that antibody HNK-1 uniquely labels these cells at the growing end of limb nerves. Myotubes and nerves were identified by using antibodies to myosin and to neurofilament protein, respectively. The removal of neural crest cells at stage 13 gave a complete Schwann cell-free embryo at the brachial level. Motor axons only grew to the base of the forelimb, forming a rudimentary plexus by stage 27, and failed to penetrate the limb. Removal of the neural tube at stage 13 did not prevent sensory axons from forming a plexus at the base of the limb; these axons subsequently developed into the brachialis longus inferior (bli n) and superior (bls n) nerves. By stage 27 the bli n had branched into the interosseus nerve (in n) and the medial-ulnar nerve (m-u n) trunks. However, unlike the result in control embryos, no nerves were detected amongst the developing fdp and fcu muscles, thus indicating that sensory axons do not grow into the muscles in the absence of motor axons. In contrast, Schwann cells were observed amongst the myotubes at the level of the in n and m-u nerve trunks. The present observations show that motor axons do not enter the limb bud and innervate limb muscles in the absence of Schwann cells. Furthermore, in the absence of motor axons (neural-tube-removed embryos) sensory axons still enter the limb (behind migrating Schwann cells) but fail to innervate developing muscles even though Schwann cells are present among the developing myotubes.


[Sleep disorders and fatigue in patients with different forms of myotonic dystrophy type 1].
To characterize sleep disorders in children and adults with different forms of myotonic dystrophy type 1 (DM1), to assess their impact on cognitive functions, excessive daytime sleepiness (EDS) and fatigue, to determine the relationship of EDS, fatigue, and sleep disorders with the quality of life of patients. The study included 48 adults and 9 children with confirmed DM1. Patients underwent an assessment of clinical and anamnestic data, neurological, cognitive status, severity of EDS, fatigue, quality of life according to international scales and questionnaires. Polysomnography was performed to identify sleep disorders. Obstructive sleep apnea syndrome (OSAS) was found in 78% of children and 79.2% of adults. The severity of OSAS in adults, in contrast to children, was influenced by obesity (p<0.001), the severity of muscle weakness (p=0.033), especially the neck muscles (p=0.018). In patients with OSAS and nocturnal hypoxemia, an increase in the duration of the 1st stage of sleep (p=0.008) and in the microactivation index (p=0.005) was revealed. EDS and fatigue were present in 31 (64.6%) and 34 (70.8%) adults, respectively, in 9 (18.8%) they emerged at the onset of the disease. The greater severity of muscle symptoms, anxiety, depression contributed to increased fatigue in adults and the presence of obesity and type 2 diabetes mellitus contributed to EDS. Increased fatigue affects the quality of life to a greater extent than EDS and sleep disturbances. OSAS, the development of which is facilitated by the presence of muscle weakness and obesity, is the leading syndrome among the spectrum of sleep disorders in all age groups. Cognitive and emotional impairments are not the result of sleep apnea, but rather develop because of a primary CNS lesion. The presence of increased fatigue reduced the quality of life of patients.


Altered functional brain networks in Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is a genetic imprinting disorder characterized mainly by hyperphagia and early childhood obesity. Previous functional neuroimaging studies used visual stimuli to examine abnormal activities in the eating-related neural circuitry of patients with PWS. It was found that patients with PWS exhibited both excessive hunger and hyperphagia consistently, even in situations without any food stimulation. In the present study, we employed resting-state functional MRI techniques to investigate abnormal brain networks related to eating disorders in children with PWS. First, we applied amplitude of low-frequency fluctuation analysis to define the regions of interest that showed significant alterations in resting-state brain activity levels in patients compared with their sibling control group. We then applied a functional connectivity (FC) analysis to these regions of interest in order to characterize interactions among the brain regions. Our results demonstrated that patients with PWS showed decreased FC strength in the medial prefrontal cortex (MPFC)/inferior parietal lobe (IPL), MPFC/precuneus, IPL/precuneus and IPL/hippocampus in the default mode network; decreased FC strength in the pre-/postcentral gyri and dorsolateral prefrontal cortex (DLPFC)/orbitofrontal cortex (OFC) in the motor sensory network and prefrontal cortex network, respectively; and increased FC strength in the anterior cingulate cortex/insula, ventrolateral prefrontal cortex (VLPFC)/OFC and DLPFC/VLPFC in the core network and prefrontal cortex network, respectively. These findings indicate that there are FC alterations among the brain regions implicated in eating as well as rewarding, even during the resting state, which may provide further evidence supporting the use of PWS as a model to study obesity and to provide information on potential neural targets for the medical treatment of overeating.


Oscillatory Brain Correlates of Live Joint Attention: A Dual-EEG Study.
Joint attention consists in following another's gaze onto an environmental object, which leads to the alignment of both subjects' attention onto this object. It is a fundamental mechanism of non-verbal communication, and it is essential for dynamic, online, interindividual synchronization during interactions. Here we aimed at investigating the oscillatory brain correlates of joint attention in a face-to-face paradigm where dyads of participants dynamically oriented their attention toward the same or different objects during joint and no-joint attention periods respectively. We also manipulated task instruction: in socially driven instructions, the participants had to follow explicitly their partner's gaze, while in color-driven instructions, the objects to be looked at were designated at by their color so that no explicit gaze following was required. We focused on oscillatory activities in the 10 Hz frequency range, where parieto-occipital alpha and the centro-parietal mu rhythms have been described, as these rhythms have been associated with attention and social coordination processes respectively. We tested the hypothesis of a modulation of these oscillatory activities by joint attention. We used dual-EEG to record simultaneously the brain activities of the participant dyads during our live, face-to-face joint attention paradigm. We showed that joint attention periods - as compared to the no-joint attention periods - were associated with a decrease of signal power between 11 and 13 Hz over a large set of left centro-parieto-occipital electrodes, encompassing the scalp regions where alpha and mu rhythms have been described. This 11-13 Hz signal power decrease was observed independently of the task instruction: it was similar when joint versus no-joint attention situations were socially driven and when they were color-driven. These results are interpreted in terms of the processes of attention mirroring, social coordination, and mutual attentiveness associated with joint attention state.


Observation of the Annihilation Decay Mode B^{0}→K^{+}K^{-}.
A search for the B^{0}→K^{+}K^{-} decay is performed using pp-collision data collected by LHCb. The data set corresponds to integrated luminosities of 1.0 and 2.0 fb^{-1} at center-of-mass energies of 7 and 8 TeV, respectively. This decay is observed for the first time, with a significance of more than 5 standard deviations. The analysis also results in an improved measurement of the branching fraction for the B_{s}^{0}→π^{+}π^{-} decay. The measured branching fractions are B(B^{0}→K^{+}K^{-})=(7.80±1.27±0.81±0.21)×10^{-8} and B(B_{s}^{0}→π^{+}π^{-})=(6.91±0.54±0.63±0.19±0.40)×10^{-7}. The first uncertainty is statistical, the second is systematic, the third is due to the uncertainty on the B^{0}→K^{+}π^{-} branching fraction used as a normalization. For the B_{s}^{0} mode, the fourth accounts for the uncertainty on the ratio of the probabilities for b quarks to hadronize into B_{s}^{0} and B^{0} mesons.


Nebulized Adrenaline in the Postoperative Management of Brachycephalic Obstructive Airway Syndrome in a Pug.
Brachycephalic obstructive airway syndrome is a common problem in certain breeds, and may necessitate surgical procedures, such as rhinoplasty, palatoplasty, laryngeal sacculectomy, and/or arytenoid laryngoplasty, to improve the quality of life. However, laryngeal edema may necessitate the use of temporary tracheostomy tubes postoperatively to maintain a patent airway. This case demonstrates that administration of nebulized adrenaline in the immediate postoperative period where upper airway obstruction is life threatening can be used to reduce edema, therefore avoiding the need for tracheostomy.


Effect of chronic N-acetylcysteine treatment on the development of spontaneous hypertension.
The imbalance between NO (nitric oxide) and ROS (reactive oxygen species) is an important factor in the development of hypertension. The aim of the present study was to determine the preventive and therapeutic effects of NAC (N-acetylcysteine) in SHRs (spontaneously hypertensive rats). Young and adult SHRs and WKY (Wistar-Kyoto) rats were treated with NAC (20 g/l in the drinking water). After 8 weeks of treatment, BP (blood pressure) and NOS (NO synthase) activity, conjugated dienes and GSH (reduced glutathione) in the kidney and left ventricle were determined. Protein expression of eNOS (endothelial NOS), inducible NOS and NF-kappaB (nuclear factor kappaB) were also determined in the left ventricle and kidney. Chronic NAC treatment partially attenuated the rise in BP in young SHRs (179+/-6 compared with 210+/-8 mmHg in untreated animals), but it had no significant effect on BP in adult SHRs. The antioxidant action of NAC, measured as a decrease of the concentration of conjugated dienes or inhibition of NF-kappaB expression, was greater in young than in adult SHRs. Similarly, eNOS protein expression was attenuated more in young than in adult SHRs, although NAC treatment increased NOS activity to a similar extent in both young and adult rats. In conclusion, both decreased ROS production and increased NOS activity appear to participate in the BP changes after NAC treatment in young SHRs. In adult SHRs with established hypertension, however, the secondary alterations (such as pronounced structural remodelling of resistance vessels) might attenuate the therapeutic effect of NAC.


[Degloving injuries of the soft tissues of the heel. An indication for microvascular revascularization!].
The sole of the foot has a unique soft tissue structure which allows weightbearing. There is no adequate reconstructive method for soft tissue defects of the weightbearing sole. Soft tissue reconstructions in this area frequently develop stress lesions. After degloving injuries of the heel, the unique vascularisation of the sole may lead to ischemia and consecutive soft tissue necrosis. Revascularisation of degloved heel pads e.g. by reconstruction of the medial calcaneal branch of the posterior tibial artery is recommended as a salvage procedure. In the primary treatment of extremity injuries with severe soft tissue damage a plastic surgeon should be involved.


[Emergency Medical Services: COVID-19 crisis].
The COVID-19 epidemic required rapid and frequent adaptations from the prehospital emergency medical services (EMS). The exposure of EMS providers is significant, particularly during procedures at risk of aerosolization such as advanced airways management or cardiopulmonary resuscitation. EMS personal need to be equipped with appropriate personal protective equipment and trained in its use. Interhospital transfers from COVID-19 patients are complex and involve mainly intubated patients. The possible shortage of resources may motivate the implementation of dedicated pre-hospital triage and orientation recommendations, which should be consistent with the hospital processes.


Using supervised machine learning to identify efficient blocking schemes for record linkage.
Record linkage enables survey data to be integrated with other data sources, expanding the analytic potential of both sources. However, depending on the number of records being linked, the processing time can be prohibitive. This paper describes a case study using a supervised machine learning algorithm, known as the Sequential Coverage Algorithm (SCA). The SCA was used to develop the join strategy for two data sources, the National Center for Health Statistics' (NCHS) 2016 National Hospital Care Survey (NHCS) and the Center for Medicare & Medicaid Services (CMS) Enrollment Database (EDB), during record linkage. Due to the size of the CMS data, common record joining methods (i.e. blocking) were used to reduce the number of pairs that need to be evaluated to identify the vast majority of matches. NCHS conducted a case study examining how the SCA improved the efficiency of blocking. This paper describes how the SCA was used to design the blocking used in this linkage.


[A study of lymphocyte subsets in the peripheral blood, liver and spleen of patients with idiopathic portal hypertension (IPH)].
Lymphocyte subsets in the peripheral blood, liver and spleen of patients with idiopathic portal hypertension (IPH) were examined by means of flow cytometry and immunohistochemical analysis using monoclonal antibodies. The patients with IPH showed a slight decrease in the percentage of Leu2a+ cells and a slight increase of the ratio of Leu3a+ to Leu2a+ cells in the peripheral blood compared with the normal subjects. Flow cytometry analysis of the intrasplenic lymphocyte subsets in the patients with IPH revealed a significant elevation in the percentage of Leu2a+ cells (p less than 0.01) and a reduction of the Leu3a+ to Leu2a+ ratio (p less than 0.05) compared with the normal subjects, and also showed an increase in the percentage of Leu2a+ cells (p less than 0.05) in comparison to the patients with cirrhosis of the liver. An immunohistochemical and histometrical study of the spleen in the patients with IPH revealed an elevation of the amount of red pulp area compared to the normal subjects, and also a significantly increased number of Leu2a+ cells in the red pulp (p less than 0.02) in comparison to the patients with cirrhosis of the liver. Most of the Leu2a+ cells in the spleen were considered to be Leu2a+.15- cells by double immunostaining method. In lymphoid follicles, the IPH cases showed an increase in the size of follicle and germinal center, and an increased number of Leu3a+ cells in the germinal center and the marginal zone compared with the normal subjects. In the liver, the IPH cases showed a similar distribution but fewer lymphocyte subsets in comparison to the patients with cirrhosis of the liver. These results suggested that some immunological disorder is present in patients with IPH.


Incidence of major adverse cardiac event in low risk chest pain patients in emergency department of Rajavithi Hospital.
Acute myocardial infarction is a major problem of public healthcare in Thailand. In the emergency room, patients who present chest pain are at low risk for myocardial infarction and short term risk of adverse cardiac events. In the present study, the incidence of major adverse cardiac events among low risk chest pain patients who presented at the emergency room of Rajavithi Hospital was investigated to improve treatment in the future. To evaluate incidence of major adverse cardiac events within 30 days among patients with low risk chest pain for myocardial infarction admitted to the emergency room at Rajavithi Hospital. This prospective observational study was undertaken at emergency the room of Rajavithi Hospital. Low risk chest pain patients, classified by normal ECG normal Troponin T level and Thrombolysis in Myocardial Infarction (TIMI) score less than 2, suspected of acute myocardial infarction, were included from October 1, 2012 to October 31, 2013. Primary endpoint was major adverse cardiac event (MACE) within 30 days after initial presentation. In all, 209 patients were enrolled in this study comprising females, 51.7% and mean age 54.84±16.44 years. A total of 84 patients had TIMI score 1 (40.2%), 67 patients had TIMI score 2 (32.1%) and 58 patients had TIMI score 0 (27.7%). At 30 days after presenting, two patients had a major adverse cardiac event (0.9%), both of them had TIMI score 2. No significant difference was observed between TIMI score 2 and other groups of TIMI scorefor major adverse cardiac adverse event (p-value = 0.075). The most common of TIMI risk factor was chest pain ≥2 episodes within 24 hours (86 patients, 41.2%). The most common underlying disease or previous history was congestive heart failure (33 patients 15.8%) but no factors had statistical significance for major adverse cardiac events among low risk chest pain patients. Incidence of a major adverse cardiac event within 30 days among low risk chest pain patients was low. No significant difference was observed between each group of TIMI score 0-2 for major adverse cardiac event and no significant risk factor was found for major adverse cardiac events in low risk chest pain patients.


Effects of Adsorbate Diffusion and Edges in a Transition from Particle to Dendritic Morphology during Silver Electrodeposition.
During silver electrodeposition on Au nanoparticle (NP)-covered highly oriented pyrolitic graphite, a transition from an initial growth of microsized particles to the growth of dendrites with pine tree shape (nanotrees) is observed, which is an advancement for material growth with hierarchical surface roughness. Using kinetic Monte Carlo simulations of an electrodeposition model, those results are explained by the interplay of diffusive cation flux in the electrolyte and relaxation of adsorbed atoms by diffusion on quenched crystal surfaces. First, simulations on NP-patterned substrates show the initial growth of faceted silver particles, followed by the growth of nanotrees with shapes similar to the experiments. Next, simulations on electrodes with large prebuilt particles explain the preferential nanotree growth at corners and edges as a tip effect. Simulations on wide flat electrodes relate the nanotree width with two model parameters describing surface diffusion of silver atoms: maximal number of random hops (G) and probability of hop per neighbor (P). Finally, simulations with small electrode seeds confirm the transition from initially compact particles to the nucleation of nanotrees and provide estimates of the transition sizes as a function of those parameters. The simulated compact and dendritic deposits show dominant (111) surface orientation, as observed in experiments. Extrapolations of simulation results to match microparticle and nanotree sizes lead to G = 4 × 1011 and P = 0.03, suggesting to interpret those sizes as diffusion lengths on the growing surfaces and giving diffusion coefficients 2 to 3 × 10-13 m2/s for deposited silver atoms. These results may motivate studies to relate diffusion coefficients with atomic-scale interactions.


Urinary tract infection and drug-resistant bacteria in different patient populations.
A 1-year survey of the pathogens causing urinary tract infections was conducted in three institutions: a rehabilitation hospital, a general hospital and outpatient clinics. Gram-negative rods accounted for 96% of the infections. In the general hospital and the outpatient clinics, Escherichia coli was the most prevalent pathogen, while Proteus sp. were most prevalent in the rehabilitation hospital. The frequency of drug-resistant isolates was significantly higher in the rehabilitation hospital than in the general hospital and the outpatient clinics. This was most conspicuous in the use of the beta-lactam antibiotics, aminoglycosides and sulfonamides against such organisms as E. coli, Klebsiella sp., Enterobacter sp. and Proteus sp. Urinary E. coli were more sensitive to antimicrobial drugs than were other urinary pathogens. Pseudomonas aeruginosa isolates were highly resistant to most antibiotics. About half of the isolates were resistant to gentamicin and another half to carbenicillin. In some instances the frequency of drug-resistant isolates was higher in the general hospital than in the outpatient clinics, reflecting the greater usage of antimicrobials in the general hospital.


Rh(III)-catalyzed [3 + 2] spiroannulation of 2,3-dihydro-1,4-benzoxazines with 4-hydroxy-2-alkynoates through ortho-C-H bond functionalization.
Rhodium(III)-catalyzed [3 + 2]-spiroannulation of 2-aryl-1,4-benzoxazines with 4-hydroxy-2-alkynoates has been developed for the synthesis of highly rigid spirolactones in good yields with high regioselectivity. The reaction proceeds through a cascade of C-H activation followed by C-H annulation and lactonization. In this approach, two C-C and C-O bonds are formed in a single step. This is the first report on the spiroannulation of 2,3-dihydro-1,4-benzoxazines with 4-hydroxy-2-alkynoates.


The physiology of endurance exercise. The marathon.
The metabolic demands of competitive marathon running require the development and integration of the respiratory, cardiovascular, and musculoskeletal systems. Environmental factors such as ambient temperature, humidity, and wind resistance can affect running performance. In addition to training, racing strategy, fluid ingestion, and dietary manipulation are specific and practical methods that can be used to augment marathon performance.


[The prevention of influenza among the troops].
Peculiarities of modern influenza and other acute respiratory diseases in the units make medical service to execute epidemiologic supervision of these infections, especially in relation of newly formed collectives and troop contingency during there moving to other regions of the country. The medical service should apply agents of specific prophylaxis of influenza in groups of increased risk during threat of occurrence of an epidemic of influenza. It is necessary to contain a sufficient reserve of influenza vaccines for this purpose. At occurrence of pandemic strain of virus of influenza tactics and measures of prophylaxis should be revised with account of new epidemiologic situation.


Reversible superhydrophilicity and superhydrophobicity on a lotus-leaf pattern.
A facile approach of fabricating a temperature-responsive coating capable of switching reversibly from being superhydrophobic to superhydrophilic is presented. The approach combines micromolding, layer-by-layer assembly of the polymer macroinitiators, and surface-initiated polymerization. Changing between superhydrophobicity and superhydrophilicity depends heavily on the surface roughness and the switching of the surface energy levels. In this study, surface roughness was introduced by replicating the surface morphology of a lotus leaf. The switching of surface energy levels was made possible by grafting a temperature-responsive polymer brush. Wetting studies reveal that the reported approach not only replicates nature but also improves its property by making it responsive to stimulus.


The effects of the tremorgenic mycotoxin penitrem A on the rat cerebellum.
Within 10 minutes of intraperitoneal injection of penitrem A (3 mg/kg), rats develop severe generalized tremors and ataxia that persist for up to 48 hours. These are accompanied by a three- to fourfold increase in cerebellar cortical blood flow. Mitochondrial swelling occurs in cerebellar stellate and basket cells within 30 minutes of dosing and persists for more than 12 hours without leading to cell death. From 2 hours, Purkinje cell dendrites show early cytoplasmic condensation accompanied by fine vacuolation of smooth endoplasmic reticulum and enlargement of perikaryal mitochondria. From 6 hours, many Purkinje cells develop intense cytoplasmic condensation with eosinophilia that resembles "ischemic cell change," and from 12 hours, many other Purkinje cells show marked watery swelling. Astrocytes begin to swell from 0.5 hours after injection and show hypertrophy of organelles from 6 hours. Also from 6 hours onward, discrete foci of necrosis appear in the granule cell layer, while permeability of overlying meningeal vessels to horseradish peroxidase becomes evident at 8 hours. All changes are more severe in vermis and paravermis. Despite widespread loss of Purkinje cells, the animals' behavior becomes almost normal within a week. While tremor occurs with doses of 1.5 and 0.5 mg/kg, cellular damage is minimal. The tremor mechanism differs from that of harmaline since destruction of inferior olivary nuclei abolishes neither the tremor response to penitrem A nor the cellular damage. No morphological changes are found in other brain regions. The affinities of penitrem A for high-conductance calcium-dependent potassium channels and for gamma-aminobutyric acid receptors with the probability of resultant excitotoxity are considered to be important underlying factors for these changes.


Moral distress in nursing personnel.
to analyze the frequency and intensity of moral distress experienced by nursing personnel in southern Brazil, covering elements of their professional practice. a survey was undertaken in two hospitals in Rio Grande do Sul, Brazil, with 247 nurses. Data was collected by means of the adapted Moral Distress Scale. the perception of situations that lead to moral distress is enhanced in nurses and in nursing staff working in institutions with greater openness to dialogue, which hold team meetings, with fewer working hours and a greater ratio of professionals to patients. understanding moral distress allows us to go beyond solving the problems of the workers themselves, enabling the development of an ethics of active individuals and wide opportunities, defined mainly by the relationship with oneself.


Noncovalent inhibitors of human 20S and 26S proteasome based on trypsin inhibitor SFTI-1.
Sunflower trypsin inhibitor (SFTI-1) is recognized as an attractive scaffold to designed potent inhibitors of various proteases. We have recently found that its analogues inhibit noncovalently both human and yeast 20S proteasomes. Here, a set of novel and more potent in vitro inhibitors is presented. The inhibitory potency of the peptides was assessed with human 20S proteasome in the presence or absence of sodium dodecyl sulfate and with human 26 proteasome. Their antiproliferative action against tumor (human melanoma cells A375) and normal cells (46 BR.1N human fibroblasts and HaCaT keratinocytes) was determined. The selected fluoresceine-labeled inhibitors were able to internalize into A375 cells and were sometimes present as foci in the cells. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 685-696, 2016.


Renal angiomyolipoma with haemorrhage treated by urgent embolization.
We present herein a case of bleeding angiomyolipoma with disruption of the renal capsule, which was treated by hyperselective embolization of the corresponding renal artery branch.


Deep vein thrombosis in a child with Down syndrome: A case report.
We report on the case of iliofemoral popliteal vein thrombosis in a child with Down syndrome who had surgery for a congenital heart defect. She was readmitted to our hospital because of gastroenteritis and generalized tonic-clonic seizures at age 14 months. On the second day of hospitalization, color Doppler ultrasonography revealed right iliofemoral and popliteal vein thrombosis. She was treated successfully with intravenous fluids and low-molecular-weight heparin. No predisposing factor other than dehydration could be found in the patient. We suggest that dehydration should be kept in mind as a cause of deep-vein thrombosis in patients with severe dehydration.


Intragenic mapping of chemically induced ad-7 mutants of Schizosaccharomyces pombe.
Thirty adenine-requiring ad-7 mutants of Schizosaccharomyces pombe, induced by ethylmethanesulfonate, methyl-methanesulfonate, and hydroxylamine and exhibiting low spontaneous reversion frequencies, were located by intragenic recombination analysis. Their identification as ad-7 mutants was assessed in relation to two previously mapped ad-7 mutants. Each mutant was found to occupy a distinct mutational site; the smallest recombination fraction observed between the two closest mutational sites was of the order of 0.5 x 10(-6).


Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia-Implications for Vaccine Design.
The human respiratory syncytial virus (hRSV) is the causative agent for high rates of hospitalizations due to viral bronchiolitis and pneumonia worldwide. Such a disease is characterized by an infection of epithelial cells of the distal airways that leads to inflammation and subsequently to respiratory failure. Upon infection, different pattern recognition receptors recognize the virus and trigger the innate immune response against the hRSV. Further, T cell immunity plays an important role for virus clearance. Based on animal studies, it is thought that the host immune response to hRSV is based on a biased T helper (Th)-2 and Th17 T cell responses with the recruitment of T cells, neutrophils and eosinophils to the lung, causing inflammation and tissue damage. In contrast, human immunity against RSV has been shown to be more complex with no definitive T cell polarization profile. Nowadays, only a humanized monoclonal antibody, known as palivizumab, is available to protect against hRSV infection in high-risk infants. However, such treatment involves several injections at a significantly high cost. For these reasons, intense research has been focused on finding novel vaccines or therapies to prevent hRSV infection in the population. Here, we comprehensively review the recent literature relative to the immunological features during hRSV infection, as well as the new insights into preventing the disease caused by this virus.


miR-29 family regulates the puberty onset mediated by a novel Gnrh1 transcription factor TBX21.
Gonadotropin-releasing hormone (GnRH) is the ultimate signal by which the neuroendocrine system controls the puberty onset and fertility in mammals. The pulsatile release of GnRH is regulated by numerous extracellular and intracellular factors, including miRNAs. Here, we report a novel regulation mechanism mediated by miR-29 family. We found that the absence of miR-29s resulted in elevated expression of Gnrh1 in GT1-7 cells. Through in silico and wet analysis, we identified Tbx21, a target gene of miR-29, as the main effector. As a transcription activator, TBX21 stimulates the expression of Gnrh1 directly by binding to its promoter region, and indirectly by activating the expression of Dlx1, another transcription activator of Gnrh1. Stereotactic brain infusion of miR-29 inhibitor into the hypothalamus caused earlier puberty onset in prepubertal female mice than that of intact controls. The female mice with ectopic expression of Tbx21 in the hypothalamus were affected in both puberty onset and fertility, as they had higher level of serum LH and FSH, larger litter size but steeper decline of fertility compared with those of controls. Our results revealed that miR-29-3p and its target Tbx21 played a role in regulating the mammalian puberty onset and reproduction by modulating the Gnrh1 expression.


Heartbeat OCE: corneal biomechanical response to simulated heartbeat pulsation measured by optical coherence elastography.
It is generally agreed that the corneal mechanical properties are strongly linked to many eye diseases and could be used to assess disease progression and response to therapies. Elastography is the most notable method of assessing corneal mechanical properties, but it generally requires some type of external excitation to induce a measurable displacement in the tissue. We present Heartbeat Optical Coherence Elastography (Hb-OCE), a truly passive method that can measure the elasticity of the cornea based on intrinsic corneal displacements induced by the heartbeat. Hb-OCE measurements were performed in untreated and UV-A/riboflavin cross-linked porcine corneas ex vivo, and a distinct difference in strain was detected. Furthermore, a partially cross-linked cornea was also assessed, and the treated and untreated areas were similarly distinguished. Our results suggest that Hb-OCE can spatially map displacements in the cornea induced by small fluctuations in intraocular pressure, similar to what is induced by the heartbeat. The described technique opens the possibility for completely passive and noncontact in vivo assessment of corneal stiffness.


Incidence, risk factors and outcomes of acute kidney injury (AKI) in patients with acute-on-chronic liver failure (ACLF) of underlying cirrhosis.
Acute kidney injury (AKI) is a life-threatening complication in patients with acute-on-chronic liver failure (ACLF) of underlying cirrhosis. However, the characteristics of AKI in these patients have not been clarified. Our aim was to determine the incidence and risk factors of AKI and the association between AKI severity and 180-day transplant-free survival. We performed a retrospective cohort analysis of patients with ACLF of underlying cirrhosis in a single center from January 2009 through December 2014. AKI was defined by the criteria proposed by International Club of Ascites (ICA). The incidence and risk factors of AKI development and its relationship to 180-day transplant-free survival rates were evaluated. Of 1032 patients with ACLF of underlying cirrhosis, 121 (11.72 %) had AKI at admission, and 319 (30.9 %) developed AKI during hospitalization. We established a logistic regression model including four independent factors with AKI development: MELD score [odds ratio (OR), 1.1; 95 % confidence interval (CI), 1.07-1.14], presence of ascites (OR, 3.80; 95 % CI, 2.13-6.78), sepsis/infection (OR, 2.25; 95 % CI, 1.66-3.03) and acute variceal bleed (OR, 1.78; 95 % CI, 1.00-3.19). The area under receiver operating characteristics of the model in internal and external validations were 0.95 and 0.85, respectively. Patients with mild-A AKI had a higher 180-day transplant-free survival rate (23.8 %) than patients with mild-B AKI (19.0 %) or marked AKI (5.9 %) (all p < 0.001). AKI patients with a peak value of sCr <1.5 mg/dl had higher 180-day transplant-free survival rates compared to those with a peak value of sCr ≧1.5 mg/dl (23.8 % vs. 14.7 %, p < 0.001). We developed a clinical risk model for predicting development of AKI with great accuracy. Combining the ICA-AKI criteria and the peak value of sCr with 1.5 mg/dl provides a good prognostic method for patients with ACLF of underlying cirrhosis.


[Histopathological diagnosis of thyroid cancer in a multicenter trial].
In the front of the problems related to the differentiation between benign and malignant thyroid tumors we decided to perform a multicentre study in order to validate diagnoses of malignant thyroid tumors and assess the inter-observer variability. Material included 690 cases of malignant and benign thyroid lesions with primary histopathology established in 1985-1999. These cases were selected to multicentre study. The studies were sent from centres which agreed to participate in the project and than coded in the independent centre--Department of Nuclear Medicine and Endocrine Oncology. 40 pathologists from 25 centres provided their diagnoses which were compared with the reference ones. 10 547 diagnoses were evaluated, both on their accuracy of the distinction between malignant and benign lesions and on their accuracy of cancer histotype definition. The reference diagnosis was made by an agreement between four expert pathologists (D.L., S.S., J.S. and A.K.). The participants diagnosed 21% of cases differently than experts. Concerning the diagnosis of cancer histotype, the difference between participants diagnosis and the reference one was even higher. The best concordance was achieved in the diagnosis of papillary thyroid cancer, however, on the cost of cancer overdiagnosis by some participants. Follicular cancer was diagnosed accurately only in 75.4% of cases. The study documents a high inter-observer variability of thyroid cancer diagnosis and confirms the lesser accuracy of diagnosis of follicular cancer.


First things first: similar list length and output order effects for verbal and nonverbal stimuli.
When participants are presented with a short list of unrelated words and they are instructed that they may recall in any order, they nevertheless show a very strong tendency to recall in forward serial order. Thus, if asked to recall in any order: "hat, mouse, tea, stairs," participants often respond "hat, mouse, tea, stairs" even though there was no forward order requirement of the task. In 4 experiments, we examined whether this tendency is language-specific, reflecting mechanisms involved with speech perception, speech production, and/or verbal short-term memory. Specifically, we examined whether we would observe similar findings when participants were asked to recall, in any order, lists of between 1 and 15 nonverbal stimuli, such as visuospatial locations (Experiment 1, Experiment 3, Experiment 4), or touched facial locations (Experiment 2). Contrary to a language-specific explanation, we found corresponding tendencies (albeit somewhat reduced) in the immediate free recall of these nonverbal stimuli. We conclude that the tendency to initiate recall of a short sequence of items with the first item is a general property of memory, which may be augmented by verbal coding.


Lower urinary tract symptoms, benign prostatic hyperplasia, erectile dysfunction, and phosphodiesterase-5 inhibitors.
Many patients who present to their healthcare provider with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) will also have erectile dysfunction (ED), and vice versa. Although alpha-adrenergic receptor blockers and 5-alpha-reductase inhibitors are highly effective in treating BPH-associated LUTS, these agents have sexual adverse effects that cause many men to discontinue therapy. The discovery of nitric oxide as a major factor in the mechanism of erection has led to the development of new drugs for ED, including the phosphodiesterase (PDE) inhibitors. Preliminary data support the theory that inhibition of PDE isoenzymes in the prostate may improve LUTS due to BPH through relaxation of prostatic smooth muscle. Further studies of PDE inhibitors in men with ED and BPH-associated LUTS are indicated.


A theoretical study of novel orthorhombic group-IVB nitride halide monolayers for photocatalytic overall water splitting.
Hydrogen energy is very important as a new clean energy source to combat the growing environmental problems. In this regard, novel photocatalyst materials for water splitting have a wide range of applications. Using first principles calculations, we theoretically studied three orthorhombic group-IVB nitride halide monolayers, Hf2N2Br2, Janus HfZrN2Br2 and Janus Hf2N2ClBr. The energy, dynamic and thermal stabilities are demonstrated for all three monolayers. Using the HSE hybrid functional, the calculations reveal that they are direct band gap semiconductors with suitable band edge positions, good optical absorptions, and anisotropic carrier mobilities, which makes them promising for water splitting applications. Importantly, the photogenerated carriers provide enough driving force to trigger the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) within wide pH ranges, and then overall water splitting can be achieved spontaneously. We conclude that orthorhombic group-IVB nitride halide monolayers have potential applications in photocatalytic nanodevices.


Comparison of Marek's Disease Virus Challenge Strains and Bird Types for Vaccine Licensing.
Marek's disease virus (MDV) is an important poultry pathogen that is controlled through widespread vaccination with avirulent and attenuated strains. However, continued evolution of field viruses to higher virulence has required ongoing improvement of available vaccine strains, and these vaccine strains offer an attractive platform for designing recombinant vector vaccines with cross-protection against MDV and additional pathogens. Recent reports of failures in vaccine licensing trials of positive controls to reach appropriately high levels of Marek's disease incidence prompted us to evaluate possible combinations of outbred specific-pathogen-free layer lines and alternative virulent challenge strains that could provide more consistent models for serotype 3 vectored vaccine development. Choice of layer line and virulent MDV challenge strain each contributed to the ability of a challenge model to reach 80% virulence in unvaccinated positive control groups in the majority of trials, without overwhelming serotype 3 vectored vaccine protection in vaccinated groups. Conversely, reducing challenge virus dose by a factor of four, or vaccine dose by half, had no consistent effect across these models. Although MDV strain 617A had the most potential as an alternative to strains that are currently approved for licensing trials, no combination of layer line and challenge virus consistently met the goals for a successful challenge model in all study replicates, indicating that high variability is an inherent difficulty in MDV challenge studies, at least when outbred birds are used.


Fingolimod increases CD39-expressing regulatory T cells in multiple sclerosis patients.
Multiple sclerosis (MS) likely results from an imbalance between regulatory and inflammatory immune processes. CD39 is an ectoenzyme that cleaves ATP to AMP and has been suggested as a novel regulatory T cells (Treg) marker. As ATP has numerous proinflammatory effects, its degradation by CD39 has anti-inflammatory influence. The purpose of this study was to explore regulatory and inflammatory mechanisms activated in fingolimod treated MS patients. Peripheral blood mononuclear cells (PBMCs) were isolated from relapsing-remitting MS patients before starting fingolimod and three months after therapy start. mRNA expression was assessed in ex vivo PBMCs. The proportions of CD8, B cells, CD4 and CD39-expressing cells were analysed by flow cytometry. Treg proportion was quantified by flow cytometry and methylation-specific qPCR. Fingolimod treatment increased mRNA levels of CD39, AHR and CYP1B1 but decreased mRNA expression of IL-17, IL-22 and FOXP3 mRNA in PBMCs. B cells, CD4+ cells and Treg proportions were significantly reduced by this treatment, but remaining CD4+ T cells were enriched in FOXP3+ cells and in CD39-expressing Tregs. In addition to the decrease in circulating CD4+ T cells and CD19+ B cells, our findings highlight additional immunoregulatory mechanisms induced by fingolimod.


Spondylodiscitis in a healthy 12-year-old girl with Extraintestinal pathogenic Escherichia coli (ExPEC) bacteraemia.
Escherichia coli (E. coli) is rarely implicated in bone or joint infections in children. We discuss the case of a healthy 12-year-old girl with an E. coli bacteraemia and a T11-T12 spondylodiscitis revealed by magnetic resonance imaging. The strain harboured serogroup O1:K1 and virulence factors common to highly virulent extra intestinal pathogenic E. coli (ExPEC). Immunological work-up was normal. The identification of E. coli in a spondylodiscitis should lead to the search for immunosuppression of the host and virulence factors of the strain, particularly those of ExPEC.


Worldwide dispersion and deposition of radionuclides produced in atmospheric tests.
Radionuclides produced in atmospheric nuclear tests were widely dispersed in the global environment. From the many measurements of the concentrations in air and the deposition amounts, much was learned of atmospheric circulation and environmental processes. Based on these results and the reported fission and total yields of individual tests, it has been possible to devise an empirical model of the movement and residence times of particles in the various atmospheric regions. This model, applied to all atmospheric weapons tests, allows extensive calculations of air concentrations and deposition amounts for the entire range of radionuclides produced throughout the testing period. Especially for the shorter-lived fission radionuclides, for which measurement results at the time of the tests are less extensive, a more complete picture of levels and isotope ratios can be obtained, forming a basis for improved dose estimations. The contributions to worldwide fallout can be inferred from individual tests, from tests at specific sites, or by specific countries. Progress was also made in understanding the global hydrological and carbon cycles from the tritium and 14C measurements. A review of the global measurements and modeling results is presented in this paper. In the future, if injections of materials into the atmosphere occur, their anticipated motions and fates can be predicted from the knowledge gained from the fallout experience.


Sub-single exciton optical gain threshold in colloidal semiconductor quantum wells with gradient alloy shelling.
Colloidal semiconductor quantum wells have emerged as a promising material platform for use in solution-processable lasers. However, applications relying on their optical gain suffer from nonradiative Auger decay due to multi-excitonic nature of light amplification in II-VI semiconductor nanocrystals. Here, we show sub-single exciton level of optical gain threshold in specially engineered CdSe/CdS@CdZnS core/crown@gradient-alloyed shell quantum wells. This sub-single exciton ensemble-averaged gain threshold of (Ng)≈ 0.84 (per particle) resulting from impeded Auger recombination, along with a large absorption cross-section of quantum wells, enables us to observe the amplified spontaneous emission starting at an ultralow pump fluence of ~ 800 nJ cm-2, at least three-folds better than previously reported values among all colloidal nanocrystals. Finally, using these gradient shelled quantum wells, we demonstrate a vertical cavity surface-emitting laser operating at a low lasing threshold of 7.5 μJ cm-2. These results represent a significant step towards the realization of solution-processable electrically-driven colloidal lasers.


Percutaneous nonendoscopic gastrostomy in children.
Surgical gastrostomy has long been a standard method of providing nutrition to infants and children. Recently, percutaneous endoscopic gastrostomy has been advocated as a safer, quicker, less expensive method in children. We report our experience with 16 percutaneous gastrostomies in 14 infants and children; in all cases, both sonographic and fluoroscopic guidance were used. Four patients had had previous surgical gastrostomy in which the tubes could not be replaced once they were removed. The remaining patients were referred for percutaneous placement of gastrostomy tubes as the first procedure. In 13 procedures, parenteral sedation and local anesthesia were used; the remaining three procedures were done with the patient under general anesthesia. Tubes were successfully placed in all procedures. In two patients, tubes became dislodged, necessitating a second procedure. There were no instances of local infections, hemorrhage, or peritonitis, and none of the patients died. Two patients had postprocedure septicemia, which responded to antibiotics. Percutaneous nonendoscopic gastrostomy can be safely and effectively performed in infants and children.


Total ankle arthroplasty.
First-generation total ankle arthroplaty designs had unacceptably high complication and failure rates compared with ankle arthrodesis. More recent prostheses have had encouraging intermediate results because of refined surgical techniques and improved designs. Mobile-bearing designs theoretically offer less wear and loosening through full conformity and minimal constraint. The less complex fixed-bearing designs avoid bearing dislocation and the potential for added wear from a second articulation. Four second-generation designs have demonstrated reasonable functional outcomes: the Scandinavian Total Ankle Replacement, the Agility Ankle, the Buechel-Pappas Total Ankle Replacement, and the TNK ankle. Intermediate results are promising but should be interpreted with care.


PbSe nanocrystal network formation during pyridine ligand displacement.
Solution-phase pyridine treatment displaced oleic acid capping ligands from the surface of PbSe nanocrystals. During ligand displacement the nanostructure morphology dramatically changed from well-stabilized, individual nanocrystals to form crystallographically connected nanocrystal networks. The network morphology was governed by the diameter of the constituent nanocrystals. Larger nanocrystals showed dipolar alignment but maintained individual nanocrystal character, while smaller nanocrystals crystallographically fused along the <100> axis. Optical studies of nanocrystal thin films showed that pyridine ligand displacement quenches the nanocrystal photoluminescence. Blends of nanocrystals and conjugated polymer showed photoluminescence quenching of the polymer with increasing nanocrystal content. The extent of photoluminescence quenching was only weakly dependent on the nanocrystal size or surface chemistry, suggesting that the interaction between nanocrystal and polymer is mostly in the form of energy transfer rather than charge transfer.


High efficiency transformation of E. coli by high voltage electroporation.
E. coli can be transformed to extremely high efficiencies by subjecting a mixture of cells and DNA to brief but intense electrical fields of exponential decay waveform (electroporation). We have obtained 10(9) to 10(10) transformants/micrograms with strains LE392 and DH5 alpha, and plasmids pUC18 and pBR329. The process is highly dependent on two characteristics of the electrical pulse: the electric field strength and the pulse length (RC time constant). The frequency of transformation is a linear function of the DNA concentration over at least six orders of magnitude; and the efficiency of transformation is a function of the cell concentration. Most of the surviving cells are competent with up to 80% transformed at high DNA concentration. The mechanism does not appear to include binding of the DNA to the cells prior to entry. Possible mechanisms are discussed and a simple procedure for the practical use of this technique is presented.


[Regulatory effect of Bcl-2 on the cortical neurons of primary cultured mice with HSV-1 infection].
To study the effect of Bcl-2 on the cortical neurons of primary cultured mice with HSV-1 infection. Analysis of the expression of Bcl-2 on the cortical neurons of primary cultured fetal mice in vitro infected with HSV-1 for 11 hours or exposed to sorbitol for 5 hours was made by flow cytometry and Western blotting. The Bcl-2 of the cultured neurons undergoing HSV-1 infection expressed upregulating compared with the mock untreated neurons. The Bcl-2 protein of HSV-1 infected and exposed to sorbitol neurons expressed upregulating compared with the control group. The Bcl-2 protein of the primary cultured 3 day cells expressed higher than that of the primary cultured 7 day cells. The higher neurovirulence, the higher expression of Bcl-2. Bcl-2 might protect the primary cultured cortical neurons of fetal mice from apoptosis where infected with HSV-1, and thereby the lifespan of host cells may be prolonged.


Melittin inhibits the invasion of MCF-7 cells by downregulating CD147 and MMP-9 expression.
Tumor invasion and metastasis are the critical steps in determining the aggressive phenotype of human cancers. Melittin, a major component of bee venom, has been reported to induce apoptosis in several cancer cells. However, the mechanisms of melittin involvement in cancer invasion and metastasis remain unclear. Our previous study indicated that melittin inhibits cyclophilin A (CypA), a ubiquitously distributed peptidylprolyl cis-trans isomerase, in macrophage cells. In the present study, the Transwell assay results showed that melittin may downregulate the invasion level of MCF-7 cells in a dose-dependent manner. Additionally, it was also found, using flow cytometry and reverse transcription-polymerase chain reaction, that melittin decreased the expression of cluster of differentiation (CD)147 and matrix metallopeptidase-9 (MMP-9), whereas CypA upregulated the expression of CD147 and MMP-9. Overall, the present study indicated that melittin decreased the invasion level of MCF-7 cells by downregulating CD147 and MMP-9 by inhibiting CypA expression. The results of the present study provide an evidence for melittin in anticancer therapy and mechanisms.


Electroanalysis of the interaction between (-)-epigallocatechin-3-gallate (EGCG) and amyloid-β in the presence of copper.
The misfolding of amyloid-beta (Aβ) peptide is one of the pathological hallmarks of Alzheimer's disease (AD). Polyphenols are strong antioxidants and metal chelators, with characteristics that are of beneficial therapeutic values for their development as candidates targeting neurodegenerative and metal-induced diseases. We have demonstrated here the electrochemical properties of a green tea component, (-)-epigallocatechin-3-gallate (EGCG), and its potent activity on Aβ peptides. Characterization of early interactions (≤48 h) between EGCG and Aβ was conducted using square wave voltammetry (SWV). The interaction of Cu(ii) ions with the Tyr-10 residue of Aβ was shown to be affected by surrounding His residues. Morphological changes due to the binding of EGCG and Cu(II) were also elucidated using transmission electron microscopy (TEM). Electroanalytical techniques are promising for facilitating the investigation of metals and flavonoids in drug screening studies.


Intervention reduces chronic pain visits.
It's hard to believe that something as simple as a 15-30 minute consultation can have an impact on chronic pain patients using the ED as their venue of choice for medical care; however, that's just what happened in the ED at Providence Newberg Medical Center in Newberg, OR. The average number of visits per patient per year dropped from 6.8 to 2.3 in just three years. Grad students met patients at the bedside, validating their physical pain while introducing the concept that there are other treatment options besides opioids. A series of letters went to patients after discharge to reinforce follow-up recommendations. Local primary care providers were enlisted to treat patients who had no "medical home."


Antiprotozoal Structure-Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action.
Leucinostatin A is one of the most potent antiprotozoal compounds ever described, but little was known on structure-activity relationships (SAR). We used Trypanosoma brucei as a protozoal model organism to test synthetically modified derivatives, resulting in simplified but equally active compounds 2 (ZHAWOC6025) and 4 (ZHAWOC6027), which were subsequently modified in all regions of the molecule to gain an in-depth SAR understanding. The antiprotozoal SAR matched SAR in phospholipid liposomes, where membrane integrity, leaking, and dynamics were studied. The mode of action is discussed based on a structure-activity analysis of derivatives in efficacy, ultrastructural studies in T. brucei, and artificial membrane models, mimicking membrane stability and membrane potential. The main site of antiprotozoal action of natural and synthetic leucinostatins lies in the destabilization of the inner mitochondrial membrane, as demonstrated by ultrastructural analysis, electron microscopy and mitochondrial staining. Long-time sublethal exposure of T. brucei (200 passages) and siRNA screening of 12'000 mutants showed no signs of resistance development to the synthetic derivatives.


Comparison of formaldehyde exposure levels in two multi-industry occupational exposure databanks using multimodel inference.
The recent increase in international multicenter epidemiologic studies of occupational hazards and the current development of risk analysis tools based on multinational exposure data provide an incentive to evaluate the extrapolation of exposure data across countries. We compared formaldehyde measurements in the French (COLCHIC) and U.S. (IMIS) occupational exposure databases for 1986-2001 using multimodel inference. In this approach, conclusions are based on a set of plausible models rather than on a single model. Modeled variables included data source, industry, year, and sample type (short-term or long-term). The model set included 72 models corresponding to testing all variables and 5 interactions and estimation of 93 coefficients. As it is impossible to classify non-detects (ND) as short-term or long-term samples, they were removed from IMIS prior to analysis. Respectively, 3143 and 2646 IMIS and COLCHIC data, spread across 28 common industries, were analyzed. The full model explained 21% of the total variability. All fixed effects and the source-industry interaction were shown as strong predictors of exposure. The temporal trend (5% yearly decrease) and difference between short-term and long-term data (short-term greater than long-term by two-fold) were similar across the two databanks. Industry-specific differences between IMIS and COLCHIC were detected only for health-related activities for which COLCHIC levels were higher (~ four-fold). Sensitivity analyses were conducted to assess the impact of excluding NDs from IMIS. They showed initial predicted industry-specific geometric means for IMIS data potentially multiplied by factors from 0.42 to 0.98 (long-term data) and from 0.11 to 1.4 (short-term data) when NDs were included with various distributions across the short-term and long-term categories. The most realistic scenario yielded 0.82 for long-term (18% overestimation) data and 1.05 (5% underestimation) for short-term data. Although tempered by a probable non-detect bias, our analysis showed that both databanks provide a similar multi-industry portrait of formaldehyde exposure despite a potential for very different occupational settings. Our results offer encouraging insight about extrapolation of exposure data across countries.


Overexpression of the transcriptional coregulator Cited2 protects against glucocorticoid-induced atrophy of C2C12 myotubes.
In patients with various catabolic conditions, glucocorticoid excess induces skeletal muscle wasting by accelerating protein degradation via the ubiquitin-proteasome pathway. Although the transcriptional coactivator p300 has been implicated in this pathological process, regulatory mechanisms and molecular targets of its action remain unclear. Here we show that CREB-binding protein (CBP)/p300-interacting transactivator with ED-rich tail 2 (Cited2), which binds to the cysteine-histidine-rich region 1 of p300 and CBP, regulates muscle mass in vitro. Adenovirus-mediated overexpression of wild-type Cited2 significantly blocked morphological alterations of C2C12 myotubes with a concomitant decrease in myosin heavy chain protein in response to synthetic glucocorticoid dexamethasone, which were attributable to the reduced induction of atrophy-related ubiquitin ligases MuRF1 and MAFbx. These myotube-sparing effects were less pronounced, however, with a carboxyl-terminally truncated mutant of Cited2 that lacked the ability to bind p300. These results suggest that the gain of Cited2 function counteracts glucocorticoid-induced muscle atrophy through inhibition of proteolysis mediated by p300-dependent gene transcription.


Comparing palliation strategies for single-ventricle anatomy with transposed great arteries and systemic outflow obstruction.
Patients with complex single-ventricle anatomy with transposed great arteries and systemic outflow obstruction (SV-TGA-SOO) undergo varied initial palliation with ultimate goal of Fontan circulation. We examine a longitudinal experience with multiple techniques, including the largest published cohort following palliative arterial switch operation (pASO), to describe outcomes and decision-making factors. Neonates with SV-TGA-SOO who underwent initial surgical palliation from 1995 to 2022 at a single institution were retrospectively reviewed. In total, 71 neonates with SV-TGA-SOO underwent index surgical palliation at a median age of 7 days (interquartile range, 6-10) by pASO (n = 23), pulmonary artery band (PAB) with or without arch repair (n = 25), or modified Norwood with Damus-Kaye-Stansel aortopulmonary amalgamation (n = 23). Single-ventricle pathology included double-inlet left ventricle (n = 37, 52%), tricuspid atresia (n = 27, 38%), and others (n = 7, 10%). All mortalities (n = 5, 7%) occurred in the first interstage period after PAB (n = 3) and Norwood (n = 2). Subaortic obstruction in the PAB group was addressed by operative resection (n = 10 total, 7 at index operation) and/or delayed aortopulmonary amalgamation (n = 13, 52%). Two patients with pASO (9%) had early postoperative coronary complications, 1 requiring operative revision. Median follow-up for survivors was 10.4 years (interquartile range, 4.5-16.6 years). Comparing patients by their initial palliation type, notable significant differences included size of bulboventricular foramen, weight at initial operation, operation duration, postoperative length of stay, time to second-stage palliation, multiple pulmonary artery reinterventions, and left pulmonary artery interventions. There were no significant differences in overall survival, Fontan completion, reintervention-free survival in the first interstage period, pulmonary artery reintervention-free survival, long-term systemic valve competency, or ventricular dysfunction. Excellent mid- to long-term outcomes are achievable following neonatal palliation for SV-TGA-SOO via pASO, PAB, and modified Norwood, with comparable survival and Fontan completion. Initial palliation strategy should be individualized to optimize anatomy and physiology for successful Fontan by ensuring an unobstructed subaortic pathway and accessible pulmonary arteries. pASO is a reasonable strategy to consider for these heterogeneous lesions.


The role of ovarian steroids in placental development and endovascular trophoblast migration in the golden hamster.
Pregnant hamsters were ovariectomized on Day 7 and daily supplements of progesterone or progesterone plus oestradiol benzoate were given. Fetal development and survival was 14% and 62% respectively. Histological examination indicated that failure of labyrinthine development in the placenta resulted in failure to form an adequate number of maternal arterial spaces communicating with the base of the trophospongium to allow trophoblast migration in the related maternal spiral arteries. Progesterone was essential at all stages of gestation to sustain decidualized tissues and allow survival of a minority of fetuses. Oestradiol supplementation significantly increased fetal survival, but not to normal levels, suggesting that other oestrogens may be essential for the maintenance of normal hamster pregnancy.


Crystal structure of a TSH receptor monoclonal antibody: insight into Graves' disease pathogenesis.
The TSH receptor (TSHR) A-subunit is more effective than the holoreceptor in inducing thyroid-stimulating antibodies (TSAb) that cause Graves' disease. A puzzling phenomenon is that 2 recombinant, eukaryotic forms of A-subunits (residues 22-289), termed active and inactive, are recognized mutually exclusively by pathogenic TSAb and mouse monoclonal antibody 3BD10, respectively. Understanding the structural difference between these TSHR A-subunit forms could provide insight into Graves' disease pathogenesis. The 3-dimensional structure of the active A-subunit (in complex with a human TSAb Fab, M22) is known, but the structural difference with inactive A-subunits is unknown. We solved the 3BD10 Fab 3-dimensional crystal structure. Guided by prior knowledge of a portion of its epitope, 3BD10 docked in silico with the known active TSHR-289 monomeric structure. Because both TSAb and 3BD10 recognize the active TSHR A-subunit monomer, this form of the molecule can be excluded as the basis for the active-inactive dichotomy, suggesting, instead a role for A-subunit quaternary structure. Indeed, in silico analysis revealed that M22, but not 3BD10, bound to a TSHR-289 trimer. In contrast, 3BD10, but not M22, bound to a TSHR-289 dimer. The validity of these models is supported experimentally by the temperature-dependent balance between active and inactive TSHR-289. In summary, we provide evidence for a structural basis to explain the conformational heterogeneity of TSHR A-subunits (TSHR-289). The pathophysiologic importance of these findings is that affinity maturation of pathogenic TSAb in Graves' disease is likely to involve a trimer of the shed TSHR A-subunit.


Substrate recognition properties of oligopeptidase B from Salmonella enterica serovar Typhimurium.
Oligopeptidase B (OpdB) is a serine peptidase broadly distributed among unicellular eukaryotes, gram-negative bacteria, and spirochetes which has emerged as an important virulence factor and potential therapeutic target in infectious diseases. We report here the cloning and expression of the opdB homologue from Salmonella enterica serovar Typhimurium and demonstrate that it exhibits amidolytic activity exclusively against substrates with basic residues in P(1). While similar to its eukaryotic homologues in terms of substrate specificity, Salmonella OpdB differs significantly in catalytic power and inhibition and activation properties. In addition to oligopeptide substrates, restricted proteolysis of histone proteins was observed, although no cleavage was seen at or near residues that had been posttranslationally modified or at defined secondary structures. This supports the idea that the catalytic site of OpdB may be accessible only to unstructured oligopeptides, similar to the closely related prolyl oligopeptidase (POP). Salmonella OpdB was employed as a model enzyme to define determinants of substrate specificity that distinguish OpdB from POP, which hydrolyzes substrates exclusively at proline residues. Using site-directed mutagenesis, nine acidic residues that are conserved in OpdBs but absent from POPs were converted to their corresponding residues in POP. In this manner, we identified a pair of glutamic acid residues, Glu(576) and Glu(578), that define P(1) specificity and direct OpdB cleavage C terminal to basic residues. We have also identified a second pair of residues, Asp(460) and Asp(462), that may be involved in defining P(2) specificity and thus direct preferential cleavage by OpdB after pairs of basic residues.


Quantification of the lamina dura and dentin density in children.
This study used 150 periapical radiographs of primary mandibular molars along with an aluminum stepwedge consisting of 5 steps from 2 to 10mm which were exposed and developed under standard conditions. A Mustek (Taiwan, R.O.C.) flatbed scanner with transparency adapter was used to digitize the radiographs. A 600 dpi, 10 bit gray level scanning transparency scanning mode were used. The thickness of the lamina dura was measured with the electronic ruler whereas density of dentin was calculated using the density function of a software program (Image Tool 2.0). Dentin density of the bifuraction area was calculated as 7.42 +/- 37 mm=A1 in primary second molars and 11.02 +/- 1.37mm = A1 for permanent first molar teeth. Differences in the thickness of the lamina dura in primary posterior teeth ranged from 0.23 +/- 0.01mm to 0.42 +/- 0.01mm.


Veerabhadrarao Kaliginedi.
"The most exciting thing about my research is getting to build new toys (instruments) to play with molecules … A good day at work starts with a crazy experimental idea." Find out more about Veerabhadrarao Kaliginedi in his Introducing … Profile.


Enhancing cartilage repair with optimized supramolecular hydrogel-based scaffold and pulsed electromagnetic field.
Functional tissue engineering strategies provide innovative approach for the repair and regeneration of damaged cartilage. Hydrogel is widely used because it could provide rapid defect filling and proper structure support, and is biocompatible for cell aggregation and matrix deposition. Efforts have been made to seek suitable scaffolds for cartilage tissue engineering. Here Alg-DA/Ac-β-CD/gelatin hydrogel was designed with the features of physical and chemical multiple crosslinking and self-healing properties. Gelation time, swelling ratio, biodegradability and biocompatibility of the hydrogels were systematically characterized, and the injectable self-healing adhesive hydrogel were demonstrated to exhibit ideal properties for cartilage repair. Furthermore, the new hydrogel design introduces a pre-gel state before photo-crosslinking, where increased viscosity and decreased fluidity allow the gel to remain in a semi-solid condition. This granted multiple administration routes to the hydrogels, which brings hydrogels the ability to adapt to complex clinical situations. Pulsed electromagnetic fields (PEMF) have been recognized as a promising solution to various health problems owing to their noninvasive properties and therapeutic potentials. PEMF treatment offers a better clinical outcome with fewer, if any, side effects, and wildly used in musculoskeletal tissue repair. Thereby we propose PEMF as an effective biophysical stimulation to be 4th key element in cartilage tissue engineering. In this study, the as-prepared Alg-DA/Ac-β-CD/gelatin hydrogels were utilized in the rat osteochondral defect model, and the potential application of PEMF in cartilage tissue engineering were investigated. PEMF treatment were proven to enhance the quality of engineered chondrogenic constructs in vitro, and facilitate chondrogenesis and cartilage repair in vivo. All of the results suggested that with the injectable self-healing adhesive hydrogel and PEMF treatment, this newly proposed tissue engineering strategy revealed superior clinical potential for cartilage defect treatment.


Efficacy of intravenous dexmedetomidine on patient's satisfaction, comfort and sedation during awake fibre-optic intubation in patients with cervical spondylotic myelopathy posted for elective cervical fixation.
Various anaesthetic drugs, in addition to airway block, are used for producing favourable intubation conditions during awake fibre-optic intubation (AFOI), but most of them cause respiratory depression and hypoxaemia. The aim of this study was to evaluate the efficacy of intravenous (IV) dexmedetomidine (DEX) on sedation, patient comfort and cardiovascular responses during AFOI in patients with cervical spondylotic myelopathy (CSM). This randomised, placebo-controlled, double-blinded, prospective study was conducted on 56 adult patients with cervical spondylotic myelopathy (CSM) undergoing elective cervical fixation, who were randomly allocated into two groups - Group D and Group C. Group D patients received DEX infusion at a rate of 1 μg/kg for the first 10 min followed by 0.5 μg/kg/h and Group C received 0.9% normal saline infusion in the same manner. Airway blocks with lignocaine were given to all patients before undergoing AFOI. Patient's alertness, sedation and cardiorespiratory changes during the procedure were assessed by the Observer Assessment Awareness and Sedation (OAA/S) scale. On the 1st post-operative day, patient's' comfort during AFOI was assessed by visual analogue scale (VAS). Patients of Group D had an acceptable level of sedation (OAA/S score: 20 to 17 with greater comfort and satisfaction (VAS: 40-60), compared to control group (VAS: 50-90, P < 0.001.). Moreover, haemodynamic parameters were less significantly altered in the DEX group during AFOI. IV DEX infusion during AFOI improves patient's tolerances with an acceptable level of sedation without significant haemodynamic instability and respiratory depression.


Genetic variation and genetic structure of five Chinese indigenous pig populations in Jiangsu Province revealed by sequencing data.
In this study, we investigated the genetic variants, including SNPs and indels (short insertions or deletions, less than 50 bp in length), in the genomes and genetic structures of five pig populations (in the northern Taihu Lake region, Jiangsu Province) using the genotyping by genome reducing and sequencing (GGRS) approach. A total of 581 million good reads with an average depth of 11× and an average coverage of 2.16% were used to call variants. In general, 202 106 SNPs and 34 415 indels were obtained, of which 2690 SNPs and 224 indels were capable of inducing protein-coding changes. The genes containing these variants were extracted for functional annotation. The results of gene enrichment analysis revealed that the SNPs under investigation may be associated with reproduction, disease resistance, meat quality and adipose tissue traits, whereas the indels were associated mainly with adipose tissue and disease. Analysis of the genetic structure showed that each population displayed comparable, large differentiations from the others, indicating their uniqueness. In conclusion, the results of our study provide the first genomic overview of the genetic variants and population structures of five Chinese indigenous pig populations.


Positive Effect of Platelet-Rich Plasma on Pain in Plantar Fasciitis: A Double-Blind Multicenter Randomized Controlled Trial.
When nonoperative treatment for chronic plantar fasciitis fails, often a corticosteroid injection is given. Corticosteroid injection gives temporary pain reduction but no healing. Platelet-rich plasma (PRP) has proven to be a safe therapeutic option in the treatment of tendon, muscle, bone, and cartilage injuries. To determine the effectiveness of PRP as compared with corticosteroid injections for chronic plantar fasciitis. Randomized controlled trial; Level of evidence, 1. Patients with chronic plantar fasciitis were allocated to have steroid injection or PRP. The primary outcome measure was the Foot Function Index (FFI) Pain score. Secondary outcome measures were function, as scored by the FFI Activity, FFI Disability, and American Orthopaedic Foot & Ankle Society, and quality of life, as scored with the short version of the World Health Organization Quality of Life (WHOQOL-BREF). All outcomes were measured at baseline and at 4, 12, and 26 weeks and 1 year after the procedure. Of the 115 patients, 63 were allocated to the PRP group, of which 46 (73%) completed the study, and 52 were allocated to the control group (corticosteroid injection), of which 36 (69%) completed the study. In the control group, FFI Pain scores decreased quickly and then remained stable during follow-up. In the PRP group, FFI Pain reduction was more modest but reached a lower point after 12 months than the control group. After adjusting for baseline differences, the PRP group showed significantly lower pain scores at the 1-year follow-up than the control group (mean difference, 14.4; 95% CI, 3.2-25.6). The number of patients with at least 25% improvement (FFI Pain score) between baseline and 12-month follow-up differed significantly between the groups. Of the 46 patients in the PRP group, 39 (84.4%) improved at least 25%, while only 20 (55.6%) of the 36 in the control group showed such an improvement (P = .003). The PRP group showed significantly lower FFI Disability scores than the control group (mean difference, 12.0; 95% CI, 2.3-21.6). Treatment of patients with chronic plantar fasciitis with PRP seems to reduce pain and increase function more as compared with the effect of corticosteroid injection. NCT00758641 (ClinicalTrials.gov identifier).


Machine Learning Approach for Prediction and Understanding of Glass-Forming Ability.
The prediction of the glass-forming ability (GFA) by varying the composition of alloys is a challenging problem in glass physics, as well as a problem for industry, with enormous financial ramifications. Although different empirical guides for the prediction of GFA were established over decades, a comprehensive model or approach that is able to deal with as many variables as possible simultaneously for efficiently predicting good glass formers is still highly desirable. Here, by applying the support vector classification method, we develop models for predicting the GFA of binary metallic alloys from random compositions. The effect of different input descriptors on GFA were evaluated, and the best prediction model was selected, which shows that the information related to liquidus temperatures plays a key role in the GFA of alloys. On the basis of this model, good glass formers can be predicted with high efficiency. The prediction efficiency can be further enhanced by improving larger database and refined input descriptor selection. Our findings suggest that machine learning is very powerful and efficient and has great potential for discovering new metallic glasses with good GFA.


Contributing factors for delayed postoperative cerebrospinal fluid leaks and suggested treatment algorithm.
Delayed postoperative cerebrospinal fluid (CSF) leaks are uncommon and largely unstudied complications. In this study we aim to identify their etiology and understand the efficacy of various reconstruction strategies. A retrospective chart analysis of 1017 endonasal skull base surgeries performed by a single neurosurgeon was completed identifying delayed CSF leaks (occurring >1 week after surgery). Seventeen cases of early (1-2 weeks after surgery) or delayed (>2 weeks after surgery) postoperative CSF leak were identified. The most common reconstruction during the initial surgery consisted of an inlay or gasket seal collagen matrix (82.4% of patients) with an onlay pedicled flap (76.5% of patients). Presenting symptoms of delayed CSF leak included rhinorrhea (82.4%), headache (41.2%), and meningitis (23.5%). The most common causes included flap dehiscence (17.6%); provoking events such as emesis, sneezing, or fall (17.6%); flap necrosis (11.8%); flap displacement (11.8%); and inadequate apposition of the flap, that is, folded flap (11.8%). Reconstructive techniques of the delayed CSF leak included fortification of the initial reconstruction with free fat grafts (29.4% of patients), combined collagen matrix with a fat graft (23.5% of patients), repositioning of the previous flap (11.8% of patients), and repair with a new flap (11.8% of patients). CSF diversion (spinal/ventricular drain or shunt) was used in 17.6% of patients. This study identifies the most common etiologic factors leading to a delayed CSF leak and its initial symptoms. Furthermore, it serves as the foundation for a reconstructive algorithm based on reinforcement of the initial repair with free abdominal fat graft with or without collagen matrix.


Predicting diabetic nephropathy in insulin-dependent patients.
We studied whether microalbuminuria (urinary albumin excretion rates of 15 to 150 micrograms per minute) would predict the development of increased proteinuria in Type I diabetes. We also studied the influence of glomerular filtration rate, renal blood flow, and blood pressure on the later development of proteinuria. Forty-four patients who had had Type I diabetes for at least seven years and who had albumin excretion rates below 150 micrograms per minute were studied from 1969 to 1976, and 43 were restudied in 1983. Of the 14 who initially had albumin excretion rates at or above 15 micrograms per minute, 12 had clinically detectable proteinuria (over 500 mg of protein per 24 hours) or an albumin excretion rate above 150 micrograms per minute at the later examination. Of the 29 who initially had albumin excretion rates below 15 micrograms per minute, none had clinically detectable proteinuria at the later examination, although four had microalbuminuria. Those whose condition progressed to clinically overt proteinuria had elevated glomerular filtration rates and higher blood pressures at the initial examination than did those in whom proteinuria did not develop. Renal blood flow was not elevated in these patients. We conclude that microalbuminuria predicts the development of diabetic nephropathy and that elevated glomerular filtration rates and increased blood pressure may also contribute to this progression.


The cost conundrum.
From the presidential campaign trail to the board rooms of the Fortune 500 to the man on the street, everyone talks about the high cost of health care, but no one knows what to do about it.


Characterization and Biological Evaluation of Diterpenoids from Casearia graveolens.
Biologically active substances that promote the neurite outgrowth of nerve cells against neuron degeneration may be useful for the treatment of Alzheimer's disease. In a continuing search for bioactive compounds from plants, an ethyl acetate-soluble extract of the twigs of Casearia graveolens showed moderate stimulatory activity of neurite outgrowth from PC12 cells. Further investigation to obtain bioactive compounds led to the isolation of 10 new clerodane diterpenoids, graveopenes A-J (1-10). Their structures including absolute configurations were elucidated based on analysis of their NMR spectroscopic data and experimental and calculated ECD spectra. Compounds 3-6 and 8 were shown to stimulate NGF-mediated neurite outgrowth from PC12 cells.


The impact of body mass index on treatment outcomes for patients with low-intermediate risk prostate cancer.
Little is known about the relationship between preoperative body mass index and need for adjuvant radiation therapy (RT) following radical prostatectomy. The goal of this study was to evaluate the utility of body mass index in predicting adverse clinical outcomes which require adjuvant RT among men with organ-confined prostate cancer (PCa). We used a prospective cohort of 1,170 low-intermediate PCa risk men who underwent radical prostatectomy and evaluated the effect of body mass index on adverse pathologic features and freedom from biochemical failure (FFbF). Clinical and pathologic variables were compared across the body mass index groups using an analysis of variance model for continuous variables or χ(2) for categorical variables. Factors related to adverse pathologic features were examined using logistic regression models. Time to biochemical recurrence was compared across the groups using a log-rank survivorship analysis. Multivariable analysis predicting biochemical recurrence was conducted with a Cox proportional hazards model. Patients with elevated body mass index (defined as body mass index ≥25 kg/m(2)) had greater extraprostatic extension (p = 0.004), and positive surgical margins (p = 0.01). Elevated body mass index did not correlate with preoperative risk groupings (p = 0.94). However, when compared with non-obese patients (body mass index <30 kg/m(2)), obese patients (body mass index ≥30 kg/m(2)) were much more likely to have higher rate of adverse pathologic features (p = 0.006). In patients with low- and intermediate- risk disease, obesity was strongly associated with rate of pathologic upgrading of tumors (p = 0.01 and p = 0.02), respectively. After controlling for known preoperative risk factors, body mass index was independently associated with ≥2 adverse pathologic features (p = 0.002), an indicator for adjuvant RT as well as FFbF (p = 0.001). Body mass index of ≥30 kg/m(2) is independently associated with adverse pathologic features, which is an indicator for additional RT, particularly in patients with low-intermediate risk disease. Future studies may determine if this select group of patients may be best treated with definitive RT to reduce toxicity from additional RT following radical prostatectomy. We propose including body mass index in clinical decision-making for appropriate treatment recommendation for patients with low-intermediate risk PCa.


[Renal cell carcinoma metastatic to the ovary].
A 45-year-old woman underwent left radical nephrectomy in April 2002. Pathological diagnosis was a renal cell carcinoma, clear cell subtype, pT3a, v(-), NO. One year later, abdominal ultrasound revealed a left ovarian tumor which had an enlargement tendency. A laparoscopic bilateral salpingooophorectomy was performed. Immunohistochemical analysis confirmed the diagnosis of metastatic ovarian renal cell carcinoma. This is the 20th case in the literature.


Modeling the First-Order Molecular Hyperpolarizability Dispersion from Experimentally Obtained One- and Two-Photon Absorption.
The search for optical materials, particularly organic compounds, is still an attractive and essential field for developing several photonic devices and applications. For example, some applications are based on light scattering with twice the energy of the incoming photon for selected compounds, that is, the nonlinear optical effect related to the second-order susceptibility term from the electronic polarization expression. The microscopic interpretation of this phenomenon is called the first-order molecular hyperpolarizability or incoherent second harmonic generation of light. Understanding such phenomena as a function of the incoming wavelength is crucial to improving the optical response of future materials. Still, the experimental apparatus, hyper-Rayleigh scattering, apparently simple, is indeed a challenging task. Therefore, we proposed a proper alternative to obtain the dispersion of the first-order hyperpolarizability using the well-known one- and two-photon absorption techniques. By the spectral analysis of both the spectra, we gathered spectroscopic parameters and applied them for predicting the first-order hyperpolarizability dispersion. This prediction is based on an n-level energy system, taking into account the position and magnitude of transition dipole moments and the difference between the permanent dipole moment of the n-excited states. Moreover, using the presented method, we can avoid underestimating the first-order hyperpolarizability by not suppressing higher-energy transitions. Quantum chemical calculations and the hyper-Rayleigh scattering technique were used to validate the proposed method.


Tangential flow filtration of haptoglobin.
Haptoglobin (Hp) is a plasma glycoprotein that scavenges cell-free hemoglobin (Hb). Hp has various potential therapeutic applications, but it has been mainly studied for treatment of acute hemolytic conditions that can arise from situations such as massive blood transfusion, infusion of stored red blood cells, severe burns, trauma, sepsis, radiation injury, and others. Therefore, Hp may also be beneficial during chronic hemolytic disease states such as hereditary spherocytosis, nocturnal hemoglobinuria, sickle-cell anemia, and malaria. Various methods have been developed to purify Hp from plasma or plasma fractions. However, none of these methods have exploited the large molecular weight (MW) range distribution of Hp polymers to easily isolate Hp from other plasma proteins. The present study used tangential flow filtration (TFF) to isolate polymeric Hp from plasma proteins using human Fraction IV (FIV) as the starting material. After removal of insoluble material from a suspension of FIV paste, the protein mixture was clarified on a 0.2 μm hollow fiber (HF) TFF filter. The clarified protein solution was then bracketed based on protein MW using HF filters with MW cut-offs (MWCOs) of 750, 500, and 100 kDa. Using untreated FIV, the Hp purity of the main bracket was ~75% with a total Hb binding capacity (HbBC) yield of 1.2 g starting from 500 g of FIV paste. However, pretreatment of FIV with fumed silica to remove lipoproteins increased Hp purity to >95% with a HbBC yield of 1.7 g per 500 g of FIV. Taken together this study provides a novel and scalable method to purify Hp from plasma or plasma fractions.


[Application of immunosuppressants for therapy of patients with vasculitis].
Immunosuppressants are applied clinically on vasculitis. Cyclophosphamide, azathioprine, and methotrexate are used most often. Other immunosuppressants, such as bredinin, FK506, monoclonal antibody, and adhesion molecule are studied in laboratory level or in small group clinical trial. In combination therapy, immunosuppressants are used with corticosteroids, which are the first choice drug on angitis. Methotrexate is administered as intermittent manner. Since immunosuppressants have side effects including oncogenicity and immunotoxicity, clinicians have to pay much attention on clinical course of the patients with vasculitis.


Telomere length and mitochondrial DNA copy number in bipolar disorder: identification of a subgroup of young individuals with accelerated cellular aging.
The 10-15-years decrease in life expectancy observed in individuals with bipolar disorder (BD) has been linked to the concept of accelerated cellular aging. Telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) have been proposed as markers of cellular aging and comparisons between individuals with BD and healthy controls (HC) sometimes led to conflicting results. Previous studies had moderate sample sizes and studies combining these two markers into a single analysis are scarce. Using quantitative polymerase chain reaction, we measured both TL and mtDNAcn in DNA (peripheral blood) in a sample of 130 individuals with BD and 78 HC. Regression analyses, receiver operating characteristic (ROC), and clustering analyses were performed. We observed significantly lower TL and mtDNAcn in individuals with BD as compared to HC (respective decrease of 26.5 and 35.8%). ROC analyses showed that TL and mtDNAcn highly discriminated groups (AUC = 0.904 for TL and AUC = 0.931 for mtDNAcn). In the whole population, clustering analyses identified a group of young individuals (age around 36 years), with accelerated cellular aging (both shorter TL and lower mtDNAcn), which consisted mostly of individuals with BD (85.5%). The subgroup of patients with young age but accelerated aging was not characterized by specific clinical variables related to the course of BD or childhood maltreatment. However, patients in this subgroup were more frequently treated with anticonvulsants. Further characterization of this subgroup is required to better understand the molecular mechanisms and the risk factors of accelerated cellular aging in BD.


Globular C1q receptor (p33) binds and stabilizes pro-inflammatory MCP-1: a novel mechanism for regulation of MCP-1 production and function.
The protein gC1qR (globular C1q receptor), also named p33, was originally identified as a binding partner of the globular heads of C1q in the complement system. gC1qR/p33 is abundantly expressed in many cell types, but the functional importance of this protein is not completely understood. Here, we investigate the impact of gC1qR/p33 on the production and function of the pathophysiologically important chemokine monocyte chemoattractant protein-1 (MCP-1) and the underlying molecular mechanisms. Knockdown of gC1qR/p33 negatively regulated the production of MCP-1, but had no effect on the expression of transcript for MCP-1 in human periodontal ligament cells, suggesting a translational/post-translational mechanism of action. Laser scanning confocal microscopy showed considerable cytosolic co-localization of gC1qR/p33 and MCP-1, and co-immunoprecipitation disclosed direct physical interaction between gC1qR/p33 and MCP-1. Surface plasmon resonance analysis revealed a high-affinity binding (KD = 10.9 nM) between gC1qR/p33 and MCP-1. Using a transwell migration assay, we found that recombinant gC1qR/p33 enhances MCP-1-induced migration of human THP-1 monocytes, pointing to a functional importance of the interaction between gC1qR/p33 and MCP-1. An in vitro assay revealed a rapid turnover of the MCP-1 protein and that gC1qR/p33 stabilizes MCP-1, hence preventing its degradation. We propose that endogenous gC1qR/p33 physically interacts with MCP-1 causing stabilization of the MCP-1 protein and stimulation of its activity in human periodontal ligament cells, suggesting a novel gC1qR/p33-mediated pro-inflammatory mechanism of action.


[A young woman with auto-immune pancreatitis].
Acute pancreatitis is a frequently diagnosed disease. The majority is caused by cholelithiasis or alcohol. There are also two forms of auto-immune pancreatitis (AIP). Type 2 AIP presents on a younger age compared with IgG4 related pancreatitis. Clinical presentation as an acute pancreatitis, a mass in the pancreas or with jaundice. There is an association with inflammatory bowel disease. A young patient with Crohn's disease developed abdominal pain compatible with acute pancreatitis. After exclusion of other etiologies a diagnosis of type 2 auto-immune pancreatitis was made with MRI/MRCP and typical histology. She was clinically successfully treated with steroids and follow up scan clearly showed improvement. Steroids were slowly withdrawn. Also young patients and patients with a normal IgG4 can have an AIP. Diagnosis is based on clinical, radiological and histological criteria. Type 2 AIP is treated with steroids without the need for maintenance therapy.