Alumni of the Massachusetts mental health center residency training.
In a preliminary survey, 484 alumni of the Massachusetts Mental Health Residency Training Program from 1912 to 1967 were surveyed. Approximately 80% were found to have devoted half or more of their professional time to the nonprivate practice of psychiatry for at least one year. These data suggest that a training program with strong academic traditions might produce a preponderance of publicity of oriented psychiatrists. Since previous surveys have indicated a greater proportion of psychiatric time spent in private practice, we suggest that future surveys of psychiatric manpower need to consider the orientation of residency training programs in order to accurately assess the need for future psychiatric manpower.


[Effect of PC-1 gene expression on migration ability of prostate cancer cells].
PC-1 gene is highly expressed in C4-2 cell line, an androgen-independent and aggressive prostate cancer cell line, but lowly expressed in LNCaP cell line, an androgen-dependent prostate cancer cell line. This study was to assess the contribution of PC-1 gene to migration of prostate cancer cells. LNCaP cell line with stable expression of PC-1 gene and C4-2 cell line with antisense nucleotide-down-regulated PC-1 were established. The migration abilities of LNCaP and C4-2 cells were tested using an in vitro transwell invasion assay. Migration cell count of LNCaP cells with up-regulation of PC-1 gene was similar to that of control LNCaP cells(P>0.05); migration cell count was significantly lower in C4-2 cells with down-regulation of endogenous PC-1 gene than in control C4-2 cells (P<0.05). PC-1 may be involved in the invasion of prostate cancer cells.


Study on dynamic sealing performance of combined sealing structure of telescopic type of downhole robot by using HTHP coupling method.
The sealing performance will directly affect the operation of downhole robot under HTHP condition. Traditional analysis methods of sealing performance are that the temperature and pressure is loaded respectively. This can not really evaluate the sealing performance. Besides, the simulation process is: Step 1: pre-compress O-ring to produce contact force. According to the contact pressure, select the compression ratio to calculate the displacement of the slip ring. Step 2: load fluid pressure on the O-ring. This simulation method is to directly load pressure on the undeformed O-ring. However, the O-ring will deform after pre-compression. Therefore, this simulation method is not accurate. In order to make the simulation data more accurate, calculate the data of shape, stress, and strain of O-ring caused by pre-compression caused by assembly. Then, import the deformation body containing the real data of shape, stress, and strain into a new model. On the basis, establish the numerical simulation model of piston, piston guide rod, O-ring, and FTS-ring with HTHP loads is. Finally, calculate and analyze. When the compression ratio of the O-ring is about 14%, the sealing performance is good. What's more, the distribution of contact stress and Von Mises of the O-ring at 8.3 mm/s of motion speed are analyzed. The results show that the foot shaped combined sealing structure can keep a good dynamic sealing performance under HTHP condition. This paper provides a theoretical basis for the analysis of the dynamic sealing performance by using HTHP coupling method. In the analysis of sealing performance: the hydraulic pressure is loaded to the real model with the real shape, stress, and strain produced by the O-ring assembly. This can more accurately evaluate the sealing performance under HTHP condition. It also provides a reference for the dynamic sealing structure design of downhole tools.


Administration of Autologous Bone Marrow-Derived Stem Cells for Treatment of Cerebral Palsy Patients: A Proof of Concept.
Stem cell therapy is a promising treatment for cerebral palsy, which refers to a category of brain diseases that are associated with chronic motor disability in children. Autologous bone marrow stem cells may be a better cell source and have been studied for the treatment of cerebral palsy because of their functions in tissue repair and the regulation of immunological processes. To assess autologous marrow stem cells as a novel treatment for patients with moderate-to-severe cerebral palsy, a total of 10 cerebral palsy patients were enrolled in this clinical study with 24 months follow-up. A total of 10 cerebral palsy patients received autologous bone marrow cells transplantation (4.5 × 108 mononuclear cells; 90% viability) into the subarachnoid cavity and rehabilitation. We recorded the gross motor function measurement scores, manual ability function measurement score, and adverse events up to 24 months post-treatment. The gross motor function measurement scores were significantly higher at month 6 post-treatment compared with the baseline scores and were stable up to 24 months follow-up. The increase in manual ability and communication function measurement scores at 6 months were not significant when compared to the baseline score. All the 10 patients survived and none of the patients experienced any serious adverse events or complications. Our results indicated that bone marrow derived MNCs are safe and effective for the treatment of motor deficits related to cerebral palsy. Further randomized clinical trials are necessary to establish the efficacy of this procedure.


Retracted: The Effect of Hyperbaric Oxygen Combined with Virtual Reality Training on Oxidative Stress Indicators and Inflammatory Factors of Swimming Athletes Suffering from Depression.
[This retracts the article DOI: 10.1155/2021/6645515.].


A phase II study of topotecan in patients with recurrent head and neck cancer. Identification of an active new agent.
This study evaluated the efficacy and safety of topotecan, a topoisomerase I inhibitor, in patients with advanced squamous cell cancer of the head and neck. Topotecan was administered intravenously (over 30 min) daily for 5 days every 3 weeks at a starting dose of 1.5 mg/m2/day. Eligibility required no prior chemotherapy, measurable disease, and performance status of < or = 2. Quality of life (QOL) assessment was performed at specified time points using the Spitzer QOL index and the symptom distress scale. Of 26 patients entered into the study, 23 and 22 patients were assessable for toxicity and response, respectively. One complete and two partial responses were observed, with response durations of 9, 4, and 1.5 months, respectively. Six patients had stable disease, including one patient with a 45% tumor shrinkage. The median survival for all patients entered was 4 months. Neutropenia was the major dose-limiting side effect, with grade 4 toxicity observed in 42% of all cycles of treatment. Grade 3 anemia occurred in 16% of all cycles, and nine patients required blood transfusions. Nonhematologic toxicities were infrequent and mild to moderate. QOL assessment revealed no significant change of total scores between each assessment point. Topotecan is a well-tolerated new agent with similar single-agent activity to that of cisplatin, 5-fluorouracil, and methotrexate in advanced head and neck cancer. Further investigation of this agent with other chemotherapeutic drugs and with concurrent radiation therapy is appropriate.


Zirconium Oxycarbide: A Highly Stable Catalyst Material for Electrochemical Energy Conversion.
Metal carbides and oxycarbides have recently gained considerable interest due to their (electro)catalytic properties that differ from those of transition metals and that have potential to outperform them as well. The stability of zirconium oxycarbide nanopowders (ZrO0.31 C0.69 ), synthesized via a hybrid solid-liquid route, is investigated in different gas atmospheres from room temperature to 800 °C by using in-situ X-ray diffraction and in-situ electrical impedance spectroscopy. To feature the properties of a structurally stable Zr oxycarbide with high oxygen content, a stoichiometry of ZrO0.31 C0.69 has been selected. ZrO0.31 C0.69 is stable in reducing gases with only minor amounts of tetragonal ZrO2 being formed at high temperatures, whereas it decomposes in CO2 and O2 gas atmosphere. From online differential electrochemical mass spectrometry measurements, the hydrogen evolution reaction (HER) onset potential is determined at -0.4 VRHE . CO2 formation is detected at potentials as positive as 1.9 VRHE as ZrO0.31 C0.69 decomposition product, and oxygen is anodically formed at 2.5 VRHE , which shows the high electrochemical stability of this material in acidic electrolyte. This peopwery makes the material suited for electrocatalytic reactions at anodic potentials, such as CO and alcohol oxidation reactions, in general.


Alumina Matrix Composites with Non-Oxide Nanoparticle Addition and Enhanced Functionalities.
The addition of SiC or TiC nanoparticles to polycrystalline alumina matrix has long been known as an efficient way of improving the mechanical properties of alumina-based ceramics, especially strength, creep, and wear resistance. Recently, new types of nano-additives, such as carbon nanotubes (CNT), carbon nanofibers (CNF), and graphene sheets have been studied in order not only to improve the mechanical properties, but also to prepare materials with added functionalities, such as thermal and electrical conductivity. This paper provides a concise review of several types of alumina-based nanocomposites, evaluating the efficiency of various preparation methods and additives in terms of their influence on the properties of composites.


Psychopathology and personality traits associated with driving while intoxicated in Beijing, China: Implications for interventions.
Driving while intoxicated (DWI) represents an area of grave concern in China, yet little research has focused on it or on the personality traits and psychiatric disorders among these drivers. We enrolled 325 of 382 residents charged with DWI in a compulsory detention center in Beijing, China. And 351 male drivers who had never had any alcohol arrests as control participants. All were screened for Axis I disorders using the Chinese version of the Structured Clinical Interview for the Diagnostic Statistical Manual of Mental Disorders IV-TR (SCID), the Minnesota Multiphasic Personality Inventory (MMPI-2), and the Sixteen Personality Factor Questionnaire (16PF). The subjects were all males with a mean (±SD) age of 34.41 ± 8.48 years, and almost 30% met DSM-IV criteria for alcohol abuse or dependence (n = 92). Compared to normal controls they showed greater Social Boldness, Abstractedness, Apprehension, Liveliness and Tension, and poorer Reasoning, Vigilance, Openness to Change, and Self-reliance. On the MMPI-2, DWI subjects showed greater Hypochondriasis, Psychopathic Deviate, Paranoia, Psychasthenia, Schizophrenia and Hypomania; and lower Social introversion. Severe alcohol problems are more common in Beijing's drunk drivers than in the Chinese general population. These DWI drivers also have a broad variety of traits that increase their tendency to be venturesome and socially bold while enjoying excitement and risk-taking. (Am J Addict 2017;26:374-378).


Alkali metal diphenylmethanides: synthetic, computational and structural studies.
In search of new synthetic precursors for the preparation of alkaline earth organometallic compounds, we investigated the application of a powerful desilylation reaction to cleanly afford a variety of contact and charge-separated alkali metal derivatives without the difficulties commonly encountered in other methods. The resulting diphenylmethanides display both contact molecules and separated ion pairs. Analysis of the structural data demonstrates that simple electrostatic models are insufficient for predicting and explaining the solid-state structures of these complexes. Detailed computational investigations were performed to probe the nature of the metal-anion and metal-donor interactions and determine the contributions of each to the observed solid-state structures.


Repeatability of quantitative individual lesion and total disease multiparametric whole-body MRI measurements in prostate cancer bone metastases.
To assess the repeatability of quantitative multiparametric whole-body MRI (mpWB-MRI) parameters in advanced prostate cancer (APC) bone metastases. 1.5T MRI was performed twice on the same day in 10 APC patients. MpWB-MRI-included diffusion weighted imaging (DWI) and T1-weighted gradient-echo 2-point Dixon sequences. ADC and relative fat-fraction percentage (rFF%) maps were calculated, respectively. A radiologist delineated up to 10 target bone metastases per study. Means of ADC, b900 signal intensity(SI), normalised b900 SI, rFF% and maximum diameter (MD) for each target lesion and overall parameter averages across all targets per patient were recorded. The total disease volume (tDV in ml) was manually delineated on b900 images and mean global (g)ADC was derived. Bland-Altman analyses were performed with calculation of 95% repeatability coefficients (RC). Seventy-three individual targets (median MD 26 mm) were included. Lesion mean ADC RC was 12.5%, mean b900 SI RC 137%, normalised mean b900 SI RC 110%, rFF% RC 3.2 and target MD RC 5.5 mm (16.3%). Patient target lesion average mean ADC RC was 6.4%, b900 SI RC 104% and normalised mean b900 SI RC 39.6%. Target average rFF% RC was 1.8, average MD RC 1.3 mm (4.8%). tDV segmentation RC was 6.4% and mean gADC RC 5.3%. APC bone metastases' ADC, rFF% and maximum diameter, tDV and gADC show good repeatability. APC bone metastases' mean ADC and rFF% measurements of single lesions and global disease volumes are repeatable, supporting their potential role as quantitative biomarkers in metastatic bone disease.


Synthesis of new proteins associated with the induction of interferon in human fibroblast cells.
The relative amounts of translatable cellular mRNAs and newly synthesized cellular proteins were examined in poly(I) x poly(C)-induced human fibroblast cells early during induction. At this time interferon and interferon mRNA synthesis are maximal and cells have not acquired their antiviral thesis are maximal and cells have not acquired their antiviral state. Translation of the mRNA from poly(I) x poly(C)-induced cells in a wheat germ cell-free system led to the synthesis of a [35S]methionine-labeled 22,000-dalton protein that is precipitated by antiserum to highly purified human fibroblast interferon. The synthesis of this protein was detected only with the mRNA preparations that, when translated in Xenopus oocytes, coded for the synthesis of biologically active human interferon. Two-dimensional gel analysis of the [35S]methionine-labeled polypeptides translated from the total mRNA of the induced and uninduced cells revealed the presence of 23 new proteins that were translated from mRNAs of the induced cells but not from the mRNAs of the controls. These polypeptides ranged from 15,000 to 70,000 daltons. Thirteen of these proteins were detected in induced cells labeled with [35S]methionine. It is concluded that, in human fibroblasts, poly(I) x poly(C) induces, in addition to interferon, the synthesis of a variety of "interferon-associated" proteins.


Developmental changes in structural and functional properties of hippocampal AMPARs parallels the emergence of deliberative spatial navigation in juvenile rats.
The neural mechanisms that support the late postnatal development of spatial navigation are currently unknown. We investigated this in rats and found that an increase in the duration of AMPAR-mediated synaptic responses in the hippocampus was related to the emergence of spatial navigation. More specifically, spontaneous alternation rate, a behavioral indicator of hippocampal integrity, increased at the end of the third postnatal week in association with increases in AMPAR response duration at SC-CA1 synapses and synaptically driven postsynaptic discharge of CA1 pyramidal neurons. Pharmacological prolongation of glutamatergic synaptic transmission in juveniles increased the spontaneous alternation rate and CA1 postsynaptic discharge and reduced the threshold for the induction of activity-dependent synaptic plasticity at SC-CA1 synapses. A decrease in GluA1 and increases in GluA3 subunit and transmembrane AMPAR regulatory protein (TARP) expression at the end of the third postnatal week provide a molecular explanation for the increase in AMPAR response duration and reduced efficacy of AMPAR modulators with increasing age. A shift in the composition of AMPARs and increased association with AMPAR protein complex accessory proteins at the end of the third postnatal week likely "turns on" the hippocampus by increasing AMPAR response duration and postsynaptic excitability and reducing the threshold for activity-dependent synaptic potentiation.


Chylous ascites and pleural effusion secondary to constrictive pericarditis presenting with signs of lymphatic obstruction.
Chylous ascites is a clinical entity characterized by accumulation of milky fluid containing high amounts of triglycerides in the peritoneal cavity. The cause is usually lymphatic obstruction secondary to neoplastic processes. Constrictive pericarditis rarely causes cylous ascites through elevated venous pressure and lymphatic stasis. To the best of our knowledge, there is no report of constrictive pericarditis leading to chylous ascites in a patient presenting with objective lymphangiographic findings of lymphatic obstruction rather than stasis. We present a case of chylous ascites and pleural effusion secondary to constrictive pericarditis presenting with signs of lymphatic obstruction in lymphangio-graphy, in whom complete clinical and laboratory improvement was achieved after pericardiectomy.


Bioethics in the third millennium: some critical anticipations.
Its promises to the contrary notwithstanding, bioethics is plural. There is a diversity of content-full moral undertandings of the good and the right. Moreover, there is no secular means in principle to set this diversity aside without begging the question. This moral diversity exists both as a sociological condition and as a moral epistemological constraint. Without succumbing to a metaphysical scepticism or moral relativism, the bioethics of the future, if it is to be honest, should learn how to live with robust moral diversity.


A review of Glycogen Synthase Kinase-3 (GSK3) inhibitors for cancers therapies.
The intricate molecular pathways governing cancer development and progression have spurred intensive investigations into novel therapeutic targets. Glycogen Synthase Kinase-3 (GSK3), a complex serine/threonine kinase, has emerged as a key player with intricate roles in various cellular processes, including cell proliferation, differentiation, apoptosis, and metabolism. Harnessing GSK3 inhibitors as potential candidates for cancer therapy has garnered significant interest due to their ability to modulate key signalling pathways that drive oncogenesis. The review encompasses a thorough examination of the molecular mechanisms underlying GSK3's involvement in cancer progression, shedding light on its interaction with critical pathways such as Wnt/β-catenin, PI3K/AKT, and NF-κB. Through these interactions, GSK3 exerts influence over tumour growth, invasion, angiogenesis, and metastasis, rendering it an attractive target for therapeutic intervention. The discussion includes preclinical and clinical studies, showcasing the inhibitors efficacy across a spectrum of cancer types, including pancreatic, ovarian, lung, and other malignancies. Insights from recent studies highlight the potential synergistic effects of combining GSK3 inhibitors with conventional chemotherapeutic agents or targeted therapies, opening avenues for innovative combinatorial approaches. This review provides a comprehensive overview of the current state of research surrounding GSK3 inhibitors as promising agents for cancer treatment.


Influence of Surface Treatment on Magnetic Properties of Fe3O4 Nanoparticles Synthesized by Electrochemical Method.
The changes of magnetic properties in magnetite nanoparticles during two different stabilization processes were investigated. Magnetic nanoparticles (MNPs) were obtained by electrochemical synthesis from two kinds of salts: (CH3)4NCl and NaCl. After that, two methods-steric and electrostatic-were used to stabilize MNPs with oleic acid (OA) and sodium hydroxide (NaOH), respectively. As a consequence, aqueous and organic dispersions were obtained after surface modification. The coated nanoparticles were characterized by TEM, zeta potential, thermogravimetry analysis (TGA), cyclic voltammetry (CV), magnetization measurements, and infrared and Mössbauer spectroscopy. The results showed that the particles were between 8 and 13 nm in size. In addition, the MNPs were coated with negative charge layers from NaOH by physisorption and coated with carboxylate groups from OA by the chemisorption process, and hence, they exhibited different reactivity and behavior depending on the nature of the electrolyte used in the electrochemical synthesis. Furthermore, the uncoated and coated MNPs had a narrow size distribution. Additionally, the saturation magnetization values showed dependence on the magnetite synthesis conditions and surface modifiers.


Subcellular distribution of enzyme I of the Escherichia coli phosphoenolpyruvate:glycose phosphotransferase system depends on growth conditions.
The phosphoenolpyruvate:glycose phosphotransferase system (PTS) participates in important functions in the bacterial cell, including the phosphorylation/uptake of PTS sugars. Enzyme I (EI), the first protein of the PTS complex, accepts the phosphoryl group from phosphoenolpyruvate, which is then transferred through a chain of proteins to the sugar. In these studies, a mutant GFP, enhanced yellow fluorescent protein (YFP), was linked to the N terminus of EI, giving Y-EI. Y-EI was active both in vitro (>/=90% compared with EI) and in vivo. Unexpectedly, the subcellular distribution of Y-EI varied significantly. Three types of fluorescence were observed: (i) diffuse (dispersed throughout the cell), (ii) punctate (concentrated in numerous discrete spots throughout the cell), and (iii) polar (at one or both ends of the cell). Cells from dense colonies grown on agar plates with LB broth or synthetic (Neidhardt) medium showed primarily bipolar or punctate fluorescence. In liquid culture, under carefully defined carbon-limiting growth conditions [ribose (non-PTS), mannitol (PTS sugar), or dl-lactate], cellular levels of enzymatically active Y-EI remain essentially constant for each carbon source, but fluorescence distribution depends on C source, cell density, growth phase, and apparently on "conditioned medium." Fluorescence was diffuse during exponential growth on LB or ribose/Neidhardt medium. On ribose they became punctate in the stationary phase, reverting to diffuse when more ribose was added. In LB, both Y-EI and a nonphosphorylatable mutant, H189Q-Y-EI, showed a diffuse fluorescence during growth, but, shortly after the addition of isopropyl beta-d-thiogalactopyranoside, Y-EI became bipolar; H189Q-Y-EI did not. The functions of EI sequestration remain to be determined.


Diversity of Interstitial Lung Fibroblasts Is Regulated by Platelet-Derived Growth Factor Receptor α Kinase Activity.
Epithelial-mesenchymal cell interactions and factors that control normal lung development are key players in lung injury, repair, and fibrosis. A number of studies have investigated the roles and sources of epithelial progenitors during lung regeneration; such information, however, is limited in lung fibroblasts. Thus, understanding the origin, phenotype, and roles of fibroblast progenitors in lung development, repair, and regeneration helps address these limitations. Using a combination of platelet-derived growth factor receptor α-green fluorescent protein (PDGFRα-GFP) reporter mice, microarray, real-time polymerase chain reaction, flow cytometry, and immunofluorescence, we characterized two distinct interstitial resident fibroblasts, myo- and matrix fibroblasts, and identified a role for PDGFRα kinase activity in regulating their activation during lung regeneration. Transcriptional profiling of the two populations revealed a myo- and matrix fibroblast gene signature. Differences in proliferation, smooth muscle actin induction, and lipid content in the two subpopulations of PDGFRα-expressing fibroblasts during alveolar regeneration were observed. Although CD140α(+)CD29(+) cells behaved as myofibroblasts, CD140α(+)CD34(+) appeared as matrix and/or lipofibroblasts. Gain or loss of PDGFRα kinase activity using the inhibitor nilotinib and a dominant-active PDGFRα-D842V mutation revealed that PDGFRα was important for matrix fibroblast differentiation. We demonstrated that PDGFRα signaling promotes alveolar septation by regulating fibroblast activation and matrix fibroblast differentiation, whereas myofibroblast differentiation was largely PDGFRα independent. These studies provide evidence for the phenotypic and functional diversity as well as the extent of specificity of interstitial resident fibroblasts differentiation during regeneration after partial pneumonectomy.


Bayesian Geostatistical Analysis and Ecoclimatic Determinants of Corynebacterium pseudotuberculosis Infection among Horses.
Kansas witnessed an unprecedented outbreak in Corynebacterium pseudotuberculosis infection among horses, a disease commonly referred to as pigeon fever during fall 2012. Bayesian geostatistical models were developed to identify key environmental and climatic risk factors associated with C. pseudotuberculosis infection in horses. Positive infection status among horses (cases) was determined by positive test results for characteristic abscess formation, positive bacterial culture on purulent material obtained from a lanced abscess (n = 82), or positive serologic evidence of exposure to organism (≥ 1:512)(n = 11). Horses negative for these tests (n = 172)(controls) were considered free of infection. Information pertaining to horse demographics and stabled location were obtained through review of medical records and/or contact with horse owners via telephone. Covariate information for environmental and climatic determinants were obtained from USDA (soil attributes), USGS (land use/land cover), and NASA MODIS and NASA Prediction of Worldwide Renewable Resources (climate). Candidate covariates were screened using univariate regression models followed by Bayesian geostatistical models with and without covariates. The best performing model indicated a protective effect for higher soil moisture content (OR = 0.53, 95% CrI = 0.25, 0.71), and detrimental effects for higher land surface temperature (≥ 35°C) (OR = 2.81, 95% CrI = 2.21, 3.85) and habitat fragmentation (OR = 1.31, 95% CrI = 1.27, 2.22) for C. pseudotuberculosis infection status in horses, while age, gender and breed had no effect. Preventative and ecoclimatic significance of these findings are discussed.


Validation of travel times to hospital estimated by GIS.
An increasing number of studies use GIS estimates of car travel times to health services, without presenting any evidence that the estimates are representative of real travel times. This investigation compared GIS estimates of travel times with the actual times reported by a sample of 475 cancer patients who had travelled by car to attend clinics at eight hospitals in the North of England. Car travel times were estimated by GIS using the shortest road route between home address and hospital and average speed assumptions. These estimates were compared with reported journey times and straight line distances using graphical, correlation and regression techniques. There was a moderately strong association between reported times and estimated travel times (r = 0.856). Reported travel times were similarly related to straight line distances. Altogether, 50% of travel time estimates were within five minutes of the time reported by respondents, 77% were within ten minutes and 90% were within fifteen minutes. The distribution of over- and under-estimates was symmetrical, but estimated times tended to be longer than reported times with increasing distance from hospital. Almost all respondents rounded their travel time to the nearest five or ten minutes. The reason for many cases of reported journey times exceeding the estimated times was confirmed by respondents' comments as traffic congestion. GIS estimates of car travel times were moderately close approximations to reported times. GIS travel time estimates may be superior to reported travel times for modelling purposes because reported times contain errors and can reflect unusual circumstances. Comparison with reported times did not suggest that estimated times were a more sensitive measure than straight line distance.


"Sequential order" rules in generalized two-dimensional correlation spectroscopy.
The widely used "sequential order" rules in the generalized two-dimensional (2D) correlation spectroscopy were adopted from the mechanical perturbation-based 2D infrared, where dynamic spectral intensity variation must be a simple sinusoid. 2D correlation analysis is fundamentally a form of parametrization of the integrated or overall relationship between two variable quantities. In generalized 2D correlation spectroscopy, however, the dynamic spectral intensity variations are generally nonperiodic and monotonic, and spectral intensity changes are largely instantaneous. The sequential orders in generalized situations are therefore localized. It is naturally necessary and important to testify whether the analysis result obtained by using the sequential order rules is consistent with the local sequential order of events, which reflects the real sequential order in generalized situations. Unfortunately, this test was not done yet. In this report, the sequential order rules have been tested in the generalized situations using simulated spectra with different local sequential orders and assuming the intensity changes of bands take the exponential forms. It has been found that the sequential order rules correctly identify the local sequential order of two events when spectral intensities of two bands increase or decrease at the same direction but fail when spectral intensities change at different directions. In addition, 2D correlation analysis cannot distinguish the local sequential order from the rate difference of events. A theoretical analysis demonstrates that the synchronous and asynchronous spectra in the generalized 2D correlation spectroscopy may also indicate the linear/nonlinear relationship, in addition to the integrated or overall sequential order of events. The synchronous and asynchronous spectra in the generalized 2D correlation spectroscopy do not necessarily provide the information on the local sequential order or rate difference of events.


Observation of ultrafast nonequilibrium collective dynamics in warm dense hydrogen.
We investigate ultrafast (fs) electron dynamics in a liquid hydrogen sample, isochorically and volumetrically heated to a moderately coupled plasma state. Thomson scattering measurements using 91.8 eV photons from the free-electron laser in Hamburg (FLASH at DESY) show that the hydrogen plasma has been driven to a nonthermal state with an electron temperature of 13 eV and an ion temperature below 0.1 eV, while the free-electron density is 2.8x10{20} cm{-3}. For dense plasmas, our experimental data strongly support a nonequilibrium kinetics model that uses impact ionization cross sections based on classical free-electron collisions.


Synovial sarcoma with relevant immunocytochemistry and special emphasis on the monophasic fibrous variant.
Monophasic fibrous synovial sarcoma (SS) is the most common variant of SS. Only a few cytological studies are available on this entity. Bcl-2 protein expression has been described as a characteristic marker of SS and is useful for its differentiation from other sarcomas. Cytokeratin and CD99 are also used in detecting SS. To evaluate synovial sarcoma and its variants cytomorphologically. During a period of 10 years 7 months, i.e. from January 1998 to July 2008, 12 cytologic specimens diagnosed as synovial sarcoma were reviewed. Ten cases were diagnosed as SS on aspiration alone but two cases required ancillary technique i.e., immunocytochemistry staining with bcl-2 and cytokeratin. The smears were stained with Papanicolaou and May-Grünwald-Giemsa stains. All cytologic specimens in our study had similar appearance. Most smears were highly cellular and were made up of densely packed tri-dimensional groups and singly scattered round to oval cells. Cellular monomorphism and vascular channels within the cell groups were the remarkable findings. Only one case showed cytologic evidence of epithelial differentiation. Bcl-2, cytokeratin, CD99 positivity was seen on immunohistochemistry staining. Results were categorized according to age, sex and morphologic variants. Although cytomorphologic features of synovial sarcomas are characteristic enough to permit its recognition, clinical correlation is necessary for accurate diagnosis. Monophasic variant is the most common entity observed in the present study.


Sulfonamides: a patent review (2008 - 2012).
The primary sulfonamide moiety is present in many clinically used drugs, such as diuretics (furosemide, indapamide, chlorthalidone, thiazides); carbonic anhydrase (CA) inhibitors (CAIs) (including acetazolamide, dichlorophenamide, dorzolamide and brinzolamide); antiepileptics (zonisamide and sulthiame); the antipsychotic sulpiride and the cycloxygenase 2 (COX2) inhibitors celecoxib and valdecoxib. Recently, novel drugs have been launched, such as apricoxib and pazopanib, which also incorporate this group. The article presents the main classes of sulfonamides investigated between 2008 and 2012. Specifically, the authors review the scientific and patent literature on CAIs, COX2 inhibitors, pazopanib and its congeners, which are multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit. Most patents deal with sulfonamide CAIs incorporating NO-donating moieties as antiglaucoma agents, or with compounds targeting the tumor-associated isoforms CA IX/XII. The antidandruff actions of sulphonamides, which inhibit yeast CAs, were also claimed. Apricoxib (a COX2 inhibitor) and pazopanib, a tyrosine kinase inhibitor, show significant antitumor activity and several patents deal with these drugs. There is a constant need of novel sulfonamides to act as selective antiglaucoma drugs (targeting CA II), as antitumor agents/diagnostic tools (targeting CA IX/XII), and to treat and diagnose other disease. This privileged structural motif is likely to be present in other drugs in the future.


Tympanostomy tube insertion practice in under-18-year-olds in the South African private healthcare sector insured by Discovery Health.
The reported rates of tympanostomy tube insertion (TTI) in children vary significantly internationally. Lack of adherence to evidence-based clinical guidelines may contribute to these differences. To study the rates of TTI in South Africa (SA) in children ≤18 years old in the private healthcare sector, both nationally and regionally, to compare these with international TTI rates, and to determine the use of preoperative audiometry and tympanometry. A retrospective analysis was done of data obtained from the Discovery Health database. Rates of TTI were analysed nationally and regionally and in different age groups, as was the use of tympanometry and audiograms. The SA TTI rates were much higher than published international rates except for the 0 - 1-year age group in Canada and Denmark and the 0 - 15-year age group in Denmark. There was a statistically significant regional variation in TTI rates as well as in the use of preoperative audiometry and tympanometry. SA private sector TTI rates are high by international standards. Significant regional variations may indicate over- or underservicing in certain regions. Further investigation of causes for the high TTI rate and regional variations is recommended. Education of healthcare professionals on recognised indications for TTI may improve patient selection.


Symptomatic retention of the Agile® patency capsule.
The Agile® capsule has shown to be useful when evaluating the patency of the small bowel in patients prior to capsule endoscopy studies. It is a safe tool and a low rate of complications have been reported, highlighting symptomatic retention, although references in literature are scarce and it is only observed in 1.2% of the procedures. We present the case of a symptomatic retention of this device in a patient with previously known colonic Crohn's disease in who a small bowel study was indicated and was sent for prior patency test.


Electrostatic Switch Function in the Mechanism of Protein Kinase A Iα Activation: Results of the Molecular Dynamics Simulation.
We used molecular dynamics to find the average path of the A-domain H → B conformational transition in protein kinase A Iα. We obtained thirteen productive trajectories and processed them sequentially using factor and cross-correlation analyses. The conformational transition is presented as partly deterministic sequence of six events. Event B represents H → B transition of the phosphate binding cassette. Main participants of this event form electrostatic switch cAMP(O6)-A202(N-H)-G199(C=O). Through this switch, cAMP transmits information about its binding to hydrophobic switch L203-Y229 and thus triggers conformational transition of A-domain. Events C and D consist in N3A-motif displacement towards phosphate binding cassette and B/C-helix rotation. Event E involves an increase in interaction energy between Y229 and β-subdomain. Taken together, events B, E, and D correspond to the hinge movement towards β-barrel. Transition of B/C-helix turn (a.a. 229-234) from α-form to π-form accounts for event F. Event G implies that π-helical turn is replaced by kink. Emerging in the resulting conformation, electrostatic interaction R241-E200 facilitates kink formation. The obtained data on the mechanism of cAMP-dependent activation of PKA Iα may contribute to new approaches to designing pharmaceuticals based on cAMP analogs.


Tolerability and efficacy of gamma knife radiosurgery on hepatocellular carcinoma with portal vein tumor thrombosis.
This is a retrospective study on the safety and efficacy of gamma knife radiosurgery (GKR) in treating hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). Patients with confirmed HCC and PVTT were allocated into two groups based on the treatments they received (palliative or GKR). A total of 138 patients were included (74 in the palliative group, 64 in GKR group). No significant differences in baseline characteristics existed between the two groups. Treatment-related adverse events (AEs) were recorded and compared between groups. The majority of AEs were mild to moderate and subsided naturally or after medication. There was no AE-induced death. The influences of baseline characteristics and treatment options on patients' OS were analyzed. The median OS of patients in the palliative and GKR group were 3.0 months (95% CI: 2.719-3.281) and 6.1 months (95% CI: 4.706-7.494) respectively (p = 0.003). Multivariate analysis revealed that GKR treatment, performance status 0-1, Child A, smaller tumor diameter and monolobar distribution were significant favorable prognosticators. Subgroup analyses showed OS benefit of GKR regardless of PVTT location (main or branch of PVTT). In conclusion, GKR is well tolerated in selected HCC-PVTT patients and can confer OS benefit, which needs validation in future prospective studies.


Treatment options for stent restenosis: insights from intracoronary imaging, clinical trials, and registries.
Although drug-eluting stents (DES) have markedly reduced the incidence of stent restenosis (SR), the increased number and complexity of percutaneous coronary interventions performed worldwide explain the sustained prevalence of SR. Intracoronary imaging techniques remain essential tools to unravel the underlying mechanical causes potentially leading to SR. Current clinical trial data suggest that DES are the most effective therapy for the management of both bare-metal stents SR and DES-SR. In this setting, however, drug-eluting balloons represent a valid therapeutic alternative with the attractive advantage of not requiring the implantation of an additional metallic layer. In this review, we will discuss trial data on the historical evolution and the evidence supporting currently available therapeutic modalities for patients with bare-metal stents SR or DES-SR.


[Association of osteopontin gene polymorphism with lupus nephritis in Chinese Han population].
To investigate the possible association of a single nucleotide polymorphism (SNP) at position 9250 in exon 7 of osteopontin gene (OPN gene 9250) with lupus nephritis (LN) in southern Chinese patients. Altogether 109 patients with LN (12 males and 97 females) diagnosed according to the American College of Rheumatology criteria (revised in 1982) for systemic lupus erythematosus (SLE) and 180 healthy ethnically matched controls (34 males and 146 females), all Han people living in South China, were enrolled in this study with informed consent. Blood samples from all subjects were collected in EDTA tube for genomic DNA extraction according to the standard isolation procedures. OPN gene 9250 polymorphism was typed by PCR-restriction fragment length polymorphism (PCR-RFLP). All the genotype frequencies of OPN gene 9250 were in Hardy-Weinberg equilibrium. Compared with the controls, LN patients showed significantly lower frequency of TT genotype of OPN gene 9250 (70% vs 51%, P<0.05) and significantly higher frequency of TC genotype (29.4% vs 45%, P<0.05). There were significant differences in OPN gene 9250 allele and phenotype frequencies between LN patients and the controls (P<0.05). Compared with the female controls, the frequency of TT genotype of OPN gene 9250 was significantly lower in female LN patients (68.5% vs 54%, P<0.05), and there was a significant difference in OPN gene 9250 allele frequency between them (P<0.05). OPN gene 9250 polymorphism appears to be associated with the susceptibility to LN in southern Chinese Han population.


An evaluation of gender differences in the implementation and impact of a comprehensive approach to domestic violence.
The primary goal of society's response to domestic violence is the protection of the victim from further abuse. Recently, the coordinated community response (CCR) has been developed as one example of an approach aimed at reaching this goal. Prior research has generally found support for the model, with male offenders recidivating at lower rates. The current study examines whether a comprehensive, community-based approach is capable of reducing recidivism rates among male and female offenders. Comparisons are made between 70 female and 131 male offenders. Specific attention is given to the intervention process, including differences in service or treatment component completion and recidivism by gender.


Effects of land-use patterns on the biogeography of the sediment bacteria in the Yarlung Tsangpo River.
Bacteria communities, as key drivers of energy flow and nutrient recycling in rivers, usually consist of a few abundant taxa and many rare taxa. During the last decades, rivers on the Tibetan Plateau have experienced dramatic land surface changes under climate change and anthropogenic disturbances. However, the responses of abundant and rare taxa to such changes and disturbances still remains unclear. In this study, we explored the biogeography and drivers of the abundant and rare bacteria in Yarlung Tsangpo River sediments on the Tibetan Plateau. Our study demonstrated that changes in surrounding land-use patterns, especially in forest land, bare land and cropland, had profound influences on the distribution of the abundant and rare sediment bacteria in the Yarlung Tsangpo River. Although both communities exhibited significant distance-decay patterns, dispersal limitation was the dominant process in the abundant community, while the rare community was mainly driven by heterogeneous selection. Our results also revealed that the abundant bacteria exhibited stronger adaptation across environmental gradients than the rare bacteria. The similar biogeographic patterns but contrasting assembly processes in abundant and rare communities may result from the differences in their environmental adaptation processes. This work provides valuable insights into the importance of land surface changes in influencing the biogeographic patterns of bacteria in fluvial sediments, which helps to predict their activities and patterns in Tibetan rivers under future global climate change and anthropogenic disturbances.


Effect of Treatment with Thyme Extract on Urinary Levels of Melatonin in an Experimental Autoimmune Encephalomyelitis Mouse Model.
Thymus vulgaris, or thyme belongs to the Lamiaceae family of aromatic plant species and has established antioxidant and anti-inflammatory properties. We examined the association between thyme extract treatment to recovered urinary levels of melatonin, a hormone with neuroprotective effects, in mice induced with EAE. Eight B6 mice induced with EAE were randomized into two groups and exposed to either 50 mg/kg of thyme extract or PBS. After EAE induction, mice were injected i.p every other day from day 0 to 21. Four B6 mice without EAE were considered the healthy control group. Urine samples were collected consecutively for two 24 h periods on day 19 and 20. We examined whether thyme extract treatment modified urinary melatonin sulfate concentration (ng/mL) in EAE-induced mice using an ELISA. The clinical score and body weight in thyme-treated EAE group were significantly lower in comparison to the EAE control group at indicated time points. The urinary melatonin concentration was significantly lower in the EAE control group compared to the healthy mice. There was no significant difference between thyme-treated and EAE groups regarding the urine melatonin concentration. Our results show that exposing EAE mice to thyme extract improved their clinical symptoms, however, there was no significant effect on urinary melatonin concentration.


Tetrazine-trans-cyclooctene Mediated Conjugation of Antibodies to Microtubules Facilitates Subpicomolar Protein Detection.
Engineering cargo-loading strategies is crucial to developing nanotechnological applications of microtubule-based biomolecular transport systems. Here, we report a highly efficient and robust bioconjugation scheme to load antibodies to microtubules. Our method takes advantage of the inverse-electron-demand Diels-Alder addition reaction between tetrazine and trans-cyclooctene: the fastest known bioorthogonal reaction, characterized by its excellent selectivity and biocompatibility. As proof of concept, we performed kinesin-1 gliding motility assays with antibody-conjugated microtubules and demonstrated the highly sensitive detection of fluorescent protein analyte down to 0.1 pM in microliter sample volumes. Importantly, the detection selectivity was retained in the presence of other fluorescent background proteins. We envision the applicability of our fast, simple, and robust conjugation method to a wide range of biosensing platforms based on biomolecular transport systems.


Theoretical studies on cycloaddition reactions between 2-azoniaallene cations and olefins.
The mechanisms of cycloaddition reactions between 2-azoniaallene cations and olefins have been explored at the B3LYP/6-31G level. It is found that the positive charge in 2-azoniaallene makes the reaction more complicated. For the reactions between olefins with Cl groups or CH(3) groups and 2-azoniaallene, the typical carboniums have been located along the reaction path. In addition, for the reactions between 1,1-dimethylethene and 1,3-dichrolo-2-azoniaallene, different paths and products have been rationalized and verified.


How do astrocytes participate in neural plasticity?
Work over the past 20 years has implicated electrically nonexcitable astrocytes in complex neural functions. Despite controversies, it is increasingly clear that many, if not all, neural processes involve astrocytes. This review critically examines past work to identify the commonalities among the many published studies of neuroglia signaling. Although several studies have shown that astrocytes can impact short-term and long-term synaptic plasticity, further work is required to determine the requirement for astrocytic Ca(2+) and other second messengers in these processes. One of the roadblocks to the field advancing at a rapid pace has been technical. We predict that the novel experimental tools that have emerged in recent years will accelerate the field and likely disclose an entirely novel path of neuroglia signaling within the near future.


Characterization of K(ATP) channels in intact mammalian skeletal muscle fibres.
1. The aim of this study was to characterize the K(ATP) channel of intact rat skeletal muscle (rat flexor digitorum brevis muscle). Changes in membrane currents were recorded with two-electrode voltage-clamp of whole fibres. 2. The K(ATP) channel openers, levcromakalim and pinacidil (10-400 microM), caused a concentration-dependent increase in whole-cell chord conductance (up to approximately 1.5 mScm(-2)). The activated current had a weak inwardly rectifying current-voltage relation, a reversal potential near E(K) and nanomolar sensitivity to glibenclamide--characteristic of a K(ATP) channel current. Concentration-effect analysis revealed that levcromakalim and pinacidil were not particularly potent (EC50 approximately 186 microM, approximately 30 microM, respectively), but diazoxide was completely inactive. 3. The ability of both classical K(ATP) channel inhibitors (glibenclamide, tolbutamide, glipizide and 5-hydroxydecanoic acid) and a number of structurally related glibenclamide analogues to antagonize the levcromakalim-induced current was determined. Glibenclamide was the most potent compound with an IC50 of approximately 5 nM. However, the non-sulphonylurea (but cardioactive) compound 5-hydroxydecanoic acid was inactive in this preparation. 4. Regression analysis showed that the glibenclamide analogues used have a similar rank order of potency to that observed previously in vascular smooth muscle and cerebral tissue. However, two compounds (glipizide and DK13) were found to have unexpectedly low potency in skeletal muscle. 5. These experiments revealed K(ATP) channels of skeletal muscle to be at least 10x more sensitive to glibenclamide than previously found; this may be because of the requirement for an intact intracellular environment for the full effect of sulphonylureas to be realised. Pharmacologically, K(ATP) channels of mammalian skeletal muscle appear to resemble most closely K(ATP) channels of cardiac myocytes.


Molecular basis of the high-affinity activation of type 1 ryanodine receptors by imperatoxin A.
Both imperatoxin A (IpTx(a)), a 33-residue peptide toxin from scorpion venom, and peptide A, derived from the II-III loop of dihydropyridine receptor (DHPR), interact specifically with the skeletal ryanodine receptor (RyR1), which is a Ca(2+)-release channel in the sarcoplasmic reticulum, but with considerably different affinities. IpTx(a) activates RyR1 with nanomolar affinity, whereas peptide A activates RyR1 at micromolar concentrations. To investigate the molecular basis for high-affinity activation of RyR1 by IpTx(a), we have determined the NMR solution structure of IpTx(a), and identified its functional surface by using alanine-scanning analogues. A detailed comparison of the functional surface profiles for two peptide activators revealed that IpTx(a) exhibits a large functional surface area (approx. 1900 A(2), where 1 A=0.1 nm), based on a short double-stranded antiparallel beta-sheet structure, while peptide A bears a much smaller functional surface area (approx. 800 A(2)), with the five consecutive basic residues (Arg(681), Lys(682), Arg(683), Arg(684) and Lys(685)) being clustered at the C-terminal end of the alpha-helix. The functional surface of IpTx(a) is composed of six essential residues (Leu(7), Lys(22), Arg(23), Arg(24), Arg(31) and Arg(33)) and several other important residues (His(6), Lys(8), Arg(9), Lys(11), Lys(19), Lys(20), Gly(25), Thr(26), Asn(27) and Lys(30)), indicating that amino acid residues involved in RyR1 activation make up over the half of the toxin molecule with the exception of cysteine residues. Taken together, these results suggest that the site where peptide A binds to RyR1 belongs to a subset of macrosites capable of being occupied by IpTx(a), resulting in differing the affinity and the mode of activation.


Discrepancies between nitroglycerin and NO-releasing drugs on mitochondrial oxygen consumption, vasoactivity, and the release of NO.
It has been generally acknowledged that the actions of glyceryl trinitrate (GTN) are a result of its bioconversion into NO. However, recent observations have thrown this idea into doubt, with many studies demonstrating that NO is present only when there are high concentrations of GTN. We have explored this discrepancy by developing a new approach that uses confocal microscopy to directly detect NO. Intracellular levels of NO in the rat aortic vascular wall have been compared with those present after incubation with 3 different NO donors (DETA-NO, 3-morpholinosydnonimine, and S-nitroso-N-acetylpenicillamine), endothelial activation with acetylcholine, or administration of GTN. We have also evaluated the relaxant effects of these treatments on isolated rings of aorta following activation of the enzyme soluble guanylyl cyclase and their inhibitory action on mitochondrial respiration, which is an index of the interaction of NO with the enzyme of the electron transport chain cytochrome C oxidase. In the case of the various NO donors and acetylcholine, we detected a concentration-dependent relationship in the intensity of vascular relaxation and degree of NO fluorescence and an increase in the Michaelis constant (Km) for O2. GTN did not produce similar effects, and although clinically relevant concentrations of this compound caused clear, concentration-related relaxations, there was neither any increase in NO-related fluorescence nor an augmented Km for O2. The nature of these differences suggests that these concentrations of GTN do not release free NO but probably a different species that, although it interacts with soluble guanylyl cyclase in vascular smooth muscle, does not inhibit O2 consumption by vascular mitochondria.


Covariate-adjusted response-adaptive designs for binary response.
An adaptive allocation design for phase III clinical trials that incorporates covariates is described. The allocation scheme maps the covariate-adjusted odds ratio from a logistic regression model onto [0, 1]. Simulations assume that both staggered entry and time to response are random and follow a known probability distribution that can depend on the treatment assigned, the patient's response, a covariate, or a time trend. Confidence intervals on the covariate-adjusted odds ratio is slightly anticonservative for the adaptive design under the null hypothesis, but power is similar to equal allocation under various alternatives for n = 200. For similar power, the net savings in terms of expected number of treatment failures is modest, but enough to make this design attractive for certain studies where known covariates are expected to be important and stratification is not desired, and treatment failures have a high ethical cost.


Can diffusion- and perfusion-weighted imaging alone accurately triage anterior circulation acute ischemic stroke patients to endovascular therapy?
Acute ischemic stroke (AIS) patients who benefit from endovascular treatment have a large vessel occlusion (LVO), small core infarction, and salvageable brain. We determined if diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) alone can correctly identify and localize anterior circulation LVO and accurately triage patients to endovascular thrombectomy (ET). This retrospective cohort study included patients undergoing MRI for the evaluation of AIS symptoms. DWI and PWI images alone were anonymized and scored for cerebral infarction, LVO presence and LVO location, DWI-PWI mismatch, and ET candidacy. Readers were blinded to clinical data. The primary outcome measure was accurate ET triage. Secondary outcomes were detection of LVO and LVO location. Two hundred and nineteen patients were included. Seventy-three patients (33%) underwent endovascular AIS treatment. Readers correctly and concordantly triaged 70 of 73 patients (96%) to ET (κ=0.938; P=0.855) and correctly excluded 143 of 146 patients (98%; P=0.942). DWI and PWI alone had a 95.9% sensitivity and a 98.4% specificity for accurate endovascular triage. LVO were accurately localized to the ICA/M1 segment in 65 of 68 patients (96%; κ=0.922; P=0.817) and the M2 segment in 18 of 20 patients (90%; κ=0.830; P=0.529). AIS patients with anterior circulation LVO are accurately identified using DWI and PWI alone, and LVO location may be correctly inferred from PWI. MRA omission may be considered to expedite AIS triage in hyperacute scenarios or may confidently supplant non-diagnostic or artifact-limited MRA.


Design, synthesis and pharmacological screening of β-amino-, thiadiazole/thiadiazine-phosphonate based triazole motifs as antimicrobial/cytotoxic agents.
Three different series of phosphonate derivatives, β-amino- and fused thiadiazolo/thiadiazine-phosphonates have been synthesized using the addition and/or addition-cyclization protocol of Horner-Wadsworth-Emmons (HWE) reagents to 1,2,4-triazole-3-thiols. The design of potentially antimicrobial and anticancer phosphor esters relied on the results of computer-assisted molecular modeling. All synthesized phosphonates were evaluated for their in vitro antimicrobial activities while anticancer properties were determined for eight out of twenty new phosphonates. The tested phosphonates, except for compounds that have a nitrile moiety, exhibited moderate to significant antimicrobial activity. Nevertheless, the most active compounds were fused thiadiazole-phosphonates, which inhibited the growth of both Gram-negative and Gram-positive bacteria better than β-aminophosphonates and fused thiadiazolophosphonates. In parallel, the antitumor activity screenings of selected phosphonates from each series and substrate 1 were also done. Their antitumor properties against ten carcinoma cell lines, including breast (MCF7, MDA-MB- 231/ ATCC, MDA-MB-435, BT-549), ovarian (IGROVI, OVCAR-3, SK-OV-3), prostate (PX-3, PU-145), and liver (HEPG2), were investigated. The results showed that all synthesized compounds reflected remarkable antitumor activity against breast (especially MDA-MB-231/ATCC and BT-549), and prostate carcinoma cell lines (PC-3 and DU-145), whereas a moderate to good effect on ovarian and liver cancer cells was observed.


Sustained attention and response inhibition in young children at risk for Attention Deficit/Hyperactivity Disorder.
Studies of school-aged children, adolescents, and adults with Attention Deficit/Hyperactivity Disorder (ADHD) have variably shown ADHD-related impairment in both inhibitory control and sustained attention. However, few studies have examined ADHD-associated patterns of performance on these tasks among younger children (below age 7 years). A combined continuous performance test and go/no-go task (CPT/GNG) and the Day-Night Stroop Task (DNST) were administered to an ethnically diverse sample of 3.44- to 6.95-year-old children rated by parents and teachers as being either high risk or low risk for ADHD. All children performed the DNST (N = 71) and a subset of the sample (N = 44) performed the CPT/GNG. Analyses assessed task validity as well as the effects of age and risk status. Significant main effects for age and risk status were found on all tasks. In addition, age x condition interactions were found for the CPT and DNST, which suggest that the tasks were sensitive to age-related changes in sustained attention and inhibitory control respectively. No significant risk status x condition interactions were found, suggesting that young children at risk for ADHD do not exhibit specific deficits in either inhibitory control or sustained attention. The most consistent effect related to risk status across tasks was the greater number of errors and longer and more variable reaction times on the part of children at risk for ADHD irrespective of condition. ADHD-associated decrements in performance on these tasks appear to be attributable either to generalized behavioral dysregulation or poor state regulation rather than to deficient inhibitory control.


Regions of poliovirus protein VP1 produced in Escherichia coli induce neutralizing antibodies.
Poliovirus type 1 cDNA was prepared from viral RNA encoding the VP1 capsid region of the virus by using a specific DNA primer and was cloned in Escherichia coli. DNA fragments corresponding to VP1 amino acid positions 129 to 302 (pPM5k3), 52 to 302 (pPMhae3), and 24 to 129 (pPMDxba) were incorporated into plasmid vectors designed to express Trp LE-poliovirus VP1 fusion proteins under the control of the inducible tryptophan promoter-operator system. Induction of bacterial cultures containing the plasmids resulted in the production of fusion proteins which accounted for 21% (pPMhae3), 68% (pPM5k3), and 27% (pPMDxba) of the total cell protein. The proteins were purified, and each reacted with polyclonal antibodies raised against intact virions as measured by an enzyme-linked immunosorbent assay. The sera from rabbits immunized with the bacterially produced fusion proteins pPMDxba and pPMhae3 contained poliovirus-neutralizing antibodies.


Gemcitabine 5'-triphosphate is a stoichiometric mechanism-based inhibitor of Lactobacillus leichmannii ribonucleoside triphosphate reductase: evidence for thiyl radical-mediated nucleotide radical formation.
Ribonucleoside triphosphate reductase (RTPR) from Lactobacillus leichmannii utilizes adenosylcobalamin and catalyzes the conversion of nucleoside triphosphates to deoxynucleoside triphosphates. One equivalent of 2',2'-difluoro-2'-deoxycytidine 5'-triphosphate, F2dCTP, rapidly inactivates RTPR. Analysis of the reaction products reveals that inactivation is accompanied by release of two fluoride ions and 0.84 equiv of 5'-deoxyadenosine and attachment of 1 equiv of corrin covalently to an active-site cysteine residue of RTPR. No cytosine release was detected. Proteolysis of corrin-labeled RTPR with endoproteinase Glu-C and peptide mapping at pH 5.8 revealed that C419 was predominantly modified. The kinetics of the inactivation have been examined by stopped-flow (SF) UV-vis spectroscopy and rapid freeze quench (RFQ) electron paramagnetic resonance (EPR) spectroscopy. Monitoring DeltaA525 nm shows that cob(II)alamin is formed with an apparent kobs of 50 s-1, only 2. 5-fold slower than a similar experiment carried out with cytidine 5'-triphosphate (CTP). The same reaction mixture was thus quenched at times from 22 ms to 30 s and examined by EPR spectroscopy. At early time points the EPR spectrum resembled a thiyl radical exchange coupled to cob(II)alamin. From 22 to 255 ms the total spin concentration remained unchanged at 1.4 spins/RTPR, twice that predicted by the amount of cob(II)alamin determined by SF. However, with time the signal attributed to the thiyl radical-cob(II)alamin disappears and new signal(s) with broad feature(s) at g = 2.33 and a sharp feature at g = 2.00 appeared, suggesting formation of cob(II)alamin and a nucleotide-based radical with only dipolar interactions. These studies have been interpreted to support the proposal that an RTPR-based thiyl radical can give rise to a nucleotide-based radical.


Numerical and structural chromosomal anomalies in undifferentiated pleomorphic sarcoma.
Malignant fibrous histiocytoma (MFH) or undifferentiated pleomorphic sarcoma (UPS) is the most common soft-tissue sarcoma of late adult life. Further advances in genetic characterization are warranted. The aim of this study was to search for numerical and structural chromosomal anomalies in UPS. We investigated five sarcoma-specific chromosomal translocations, five oncogene amplifications as well as the numerical karyotype of 19 UPS samples and one UPS/MFH cell line (U2197) using FISH probes on interphase nuclei. Our results demonstrate that chromosomal translocations involving CHOP, SYT, EWS, FUS and FKHR genes are absent. Furthermore, amplification of ERBB2 (10.5%) and MDM2 (10.5%) was observed whereas the EGFR, C-MYC and N-MYC genes were not amplified. Interestingly, predominant aneuploidies were found in eight chromosomes. The data demonstrate rarity of sarcoma-specific chromosomal breaks and oncogene amplifications in UPS, yet polysomic chromosomes appear more characteristically in this condition.


Purine Release, Metabolism, and Signaling in the Inflammatory Response.
ATP, NAD+, and nucleic acids are abundant purines that, in addition to having critical intracellular functions, have evolved extracellular roles as danger signals released in response to cell lysis, apoptosis, degranulation, or membrane pore formation. In general ATP and NAD+ have excitatory and adenosine has anti-inflammatory effects on immune cells. This review focuses on recent advances in our understanding of purine release mechanisms, ectoenzymes that metabolize purines (CD38, CD39, CD73, ENPP1, and ENPP2/autotaxin), and signaling by key P2 purinergic receptors (P2X7, P2Y2, and P2Y12). In addition to metabolizing ATP or NAD+, some purinergic ectoenzymes metabolize other inflammatory modulators, notably lysophosphatidic acid and cyclic GMP-AMP (cGAMP). Also discussed are extracellular signaling effects of NAD+ mediated by ADP-ribosylation, and epigenetic effects of intracellular adenosine mediated by modification of S-adenosylmethionine-dependent DNA methylation.


Autologous tooth transplantation to replace molars lost in patients with juvenile periodontitis.
A method is described to replace perodontally destroyed first molars in patients with juvenile periodontitis by auto-transplantation of third molars. Fifteen molars which had been extracted due to periodontal destruction were replaced by autologous third molars with incomplete root formation. The patients were then observed for a period up to 7 years. In all cases complete regeneration of the alveolar bone took place and radiographically a normal periodontal membrane was extablished. All of the transplanted teeth continued their root formation and there was no radiographic evidence for root resorption, ankylosis or necrosis of the pulp. None of the transplanted teeth displayed pocket depths over 3 mm and no abnormal mobility was detectable.


Adsorption Process of Various Antimicrobial Peptides on Different Surfaces of Cellulose.
Current antimicrobial challenges in hospitals, pharmaceutical production units, and food packaging have motivated the development of antimicrobial agents, among them the antimicrobial compounds based on cellulose and peptides. Herein, we develop molecular dynamics (MD) models to dissect and characterize the adsorption process of antimicrobial peptides (AMPs) such as protegrin 1, magainin 2, and cyclic indolicidin on various surfaces of cellulose including [-1-10], [1-10], [-100], [100], [-110], and [110]. Our results suggest that the magainin 2 antimicrobial peptide loses most of its initial helix form, spreads on the cellulose surface, and makes the most rigid structure with [110] surface. The cyclic indolicidin peptide has the lowest affinity to adsorb on the cellulose surfaces, and the protegrin 1 peptide successfully adsorbs on all the proposed cellulose surfaces. Our MD simulations confirmed that cellulose can improve the corresponding peptides' structural stability and change their secondary structures during adsorption. The [-1-10] and [100] surfaces of cellulose show considerable affinity against the AMPs, exhibiting greater interactions with and adsorption to the peptides. Our data imply that the stronger adsorptions are caused by a set of H-bonds, van der Waals, and electrostatic interactions, where van der Waals interactions play a prominent role in the stability of the AMP-cellulose structures. Our energy analysis results suggest that glutamic acid and arginine amino acids have key roles in the stability of AMPs on cellulose surfaces due largely to stronger interactions with the cellulose surfaces as compared with other residues. Our results can provide useful insight at the molecular level that can help design better antimicrobial biomaterials based on cellulose.


Diagnosis of Non-small Cell Lung Cancer for Early Stage Asymptomatic Patients.
In 2016 in the United States, 7 of 10 patients were estimated to die following lung cancer diagnosis. This is due to a lack of a reliable screening method that detects early-stage lung cancer. Our aim is to accurately detect early stage lung cancer using algorithms and protein biomarkers. A total of 1,479 human plasma samples were processed using a multiplex immunoassay platform. 82 biomarkers and 6 algorithms were explored. There were 351 NSCLC samples (90.3% Stage I, 2.3% Stage II, and 7.4% Stage III/IV). We identified 33 protein biomarkers and developed a classifier using Random Forest. Our test detected early-stage Non-Small Cell Lung Cancer (NSCLC) with a 90% accuracy, 80% sensitivity, and 95% specificity in the validation set using the 33 markers. A specific, non-invasive, early-detection test, in combination with low-dose computed tomography, could increase survival rates and reduce false positives from screenings.


Comparison of urinary iodine excretion in neonates and their mothers in Isfahan, Iran.
To determine the urinary iodine excretion of neonates (28 days of age or younger) and their mothers in Isfahan, a centrally located city in Iran, in 1997 after 8 years of iodized salt distribution in an effort to ameliorate iodine deficiency. Through a cross-sectional study and by means of convenient sampling, 146 mother-neonate pairs were selected among neonates born in Shahid Sadoughi Hospital in Isfahan. In order to eliminate the effect of povidone-iodine on breast milk and urinary iodine, Savlon antiseptic solution was used in normal vaginal delivery and on the umbilical cord. Normal values of urinary iodine concentration for the mothers and their neonates were > or = 10.0 microg/dL and >5.0 microg/dL, respectively. The data were analyzed and compared by the Student t test and Pearson correlation coefficient in SPSS software. P values <0.05 were considered statistically significant. In only 3% of the neonates and 14% of the mothers, urinary iodine excretion was below the normal range. No mother or neonate had severe iodine deficiency. In 2% of the mothers and 2% of the neonates, mild iodine deficiency was found. The mean urinary iodine concentration of neonates whose mothers were iodine deficient was significantly lower than that of neonates whose mothers were iodine sufficient (17.34 +/- 7.83 microg/dL versus 22.21 +/- 7.57 microg/dL; P<0.01). A direct significant correlation was noted between the urinary iodine excretion of neonates and that of their mothers (r = 0.37; P<0.01). The urinary iodine excretion in mothers paralleled the urinary iodine concentration of their neonates. If urinary iodine concentration is considered an index of total body iodine content, this study demonstrated that prolonged iodized salt intake has minimized the occurrence of iodine deficiency in Isfahan.


The present profile of chronic hepatitis B virus infection highlights future challenges: An analysis of the Multicenter Italian MASTER-B cohort.
Chronic hepatitis B virus (HBV) infection remains a primary cause of morbidity and mortality worldwide. The study is aimed at updating the clinical and epidemiological profile of chronic HBV infection in Italy. A cross-sectional multicenter prospective study enrolled consecutive HBsAg positive patients seen in 73 Italian centers in the period 2012-2015. Individual patient data were collected using an electronic platform and analyzed using standard statistical methods. Among 2877 HBsAg positive individuals (median age 49.8 years, 68% males), 27% were non-Italian natives (NINs); 20% had chronic infection, 58.5% chronic hepatitis and 21.5% cirrhosis. Among NINs, age was younger, male gender was less prevalent and liver disease less advanced than in Italians (all p < 0.0001). HBeAg positive cases were 23.6% among NINs vs 8.2% in Italians (p < 0.0001); HDV coinfections 11.1% vs 7.3% (p = 0.006) and HCV coinfections 2.3% vs 4.2% (p = 0.017), respectively. Anti-HDV or anti-HCV antibodies were detected more frequently in patients with cirrhosis. Fifty percent of NINs with cirrhosis were aged below 45 years. The study offers an insight into the evolving burden of chronic hepatitis B virus infection in the near future and highlights new territories for public health interventions.


Interferometric characterization of pulse front tilt of spatiotemporally focused femtosecond laser pulses.
We report on an experimental measurement of the pulse front tilt (PFT) of spatiotemporally focused femtosecond laser pulses in the focal plane in both air and bulk transparent materials, which is achieved by examination of the interference pattern between the spatiotemporally focused pulse and a conventional focused reference pulse as a function of time delay between the two pulses. Our simulation results agree well with the experimental observations.


A review of the history, epidemiology and treatment of squamous cell carcinoma of the scrotum.
Squamous cell carcinoma of the scrotum is a tumor that is of interest for clinical and historical reasons. It was the first cancer linked to occupational exposure when, in 1775, Perivall Pott described it in chimney sweeps in England. Other occupations that had a preponderance of the disease included people who worked with the distillates of coal and men exposed to mineral oil. Currently, the disease is very rare and most cases are thought to result from poor hygiene and chronic irritation. Surgery with a negative resection margin offers the best hope of cure as adjunctive therapy has not proved useful. Prognosis correlates with the extent of nodal involvement.


A conformational change in the actin subunit can change the flexibility of the actin filament.
The mechanical properties of F-actin are very significant, given the central structural role played by actin filaments within muscle and the cytoskeleton. We have determined that actin can exist in a state that has a fourfold increase in flexibility over normal F-actin, and nucleotide. Three-dimensional reconstructions from electron micrographs suggest that this increased flexibility arises from a rotation of subdomain-2, the smallest subdomain, of the actin subunit. The modulation of actin's flexibility by Ca2+ and Mg2+ may have important physiological consequences within the cell. Further, since it has been shown that myosin-decorated actin filaments are more flexible than pure F-actin, it is possible that myosin induces this more flexible state in actin.


Hyperglycaemia-induced cardiomyocyte death is mediated via MCP-1 production and induction of a novel zinc-finger protein MCPIP.
Cardiomyocyte apoptosis contributes to the development of diabetic cardiomyopathy. How the elevated glucose levels associated with diabetes cause cell death is unknown. Here we report that high glucose-induced cardiomyocyte death is mediated via monocyte chemotactic protein-1 (MCP-1) production and induction of a novel zinc-finger protein. H9c2 cardiomyoblasts treated with 28 mmol/L glucose were evaluated for MCP-1 production and induction of the zinc-finger protein, MCP-1-induced protein (MCPIP). Disruptors of MCP-1 interaction with its receptor, CCR2, and knockdown of MCPIP with siRNA were used to determine if MCP-1 and MCPIP mediate glucose-induced cell death. The molecular mechanisms were evaluated by assessing reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, and autophagy. Key findings were confirmed in isolated neonatal rat cardiomyocytes. Glucose treatment of H9c2 cardiomyoblasts and isolated cardiomyocytes caused MCP-1 production, MCPIP induction, ROS production, ER stress, autophagy, and cell death. Treatment with CCR2 antagonists and knockdown of MCPIP attenuated glucose-induced ROS production, ER stress, autophagy, and cell death. Inhibition of ROS with 1400 W, tiron, and cerium oxide (CeO(2)) nanoparticles attenuated ER stress, autophagy, and cell death. Specific inhibitors of ER stress and knockdown of IRE-1 attenuated glucose-induced autophagy and cell death. Inhibitors of autophagy and knockdown of beclin-1 attenuated glucose-induced death. Glucose-induced cardiomyocyte death is mediated via MCP-1 production and MCPIP induction, which causes sequential events--ROS production, ER stress, autophagy, and cell death.


[Effect of Electroacupuncture on Pain Reaction and Content of Proteinase-activated Receptors 2 in Dorsal Root Ganglion in Hyperalgesia Rats].
To observe the effect of electroacupuncture (EA) on mechanical hyperalgesia threshold (MHTs) and thermal hyperalgesia threshold (THTs) and content of proteinase-activated receptors 2 (PAR 2) in dorsal root ganglia (DRG) in rats with inflammatory pain, so as to explore its peripheral mechanism underlying improvement of inflammatory pain. The present study contains two parts. 1) In the first part, 27 male SD rats were randomized into sham hyperalgesic priming (sham-HP) group and real hyperalgesic priming (HP) group (n=5 in the sham-HP group and n=6 in the HP group for the test of MHTs, n=8 in the two groups for the test of THTs). The sham-HP model was established by subcutaneous injection of normal saline into the left plantar part of the hind-paw, and the HP model established by subcutaneous injection of 1% carragenan (the first injection) into the same left hind paw, followed by injection of PGE2 (100 ng/25 μL, the second injection) into the dorsum pedis of the same hind paw 7 days after the first injection. The ipsilateral paw withdrawal latencies (MHTs and THTs) were detected before and 5 h, 3 d and 6 d after the first injection, 0.5, 4 and 24 h after the second injection. 2) In the second part, 64 male SD rats were randomly divided into sham-HP, HP, sham-EA and EA groups (n=16 in each group). The sham-HP and HP models were made in the same way as the first part. Both"Zusanli"(ST 36)and "Kunlun"(BL 60) were punctured with filiform needles in the sham-EA group and also stimulated with EA: 2 Hz/100 Hz, 0.5-1.5 mA (0.5 mA increase per 10 min) for 30 min in the EA group, 1 time/d for 7 d. Both ipsilateral MHTs and THTs were observed at the same time-points of the first part and the PAR 2 protein content in the L 4-L 6 DRGs was assayed by ELISA 24 h after the second injection. 1) In the first part of the study, compared with the sham-HP group, the MHTs at 5 h and 3 d, and THT at 5 h after the first injection, and MHTs, and THTs at 4 and 24 h after the se-cond injection were significantly decreased in the HP group (P<0.01, P<0.05). 2) In the second part of the study, compared with the HP group, the MHTs at 4 and 24 h after the second injection and the THTs at 3 d after the first injection, 4 and 24 h after the second injection were significantly up-regulated in the EA group (P<0.01, P<0.05). The content of PAR 2 in the DRGs (L 4-L 6) was significantly higher in the HP group than in the sham-HP group (P<0.05), but considerably lower in the EA group than in the HP group (P<0.05). EA can suppress hyperalgesia priming in inflammatory pain rats which may be related to its effect in down-regulating PAR 2 level in the lumbar DRGs.


Interactions of trimeric purine nucleoside phosphorylases with ground state analogues--calorimetric and fluorimetric studies.
Binding enthalpies, dissociation constants and stoichiometry of binding for interaction of trimeric calf spleen and Cellulomonas sp. purine nucleoside phosphorylases with their ground state analogues (substrates and inhibitors) were studied by calorimetric and spectrofluorimetric methods. Data for all ligands, with possible exception of hypoxanthine, are consistent with three identical non-interacting binding sites.


Diabetes Mellitus and Heart Failure.
Diabetes mellitus and heart failure are two multifaceted entities characterised by high morbidity and mortality. Early epidemiological and prospective studies have observed the frequent co-existence of both conditions. Importantly, diabetes mellitus can precipitate or worsen heart failure due to the accumulation of advanced glycation end products, oxidative stress, inflammatory status impairment, decay of intracellular calcium, changes in microRNAs expression, not to mention atherosclerosis progression and coronary artery disease. Heart failure also impairs glucose metabolism through less well-known mechanisms. Attention must especially be given in the treatment as there are frequently adverse interactions between the two diseases and novel agents against diabetic cardiomyopathy are under investigation. As several missing links still exist in the connection between heart failure and diabetes mellitus we will review, in this article, the most recent data underlying the interaction of them and provide an overview of the most important clinical perspectives.


Evolution of Brazilian elderly with hip fracture secondary to a fall.
To contribute to fall prevention by studying the epidemiological profile, mortality, and functional evolution of elderly persons with hip fracture, in Brazil, in the year following a fracture. Fifty-six elderly patients aged 60 years and over with hip fracture secondary to a fall and admitted in 2000 were included. In addition to the medical record data, patients or their guardians filled a form providing information regarding personal data, history of fall and fracture, physical evaluation, and ability to perform basic and instrumental activities of daily living prior to and 1 year after their fracture, using Katz's Index and Lawton's Index, respectively. Fractures were more common among Caucasian widowed women, and most falls occurred at home. General mortality within 1 year after the occurrence of fracture was 30.35% and was associated with sex and age. There was an increase in the inability to walk and in the use of a supporting device. A significant reduction in the functional ability to perform basic and instrumental activities of daily living was found. The evolution of hip fracture in the year following it is related to high mortality and to a decrease in functional ability, with age and male sex being the factors associated with a worse prognosis, emphasizing the need for special follow-up care of these groups during the immediate and late postoperative periods.


[Characteristics of patients with chronic thromboembolic pulmonary hypertension according to the Russian National Registry].
To assess demographic and clinical characteristics, to describe of the functional and hemodynamic status, profile of concomitant pathology, data of instrumental examination in chronic thromboembolic pulmonary hypertension (CTEPH) patients; to study the features of specific and supportive therapy according to the data of the Russian national registry. From 2012 till 2020 a multicenter, prospective study in 15 regional expert centers of the Russian Federation (www.medibase.pro) included 404 newly diagnosed CTEPH patients over the age of 18 years in the Russian registry of patients with pulmonary arterial hypertension and CTEPH (NCT03707561). The diagnosis was established by European and Russian clinical guidelines for the diagnosis and management of pulmonary hypertension. 154 inoperable CTEPH patients an additional analysis of specific and supportive therapy was performed. The study included 404 patients (55.6% women and 44.3% men) at the age of 58.6 [48.6; 69.3] years. Median time from symptom onset to the diagnosis verification waswas 2.4 years (from 0.1 to 2.9 years). 79.1% of patients were in the III and IV functional class (World Health Organization) at the time of diagnosis and in 44.1% with RHF (right heart failure). In assessing the profile of concomitant pathology, it was noted that CTEPH patients were more often with arterial hypertension (39.1%), erosive-ulcerative lesions of the stomach/duodenum (16.1%), atrial fibrillation (13.8%), obesity (13.1%). Distance in 6MWD (6-min walk distance) was 337.2 [250; 422] m, Borg dyspnea index scale 4.1 [3.0; 5.0] points. Hemodynamic parameters according to right heart catheterization were: Mean PAP (pulmonary arterial pressure) (51.114.04) mmHg, CO (cardiac output) (3.50.98) l/min, CI (cardiac index) (2.00.48) l/min/m2, PVR (2008528) dyns/cm5. According to the Russian registry, inoperable CTEPH patients had precapillary PH (pulmonary hypertension) with severe functional status, in combination with frequent concomitant pathology (arterial hypertension, erosive-ulcerative lesions of the stomach/duodenum, atrial fibrillation, obesity, right heart failure). 66% of inoperable CTEPH patients received specific drug therapy.


Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis.
Mesenchymal stem cells (MSCs) have potential to differentiate into multiple cell lineages. Recently, it was shown that MSCs also have anti-inflammatory and immunomodulatory functions. In this report, we investigated the regulatory function of MSCs in the development of inflammatory bone destruction in rats with adjuvant-induced arthritis (AA rats). MSCs were isolated from rat bone marrow tissues, expanded in the presence of basic FGF, and intraperitoneally injected into AA rats. MSC administration significantly suppressed inflammatory parameters: swelling score, swelling width, and thickness of hind paw. Radiographic evaluation indicated that MSC significantly suppressed bone destruction. Histological analysis showed that administration of MSCs markedly suppressed osteoclastogenesis in AA rats. To further delineate their effects on osteoclastogenesis, MSCs were added to in vitro bone marrow cultures undergoing osteoclastogenesis. MSCs significantly suppressed osteoclastogenesis in this system. Chemokine receptor expression in MSCs was assessed by RT-PCR, and a chemotactic assay was performed using a transwell culture system. MSCs showed significant chemotaxis to MIP-1α (CCL3) and SDF-1α (CXCL12), chemokines preferentially expressed in the area of inflammatory bone destruction. Furthermore, MSCs expressed IL-10 and osteoprotegerin, cytokines that suppress osteoclastogenesis. These data suggest that recruitment of MSC to the area of bone destruction in AA rats could suppress inflammatory bone destruction and raise the possibility that MSCs may have potential for the treatment of inflammatory bone destruction in arthritis.


MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy.
A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors resulted in clonal dominance of these 'sub-haploinsufficient' cells, which was reflected in all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a clonal myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. We conclude that downregulation of MYBL2 activity below levels predicted by classical haploinsufficiency underlies the clonal expansion of hematopoietic progenitors in a large fraction of human myeloid malignancies. DOI:http://dx.doi.org/10.7554/eLife.00825.001.


A Non-Gas-Based Cryotherapy System for the Treatment of Cervical Intraepithelial Neoplasia: A Mixed-Methods Approach for Initial Development and Testing.
Gas-based cryotherapy is the most widely used treatment strategy for cervical intraepithelial neoplasia (CIN) in low-resource settings, but reliance on gas presents challenges in low- and middle-income countries (LMICs). Our team adapted the original CryoPen Cryosurgical System, a cryotherapy device that does not require compressed gas and is powered by electricity, for use in LMICs. A mixed-methods approach was used involving both qualitative and quantitative methods. First, we used a user-centered design approach to identify priority features of the adapted device. U.S.-based and global potential users of the adapted CryoPen participated in discussion groups and a card sorting activity to rank 7 features of the adapted CryoPen: cost, durability, efficacy and safety, maintenance, no need for electricity, patient throughput, and portability. Mean and median rankings, overall rankings, and summary rankings by discussion group were generated. In addition, results of several quantitative tests were analyzed including bench testing to determine tip temperature and heat extraction capabilities; a pathology review of CIN grade 3 cases (N=107) to determine target depth of necrosis needed to achieve high efficacy; and a pilot study (N=5) investigating depth of necrosis achieved with the adapted device to assess efficacy. Discussion groups revealed 4 priority themes for device development in addition to the need to ensure high efficacy and safety and low cost: improved portability, durability, ease of use, and potential for cure. Adaptions to the original CryoPen system included a single-core, single-tip model; rugged carrying case; custom circuit to allow car battery charging; and sterilization by high-level disinfection. In bench testing, there were no significant differences in tip temperature or heat extraction capability between the adapted CryoPen and the standard cryotherapy device. In 80% of the cases in the pilot study, the adapted CryoPen achieved the target depth of necrosis 3.5 mm established in the pathology review. The LMIC-adapted CryoPen overcomes barriers to standard gas-based cryotherapy by eliminating dependency on gas, increasing portability, and ensuring consistent freeze temperatures. Further testing and evaluation of the adapted CryoPen will be pursued to assess scalability and potential impact of this device in decreasing the cervical cancer burden in LMICs.


Therapy for acute retinal necrosis.
Acute retinal necrosis is a progressive necrotizing retinopathy caused by herpes simplex virus (HSV) or varicella zoster virus (VZV). The mainstay of its treatment is antiviral therapy against these pathogenic organisms, such as intravenous acyclovir or oral valacyclovir. Systemic and topical corticosteroids together with antiviral therapy are used as an anti-inflammatory treatment to minimize damages to the optic nerve and retinal blood vessels. Because the majority of severe cases of the disease show occlusive retinal vasculitis, a low dosage of aspirin is used as anti-thrombotic treatment. Vitreo-retinal surgery is useful to repair rhegmatogenous retinal detachment, one of the main late-stage complications. Moreover, recent articles have reported some encouraging results of prophylactic vitrectomy before rhegmatogenous retinal detachment occurs. The efficacy of laser photocoagulation to prevent the development or extension of rhegmatogenous retinal detachment is controversial. Despite these treatments, the visual prognosis of acute retinal necrosis is still poor, in particular VZV-induced acute retinal necrosis.


Estimation of the equilibrium free energy for glasses using the Jarzynski equality.
The free energy of glasses cannot be estimated using thermodynamic integration as glasses are intrinsically not in equilibrium. We present numerical simulations showing that, in contrast, plausible free-energy estimates of a Kob-Andersen glass can be obtained using the Jarzynski relation. Using the Jarzynski relation, we also compute the chemical potential difference of the two components of this system and find that, in the glassy regime, the Jarzynski estimate matches well with the extrapolated value of the supercooled liquid. Our findings are of broader interest as they show that the Jarzynski method can be used under conditions where the thermodynamic integration approach, which is normally more accurate, breaks down completely. Systems where such an approach might be useful are gels and jammed glassy structures formed by compression.


Comparison of Long-Term Clinical Outcomes Between Segmental and Circumferential Pulmonary Vein Isolation in Patients Undergoing Repeat Atrial Fibrillation Ablation.
Circumferential pulmonary vein isolation (CPVI) has supplanted segmental PVI (SPVI) as standard procedure for atrial fibrillation (AF). However, there is limited evidence examining the efficacy of these strategies in redo ablations. In this study, we investigated the difference in recurrence rates between SPVI and CPVI in redo ablations for PV reconnection.Methods and Results: This study retrospectively enrolled 543 patients who had undergone AF ablation between 2015 and 2017. Among them, 167 patients (30.8%, including 128 male patients and 100 patients with paroxysmal AF) underwent redo ablation for recurrent AF. Excluding 26 patients without PV reconnection, 141 patients [90 patients of SPVI (Group 1) and 51 patients of CPVI (Group 2)] were included. The AF-free survival rates were 53.3% and 56.9% in Group 1 and Group 2, respectively (P=0.700). The atrial flutter (AFL)-free survival rates were 90% and 100% in Group 1 and Group 2, respectively (P=0.036). The ablation time was similar between groups, and there no major complications were observed. For redo AF ablation procedures, SPVI and CPVI showed similar outcomes, except for a higher AFL recurrence rate for SPVI after long-term follow-up (>2 years). This may be due to a higher probability of residual PV gaps causing reentrant AFL.


Why do women miss oral contraceptive pills? An analysis of women's self-described reasons for missed pills.
Inconsistent use of oral contraceptives (OCs) exposes women to risks of unintended pregnancy. This study explored women's self-described reasons for missed OC pills. Data from diary cards completed by 141 women were studied to see how reasons for missing pills were related to patterns of pill use. The findings suggest that practitioners might improve OC use by focusing on the reasons that women miss pills, thus providing a more tailored approach that addresses individual risks based on women's personal experiences.


Confusion, Faciobrachial Dystonic Seizures, and Critical Hyponatremia in a Patient with Voltage-Gated Potassium Channel Encephalitis.
Autoimmune limbic encephalitis is a rare cause of encephalitic disease. It is associated with various target antigens and is difficult to diagnose, and experience with its treatment is limited. This case report describes a 69-year-old man, who presented with life-threatening hyponatremia and confusion, following several months of gradually worsening faciobrachial dystonic seizures. Faciobrachial dystonic seizures are a well-described feature classically observed in voltage-gated potassium channel autoimmune encephalitis. The presence of chronic hyponatremia without cognitive dysfunction, eventually culminating in an acute episode of encephalopathy and severe hyponatremia, is a pattern of natural history not previously documented in this condition.


Bradycardia in perspective-not all reductions in heart rate need immediate intervention.
According to Wikipedia, the word 'bradycardia' stems from the Greek βραδύς, bradys, 'slow', and καρδία, kardia, 'heart'. Thus, the meaning of bradycardia is slow heart rate but not necessarily too slow heart rate. If looking at top endurance athletes they may have a resting heart rate in the very low thirties without needing emergent intervention with anticholinergics, isoprenaline, epinephrine, chest compressions or the insertion of an emergency pacemaker (Figure 1). In fact, they withstand these episodes without incident, accommodating with a compensatory increase in stroke volume to preserve and maintain cardiac output. With this in mind, it is difficult for the authors to fully understand and agree with the general sentiment amongst many pediatric anesthesiologists that all isolated bradycardia portends impending doom and must be immediately treated with resuscitative measures.


[Clinical variability of Best's disease].
Retrospective view of the various phenotypes 20 persons affected by classic solitary form of vitelliform macular dystrophy, in 3 pedigrees with autosomal dominant transmission and in 4 single cases. Long-term monitoring allows to observe the variability of expression, from classic course to peculiarity of the clinical expression in the disc development and their corresponding functions of the central retina.


Origin of the stability of Ge(105) on si: a new structure model and surface strain relaxation.
The structure of Ge(105)-(1 x 2) grown on Si(105) is examined by scanning tunneling microscopy (STM) and first-principles calculations. The morphology evolution with an increasing amount of Ge deposited documents the existence of a tensile surface strain in Si(105) and its relaxation with increasing coverage of Ge. A detailed analysis of high-resolution STM images and first-principles calculations produce a new stable model for the Ge(105)-(1 x 2) structure formed on the Si(105) surface that includes the existence of surface strain. It corrects the model developed from early observations of the facets of "hut" clusters grown on Si(001).