Solvent-Driven Variations of Third-Order Nonlinear Thermo-Optical Features of Glutaric Acid-Directed Self-Healing Supramolecular Ni(II) Metallogels.
The generation of solvent-directed self-healing supramolecular Ni(II) metallogels of glutaric acid (i.e., Ni-Glu-DMF and Ni-Glu-DMSO) is described in this article. Polar aprotic solvents like N,N'-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) are separately entrapped into the Ni(II)-acetate salt and glutaric acid-mediated networks to attain the semisolid flexible scaffolds. The gel nature of the fabricated materials is experimentally proven through different rheological tests such as amplitude sweep, frequency sweep, and thixotropic (time sweep) measurements. The self-repairing strategy and load-bearing features of the synthesized metallogel are studied in this work. The different supramolecular noncovalent interactions working within the soft scaffold are clearly explored. The formation strategy and the microstructural features of these synthesized metallogels are scrutinized through a Fourier transform infrared (FT-IR) spectroscopy study and field-emission scanning electron microscopy (FESEM) morphological analyses. The FT-IR spectroscopy observation displays a considerable amount of shifting of the infrared (IR) peaks of the xerogel samples of both the metallogels Ni-Glu-DMF and Ni-Glu-DMSO. The electrospray ionization (ESI)-mass spectroscopy result demonstrates the plausible construction of the metallogel network. In order to examine the nonlinear optical characteristics of the two synthesized self-healing metallogels Ni-Glu-DMSO and Ni-Glu-DMF, Z-scan measurements are carried out with a continuous wave (CW) diode-pumped solid-state (DPSS) laser at 532 nm. The nonlinear refractive index, nonlinear absorption coefficient, thermo-optical coefficient, and third-order susceptibility of these metallogels were evaluated by analyzing the experimental data from the Sheik-Bahae formalism. The nonlinear thermo-optical study reveals that these solvent-dependent metallogels show negative signs of nonlinear refractive index and nonlinear absorption coefficient. The figure of merit calculated for these compounds shows good agreement for their use in nonlinear photonic devices.


Suppression of exciton dephasing in sidewall-functionalized carbon nanotubes embedded into metallo-dielectric antennas.
Covalent functionalization of single-walled carbon nanotubes (SWCNTs) is a promising route to enhance the quantum yield of exciton emission and can lead to single-photon emission at room temperature. However, the spectral linewidth of the defect-related E11* emission remains rather broad. Here, we systematically investigate the low-temperature exciton emission of individual SWCNTs that have been dispersed with sodium-deoxycholate (DOC) and polyfluorene (PFO-BPy), are grown by laser vaporization (LV) or by CoMoCat techniques and are functionalized with oxygen as well as 3,5-dichlorobenzene groups. The E11 excitons in oxygen-functionalized SWCNTs remain rather broad with up to 10 meV linewidth while exciton emission from 3,5-dichlorobenzene functionalized SWCNTs is found to be about one order of magnitude narrower. In all cases, wrapping with PFO-BPy provides significantly better protection against pump induced dephasing compared to DOC. To further study the influence of exciton localization on pump-induced dephasing, we have embedded the functionalized SWCNTs into metallo-dielectric antenna cavities to maximize light collection. We show that 0D excitons attributed to the E11* emission of 3,5-dichlorobenzene quantum defects of LV-grown SWCNTs can display near resolution-limited linewidths down to 35 μeV. Interestingly, these 0D excitons give rise to a 3-fold suppressed pump-induced exciton dephasing compared to the E11 excitons in the same SWCNT. These findings provide a foundation to build a unified description of the emergence of novel optical behavior from the interplay of covalently introduced defects, dispersants, and exciton confinement in SWCNTs and might further lead to the realization of indistinguishable photons from carbon nanotubes.


Photophysical properties and electronic structure of bacteriochlorin-chalcones with extended near-infrared absorption.
Synthetic bacteriochlorins enable systematic tailoring of substituents about the bacteriochlorin chromophore and thereby provide insights concerning the native bacteriochlorophylls of bacterial photosynthesis. Nine free-base bacteriochlorins (eight prepared previously and one prepared here) have been examined that bear diverse substituents at the 13- or 3,13-positions. The substituents include chalcone (3-phenylprop-2-en-1-onyl) derivatives with groups attached to the phenyl moiety, a "reverse chalcone" (3-phenyl-3-oxo-1-enyl), and extended chalcones (5-phenylpenta-2,4-dien-1-onyl, retinylidenonyl). The spectral and photophysical properties (τs, Φf, Φ(ic), Φ(isc), τT, k(f), k(ic), k(isc)) of the bacteriochlorins have been characterized. The bacteriochlorins absorb strongly in the 780-800 nm region and have fluorescence quantum yields (Φf) in the range 0.05-0.11 in toluene and dimethylsulfoxide. Light-induced electron promotions between orbitals with predominantly substituent or macrocycle character or both may give rise to some net macrocycle ↔ substituent charge-transfer character in the lowest and higher singlet excited states as indicated by density functional theory (DFT) and time-dependent DFT calculations. Such calculations indicated significant participation of molecular orbitals beyond those (HOMO - 1 to LUMO + 1) in the Gouterman four-orbital model. Taken together, the studies provide insight into the fundamental properties of bacteriochlorins and illustrate designs for tuning the spectral and photophysical features of these near-infrared-absorbing tetrapyrrole chromophores.


Professional Ethics for Digital Age Psychiatry: Boundaries, Privacy, and Communication.
Internet and social media use continue to expand rapidly. Many patients and psychiatrists are bringing digital technologies into the treatment process, but relatively little attention has been paid to the ethical challenges in doing this. This review presents ethical guidelines for psychiatry in the digital age. Surveys demonstrate that patients are eager to make digital technologies part of their treatment. Substantial numbers search for professional and personal information about their therapists. Attitudes among psychiatrists about using digital technologies with patients range from dread to enthusiastic adoption. Digital technologies create four major ethical challenges for psychiatry: managing clinical boundaries; maintaining privacy and confidentiality; establishing realistic expectations regarding digital communications; and upholding professional ideals. Traditional ethical expectations are valid for the evolving digital arena, but guidance must be adapted for actual application in practice.


Changes in concentrations of insulin, growth hormone and metabolites in plasma with spontaneous feeding in lactating dairy cows.
Changes in plasma levels of growth hormone (GH), insulin and metabolites and their relationships to spontaneous feeding in four lactating dairy cows were studied. Cows were fed a 60:40 (concentrate:silage) mixed ration through 100 days postpartum. Jugular blood samples were withdrawn at 10-minute intervals for 24 hours at day 90 postpartum; feeding behavior was monitored by time-lapse photography during this period. Insulin concentration increased immediately upon feeding and remained elevated for up to 50 minutes after meal termination, despite no significant change in plasma glucose levels. Plasma GH was depressed at 20 minutes postmeal and rose thereafter. Feeding appeared to dampen the fluctuations in free fatty acids (FFA) observed during premeal intervals. Time spent eating during a meal was not correlated with concentrations of these humoral factors at any premeal interval. The correlations of GH/glucose and GH/FFA were significant during eating, noneating and all other intervals during 24 hours. Correlation coefficients of other hormone/metabolite relationships were lower during eating as compared to non-eating periods. The consistent GH/metabolite relationships and rapid, feeding-induced changes in insulin, suggest their importance in the control of feed intake and energy balance.


Keratoconus Diagnosis and Treatment: Recent Advances and Future Directions.
Keratoconus is a disorder characterized by progressive corneal thinning and steepening that may result in significant visual impairment secondary to high astigmatism, corneal scarring, or even corneal perforation. Early detection and screening of keratoconus are essential for effective management and treatment. Several screening methods, such as corneal topography and tomography, corneal biomechanics, and genetic testing, are being developed to detect keratoconus at an early stage. Once detected, prevention of progression is the mainstay of keratoconus management. Corneal collagen cross-linking is a minimally invasive treatment option that can slow or halt the progression of keratoconus. Additionally, recent studies have investigated the potential use of copper sulfate eye drops (IVMED-80) and extracellular vesicles to prevent the progression of keratoconus as non-invasive treatment options. For visual rehabilitation, currently available treatments include scleral lenses, intracorneal ring segments, corneal allogenic intrastromal ring segments, and deep anterior lamellar keratoplasty. The safety and efficacy of these emerging treatment options for keratoconus are currently being investigated.


Biomass-based polyols through oxypropylation reaction.
Biomass residues are a potential renewable source for the sustainable production of chemicals, materials, fuels, and energy embodying the so-called biorefinery concept. In this context, agro-forestry and agro-food industry by-products have attracted considerable interest of researchers in academia and industry as a renewable source of polymeric materials. The research developed to date on the valorization of biomass residues by converting them into polyols through oxypropylation is the subject of this review. These bio-based polyols exhibit properties similar to their petrochemical counterparts and, as such, can be used with economical advantage in the production of polyurethanes. The operating conditions of the oxypropylation reaction depend on the biomass and on the desired polyol properties. The discussion of their influence and the economic viability of the process are also presented.


Pathogenicity of two strains of Mycoplasma gallisepticum in broilers.
Strains F and R of Mycoplasma gallisepticum (MG) were compared in two laboratory trials for their relative pathogenicity in terms of inducing airsacculitis and antibody production to MG. Chickens exposed to the R strain had significantly higher incidence of air-sac lesions (P less than 0.05) and greater severity of airsacculitis than did chicks exposed to the F strain. In both trials, chickens vaccinated simultaneously with Newcastle disease-infectious bronchitis vaccine and exposed to MG had more severe lesions than did chickens exposed to mycoplasma alone. chickens exposed to the F strain had significantly lower geometric mean hemagglutination-inhibition antibody titers to MG than did chicks exposed to the R strain. Chickens vaccinated simultaneously with Newcastle disease-infectious bronchitis vaccine and exposed to R strain had significantly lower body weights than did chickens in the other group.


Distribution Patterns of DNA N6-Methyladenosine Modification in Non-coding RNA Genes.
N6-methyladenosine (6mA) DNA modification played an important role in epigenetic regulation of gene expression. And the aberrational expression of non-coding genes, as important regular elements of gene expression, was related to many diseases. However, the distribution and potential functions of 6mA modification in non-coding RNA (ncRNA) genes are still unknown. In this study, we analyzed the 6mA distribution of ncRNA genes and compared them with protein-coding genes in four species (Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, and Homo sapiens) using single-molecule real-time (SMRT) sequencing data. The results indicated that the consensus motifs of short nucleotides at 6mA location were highly conserved in four species, and the non-coding gene was less likely to be methylated compared with protein-coding gene. Especially, the 6mA-methylated lncRNA genes were expressed significant lower than genes without methylation in A. thaliana (p = 3.295e-4), D. melanogaster (p = 3.439e-11), and H. sapiens (p = 9.087e-3).. The detection and distribution profiling of 6mA modification in ncRNA regions from four species reveal that 6mA modifications may have effects on their expression level.


Impact of the AGE-ON Tablet Training Program on Social Isolation, Loneliness, and Attitudes Toward Technology in Older Adults: Single-Group Pre-Post Study.
The internet and technology can help older adults connect with family and friends. However, many older adults face obstacles to internet and technology use, such as lack of knowledge or self-efficacy. The purpose of this study was to explore the impact of the AGE-ON tablet training program on social isolation, loneliness, and quality of life. Adults aged >60 years took part in a series of 6 weekly workshops covering the basic features of a tablet. Before and after the program, social isolation, loneliness, social support, and quality of life were assessed. In addition, data on current tablet use and attitudes toward technology use were collected. Satisfaction with the program was also assessed at the end of the study using 6 Likert scale questions. The participants (N=32; mean age 76.3, SD 8.6 years) were predominantly female (n=20, 63%) and retired (n=30, 94%). The participants reported that they were highly satisfied with the program. After completing the program, no differences in social isolation, loneliness, social support, or quality of life were found. Frequency of tablet use increased and the attitudes of the participants toward technology improved. The AGE-ON program resulted in increased tablet use frequency and may improve comfort and attitudes toward tablet use among older adults. This program may assist older adults in overcoming obstacles to internet and technology use to better connect with family and friends; however, further work targeting older adults who are socially isolated or at risk of social isolation is needed to more fully understand whether tablet training programs are beneficial in this population. ClinicalTrials.gov NCT03472729; https://clinicaltrials.gov/ct2/show/NCT03472729.


Critical Evaluation of NIR and ATR-IR Spectroscopic Quantifications of Rosmarinic Acid in Rosmarini folium Supported by Quantum Chemical Calculations.
The present study evaluates the analytical performance of near infrared as well as attenuated total reflection infrared spectroscopy for the determination of the rosmarinic acid content in Rosmarini folium. Therefore, the recorded near infrared and attenuated total reflection infrared spectra of 42 milled Rosmarini folium samples were correlated with reference data (range: 1.138-2.199 rosmarinic acid %) obtained by HPLC analysis. Partial least squares regression models were established as a quantitative multivariate data analysis tool. Evaluation via full cross-validation and test set validation resulted in comparable performances for both techniques: near infrared [coefficient of determination: 0.90 (test set validation); standard error of cross-validation: 0.060 rosmarinic acid %; standard error of prediction: 0.058 rosmarinic acid %] and attenuated total reflection infrared [coefficient of determination: 0.91 (test set validation); standard error of cross-validation: 0.063 rosmarinic acid %; standard error of prediction: 0.060 rosmarinic acid %]. Furthermore, quantum chemical calculations were applied to obtain a theoretical infrared spectrum of rosmarinic acid. Good agreement to the spectrum of pure rosmarinic acid was achieved in the lower wavenumber region, whereas the higher wavenumber region showed less compliance. The knowledge of the vibrational modes of rosmarinic acid was used for the association with the high values of the regression coefficient plots of the established partial least squares regression models.


Local visual energy mechanisms revealed by detection of global patterns.
A central goal of visual neuroscience is to relate the selectivity of individual neurons to perceptual judgments, such as detection of a visual pattern at low contrast or in noise. Since neurons in early areas of visual cortex carry information only about a local patch of the image, detection of global patterns must entail spatial pooling over many such neurons. Physiological methods provide access to local detection mechanisms at the single-neuron level but do not reveal how neural responses are combined to determine the perceptual decision. Behavioral methods provide access to perceptual judgments of a global stimulus but typically do not reveal the selectivity of the individual neurons underlying detection. Here we show how the existence of a nonlinearity in spatial pooling does allow properties of these early mechanisms to be estimated from behavioral responses to global stimuli. As an example, we consider detection of large-field sinusoidal gratings in noise. Based on human behavioral data, we estimate the length and width tuning of the local detection mechanisms and show that it is roughly consistent with the tuning of individual neurons in primary visual cortex of primate. We also show that a local energy model of pooling based on these estimated receptive fields is much more predictive of human judgments than competing models, such as probability summation. In addition to revealing underlying properties of early detection and spatial integration mechanisms in human cortex, our findings open a window on new methods for relating system-level perceptual judgments to neuron-level processing.


Ex vivo toxicity of nitrogen dioxide in human nasal epithelium at the WHO defined 1-h limit value.
Current pollution limits indicating potential harm to human health caused by nitrogen dioxide have prompted a variety of studies on the cytotoxicity and genotoxicity of nitrogen dioxide (NO₂) in vitro. The present study focuses on toxic effects of NO₂ at the WHO defined 1-h limit value of 200 μg NO₂/m(3) air, equivalent to 0.1 ppm NO₂. Nasal epithelial mucosa cells of 10 patients were cultured as an air-liquid interface and exposed to 0.1 ppm NO₂ for 0.5 h, 1 h, 2 h and 3 h and synthetic air as negative control. After exposure, analysis of genotoxicity was performed by the alkaline single cell microgel electrophoresis (comet) assay and by the micronucleus test. Depression of proliferation and cytotoxic effects were checked by the micronucleus assay and the trypan blue exclusion assay. The experiments demonstrated significant DNA fragmentation even at the shortest exposure duration of half an hour in the comet assay. The amount of DNA fragmentation significantly increased with extended NO₂ exposure durations. The amount of DNA fragmentation increased with extended exposure durations to synthetic air at a significantly lower level as compared to NO₂ exposure. Micronucleus inductions were seen only at the longest exposure duration of 3h. There were no changes in proliferation seen in the micronucleus assay under any experimental setup. Moreover, no signs of necrosis, apoptosis or changes in viability were detected. Data demonstrate genotoxicity of NO₂ at concentrations found in the urban atmosphere during short exposure durations. DNA alterations in the micronucleus assay at an exposure time of 3h indicate a significant DNA alteration possibly being hazardous to humans.


Stability of Charge Distributions in Electret Films on the nm-Scale.
Electret materials find use in various applications, such as microphones or filter media. In recent years, electrets have been used also increasingly on the micrometer scale, for example, in MEMS or for nano-xerography. However, for these applications, it becomes more important to prepare defined charge structures with sub-micrometer features. On the macroscopic level, the technique of isothermal potential decay at elevated temperatures has been developed to study aging effects and charge retention capabilities in electret materials. Here, we extend this technique to the nm-level by means of AFM-based methods, such as contact charging by AFM and the Kelvin probe force microscopy. Defined charge distributions in polyetherimide (PEI) ULTEM 1000 thin-film electrets have been studied for the first time with a high lateral resolution on the nanometer scale. We found a linear correlation between externally applied contact charging potential on the AFM-tip and the resulting relative surface potential on the PEI film. Charge decay at elevated temperatures is independent from the length scale. The same time dependence as for macroscopic, homogenously charged films could be established. We observe a potential decay only at an elevated temperature of 120 °C and no significant lateral charge transport. Thus, we propose a thermally enhanced charge carrier release from surface traps and a subsequent charge migration to the back electrode as the dominant mechanism. This finding is in-line with the observation that potential decay can be reduced also on the nm-level by pre-annealing the film slightly below the glass transition temperature. In contrast to many polymeric or inorganic electrets, no lateral charge migration is observed. Therefore, the charge patterns are preserved for PEI ULTEM 1000 thin-film electrets, which makes it a good candidate as electret for applications in MEMS or similar applications.


Biological Machine Learning Combined with Campylobacter Population Genomics Reveals Virulence Gene Allelic Variants Cause Disease.
Highly dimensional data generated from bacterial whole-genome sequencing is providing an unprecedented scale of information that requires an appropriate statistical analysis framework to infer biological function from populations of genomes. The application of genome-wide association study (GWAS) methods is an appropriate framework for bacterial population genome analysis that yields a list of candidate genes associated with a phenotype, but it provides an unranked measure of importance. Here, we validated a novel framework to define infection mechanism using the combination of GWAS, machine learning, and bacterial population genomics that ranked allelic variants that accurately identified disease. This approach parsed a dataset of 1.2 million single nucleotide polymorphisms (SNPs) and indels that resulted in an importance ranked list of associated alleles of porA in Campylobacter jejuni using spatiotemporal analysis over 30 years. We validated this approach using previously proven laboratory experimental alleles from an in vivo guinea pig abortion model. This framework, termed µPathML, defined intestinal and extraintestinal groups that have differential allelic porA variants that cause abortion. Divergent variants containing indels that defeated automated annotation were rescued using biological context and knowledge that resulted in defining rare, divergent variants that were maintained in the population over two continents and 30 years. This study defines the capability of machine learning coupled with GWAS and population genomics to simultaneously identify and rank alleles to define their role in infectious disease mechanisms.


Formulation and in vitro evaluation of cysteamine hydrochloride viscous solutions for the treatment of corneal cystinosis.
In the present study, viscous solutions of cysteamine hydrochloride (CH) were prepared by using 0.5%, 1.0%, 1.5% or 3.0% of hydroxypropylmethylcellulose (HPMC) and were evaluated for their in-vitro characteristics and stability. Osmolalities, pH and viscosity of the formulations were determined. The influence of benzalkonium chloride and autoclave sterilization on solution characteristics was also investigated. For stability assessment, the viscous solutions were stored at +4 and +25 degrees C over 12 months. In-vitro characteristics and CH contents of the stored solutions were monitored. Irritation tests for the formulations were evaluated on rabbit eyes. Dialysis sac technique was used to perform in vitro release study of the solutions containing 1.0% and 1.5% HPMC. All of the viscous solutions tested showed non-newtonian (dilatant) flow behavior. Osmolality values were ranked between 351.2+/-6.2 and 355.1+/-7.9 mOsm kg(-1), and pH values were between 3.97+/-0.1 and 3.98+/-0.2 for all the solutions. Furthermore, no significant changes in dilatant behavior, osmolality or pH values of the pure HPMC solutions were observed. After addition of the excipients or CH-excipients, increased viscosity values were noted in these formulations. Neither benzalkonium chloride nor autoclave sterilization had any influence on viscosity, pH or osmolality values of the solution containing 1.5% HPMC. Stability studies showed that a faster decrease in the concentration of CH was observed in the formulations stored at 25 degrees C compared to those kept at 4 degrees C; no changes were determined in osmolality values of the solutions at all storage conditions. Increased pH and decreased viscosity values were noted in HPMC solutions containing CH and excipients, while no changes in these values were observed for pure HPMC solutions kept at 4 and 25 degrees C. In vitro release tests revealed that 81.2% and 85.3% of CH were released from the viscous solutions containing 1.5% and 1% HPMC, respectively, in 8h. No irritation was observed when the viscous solutions were tested on rabbit and human eyes.


Kidney failure outcomes in children and young adults with sickle cell disease in the United States Renal Data System.
Children and young adults with sickle cell disease (SCD) develop kidney disease early in childhood, with some patients progressing to require dialysis and kidney transplantation. The prevalence and outcomes of children with kidney failure (chronic kidney disease stage 5) due to SCD are not well described. This study aimed to assess the outcome of children and young adults with SCD with kidney failure compared to matched children and young adults without SCD with kidney failure in a large national database. Utilizing the United States Renal Data System (USRDS), we retrospectively examined kidney failure outcomes in children and young adults with SCD from 1998 to 2019. We identified 97 patients with SCD who developed kidney failure and identified 96 matched controls with a median age of 19 years (IQR 17, 21) at the time of kidney failure diagnosis. SCD patients had significantly shorter survival (8.4 years vs. 14.0 years, p < 0.001) and had a longer waiting time for their first transplant when compared to matched non-SCD kidney failure patients (12.1 years vs. 7.3 years, p < 0.001). Children and young adults with SCD kidney failure have significantly higher mortality when matched to non-SCD kidney failure children and experience a longer mean time to kidney transplant.


Phenotypic repertoire of the FNR regulatory network in Escherichia coli.
The FNR protein in Escherichia coli is an O(2) sensor that modifies global gene expression to adapt the cell to anaerobic growth. Regulation of FNR involves continuous cycling of the protein between its active and inactive states under aerobic conditions without apparent function. This raises the question of what benefit to the overall life cycle might compensate for the cost of cycling and reveals that the role of this process is poorly understood. To address this problem, we introduce the concept of a 'system design space', which provides a rigorous definition of phenotype at the molecular level and a means of visualizing the phenotypic repertoire of the system. Our analysis reveals undesirable and desirable phenotypes with an optimal constellation of parameter values for the system. To facilitate a more concrete understanding of what the design space represents, we analyse mutations that alter the apparent dimerization rate constant of FNR. We show that our estimated wild-type value of this rate constant, which is difficult to measure in situ, is located within this constellation and that the behaviour of the system is compromised in mutants if the value of the apparent dimerization rate constant lies beyond the bounds of this optimal constellation.


[Neurologic disorders in myeloma disease].
A comprehensive examination involving the use of electroencephalography (EEG), rheoencephalography of the main vessels of the head (REG) and vessels of the limbs, electromyography with the application of neurohistological investigation was conducted in 120 myeloma patients. Neurological disorders systematized into syndromes of encephalopathy, local spondylalgia, radiculalgia, myelopathy, meningomyelopolyradicular and encephalomyelopolyradiculoneuropathic syndromes were observed in 91.7% of the cases. The leading role in the pathogenesis of neurological disturbances was played by toxico-dyscirculatory disorders secondary to infiltration of vessel walls by plasmatic cells, dysproteinosis, kidney failure, as well as mechanical impact of the deformed vertebral column on the spinal cord, its radices and vessels. Modern medicated correction of neurological disturbances is considered necessary in myeloma.


HMGA2 expression analysis in cytological and paraffin-embedded tissue specimens of thyroid tumors by relative quantitative RT-PCR.
The distinction between benign and malignant thyroid tumors in some cytological and histological specimens remains challenging. The aim of this study was to evaluate the use of High Mobility Group A2 (HMGA2) mRNA expression to distinguish benign from malignant thyroid tumors in cytological and histological specimens. RNA samples from 170 thyroid formalin-fixed paraffin-embedded (FFPE) tissues and 226 fine needle aspiration (FNA) specimens were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The FFPE tissues included 34 follicular adenomas, 10 Hürthle cell adenomas (HA), 6 hyperplastic nodules, 4 atypical adenomas, 44 classic papillary thyroid carcinomas (PTC), 29 follicular variant of PTC, 23 follicular thyroid carcinomas, 17 Hürthle cell carcinomas (HC), and 3 anaplastic thyroid carcinomas. The FNA specimens included 55 follicular adenomas, 34 HA, 20 hyperplastic nodules, 8 Hashimoto thyroiditis, 32 PTC, 24 follicular variant of PTC, 30 follicular thyroid carcinomas, 21 HC, and 2 anaplastic thyroid carcinomas. HMGA2 mRNA levels were expressed as relative fold change after normalizing with a calibrator. HMGA2 expression in thyroid carcinomas (16.8-fold for FFPE and 18.2-fold for FNA) was significantly higher than in benign lesions (0.8-fold for FFPE and 0.8-fold for FNA). HMGA2 expression in HC was relatively low (1.8-fold for FFPE and 8.5-fold for FNA) compared with the other types of carcinomas. HMGA2 expression values of 4.5-fold and 5.9-fold were used as cutoff points for FFPE and FNA (excluding HA and HC), respectively, to separate benign and malignant thyroid tumors, with 97.5% clinical specificity and 79.8% sensitivity for FFPE, and 95.2% clinical specificity and 88.6% sensitivity for the FNA specimens. Conventional RT-PCR supported the qRT-PCR results. Detection of HMGA2 mRNA expression by qRT-PCR may be a useful tool to assist in the diagnosis of well-differentiated thyroid carcinomas. The 1-step qRT-PCR method is a sensitive, accurate, and reliable technique for gene expression analysis of thyroid tumors.


Mechanisms of hepatocyte growth factor-induced retinal endothelial cell migration and growth.
Hepatocyte growth factor (HGF), also called scatter factor, stimulates growth and motility in nonocular endothelial cells and smooth muscle cells through its receptor c-Met. Recent reports suggest that HGF is increased in the serum and vitreous of patients with proliferative diabetic retinopathy and that smooth muscle cells and retinal pigment epithelial cells secrete HGF in the eye. However, little is known about HGF's action in the retina. In this study, the activity, expression, and signaling pathways of HGF were investigated in bovine retinal microvascular endothelial cells (BRECs). Mitogenic and motogeneic effects of HGF on BRECs were examined using cell counts, thymidine uptake, and migration assays. MAP kinase (MAPK) phosphorylation was examined by Western blot analysis. Protein kinase C (PKC), MAPK, and PI3 kinase involvement were evaluated using selective inhibitors and activity assays. Expression of HGF and c-Met was evaluated by reverse transcription-polymerase chain reaction. HGF and c-Met were both expressed in BRECs. HGF stimulated BREC growth in a time- and dose-dependent manner, observed at HGF concentrations of 5 ng/ml or more and maximal (410%) at 100 ng/ml (P < 0.001). HGF increased BREC migration in a dose-dependent manner with a maximal 3.4-fold increase at 50 ng/ml after 5 hours. HGF induced time- and dose-dependent MAPK phosphorylation, initially evident at 5 minutes (P < 0.001) or 5 ng/ml (P < 0.050) and maximal after 15 minutes (>80-fold, P < 0.001) or 50 ng/ml (>20-fold, P < 0.001), respectively. MAPK phosphorylation was maintained for more than 2 hours. This response was inhibited 31% by 0.1 microm wortmannin and 76% by 30 microm LY294002, another PI3 kinase inhibitor. The non-isoform-selective PKC inhibitor GFX inhibited HGF-induced MAPK phosphorylation by only 15% at 5 microm. Combined PKC and PI3 kinase inhibition was additive (P < 0.05). Cell migration was inhibited 30% by wortmannin (P < 0.01) and 32% by GFX (P < 0.05), and again the effect was additive (P < 0.001). HGF-induced BREC growth was suppressed by PI3 kinase, PKC, or MAPK inhibition (all P < 0.01). HGF (50 ng/ml) stimulated PI3 kinase activity 347% (P < 0.001) and PKC activity 37% (P < 0.05). HGF-induced MAPK phosphorylation and mitogenesis were not inhibited by vascular endothelial growth factor (VEGF)-neutralizing antibody. HGF and its receptor are expressed in BREC, and HGF stimulates both BREC growth and migration at concentrations observed in the human eye with diabetic retinopathy. HGF signaling appears to involve activation of both PKC and PI3 kinase, inducing MAPK phosphorylation that is critical for migration and growth. However, VEGF does not appear to mediate these initial HGF effects. These results indicate that HGF could have a significant role in mediating retinal endothelial cell proliferation and migration in diabetic retinopathy, and they begin to elucidate the signal transduction pathway by which this action may occur.


Impact of referral bias on clinical and epidemiological studies of Alzheimer's disease.
We used the resources of the Rochester Epidemiology Project to compare sociodemographic and clinical characteristics in three groups of Alzheimer's disease patients. The first group included incidence cases occurring among residents of Rochester, Minnesota (population-based series; n = 241). The second group was a sample of patients referred to the Mayo Clinic form the remainder of Minnesota and the four surrounding states (n = 58); the third was a sample referred from the remainder of the United States (n = 94). Patients from Rochester were more frequently women, less highly educated, less commonly white collar workers, more frequently institutionalized, less frequently married, and more often lived along than those in the two referral groups. Patients from Rochester also had a more advanced age of onset of dementia. For occupation, education, and living arrangement, the differences across groups increased with increasing distance of referral. Clinical and epidemiological studies based on patients referred form primary to secondary or tertiary care centers may suffer from severe selection bias.


Untangling the water-food-energy-environment nexus for global change adaptation in a complex Himalayan water resource system.
Holistic water management approaches are essential under future climate and socio-economic changes, especially while trying to achieve inter-disciplinary societal goals such as the Sustainable Development Goals (SDGs) of clean water, hunger eradication, clean energy and life on land. Assessing water resources within a water-food-energy-environment nexus approach enables the relationships between water-related sectors to be untangled while incorporating impacts of societal changes. We use a systems modelling approach to explore global change impacts on the nexus in the mid-21st century in a complex western Himalayan water resource system in India, considering a range of climate change and alternative socio-economic development scenarios. Results show that future socio-economic changes will have a much stronger impact on the nexus compared to climate change. Hydropower generation and environmental protection represent the major opportunities and limitations for adaptation in the studied system and should, thereby, be the focus for actions and systemic transformations in pursue of the SDGs. The emergence of scenario-specific synergies and trade-offs between nexus component indicators demonstrates the benefits that water resource systems models can make to designing better responses to the complex nexus challenges associated with future global change.


Central, but not basolateral, amygdala is critical for control of feeding by aversive learned cues.
Environmental factors contribute to the motivation to eat and can override homeostatic signals to stimulate eating in sated states, or inhibit eating in states of hunger. In particular, stress, fear, and anxiety have been linked to suppression of eating and anorexia nervosa. Here, we use a rodent model of an aversive cue-induced cessation of feeding. In this setting, food-deprived rats suppress eating when presented with a tone [conditioned stimulus (CS)] that was previously paired with footshocks [unconditioned stimulus (US)]. To begin to delineate the underlying neural circuitry we examined the two regions of the amygdala with well known roles in associative learning--the central nucleus (CEA) and the basolateral area (BLA; includes the basolateral, basomedial, and lateral nuclei). We produced selective, bilateral, neurotoxic lesions of the CEA or BLA, and then trained these rats together with sham-lesioned controls in a behavioral protocol that allowed a test for food consumption in the presence of an aversive CS. Both sham- and BLA-lesioned rats showed inhibition of eating when presented with the CS. In contrast, bilateral, neurotoxic lesions of the CEA abolished this effect. These results demonstrate that the CEA, but not BLA, is critical for control of feeding by an aversive CS. Previously we demonstrated that enhancement of eating by an appetitive CS is dependent on the integrity of BLA, but not CEA. Those findings together with the current results show a double dissociation between amygdalar subsystems that control food consumption by appetitive and aversive learned cues.


Systems biology of molecular chaperone networks.
Molecular chaperones are not only fascinating molecular machines that help the folding, refolding, activation or assembly of other proteins, but also have a number of functions. These functions can be understood only by considering the emergent properties of cellular networks--and that of chaperones as special network constituents. As a notable example for the network-related roles of chaperones they may act as genetic buffers stabilizing the phenotype of various cells and organisms, and may serve as potential regulators of evolvability. Why are chaperones special in the context of cellular networks? Chaperones: (1) have weak links, i.e. low affinity, transient interactions with most of their partners; (2) connect hubs, i.e. act as 'masterminds' of the cell being close to several centre proteins with a lot of neighbours; and (3) are in the overlaps of network modules, which confers upon them a special regulatory role. Importantly, chaperones may uncouple or even quarantine modules of protein-protein interaction networks, signalling networks, genetic regulatory networks and membrane organelle networks during stress, which gives an additional chaperone-mediated protection for the cell at the network-level. Moreover, chaperones are essential to rebuild inter-modular contacts after stress by their low affinity, 'quasi-random' sampling of the potential interaction partners in different cellular modules. This opens the way to the chaperone-regulated modular evolution of cellular networks, and helps us to design novel therapeutic and anti-ageing strategies.


Prolonged expression and effective readministration of erythropoietin delivered with a fully deleted adenoviral vector.
Helper-dependent (HD) adenoviral (Ad) vectors, in which all viral coding sequences are deleted, have been generated. We show here that intravenous delivery of a mouse EPO (mEPO) expression cassette cloned in an HD vector in immunocompetent mice is effective and long lasting, but not permanent. A precise dose-response relationship between the dose of injected virus and stable EPO serum levels was observed, together with a 100-fold increase in gene expression per infectious particle when compared with a first-generation Ad vector bearing the same cassette. As a direct consequence, therapeutic increases in hematocrit that lasted more than 6 months were achieved with minute amounts of virus, which caused no detectable production of neutralizing antibodies. Intravenous readministration of the HD-mEPO vector in the same mice was as effective as in naive animals without any need for prior immunosuppression. Finally, HD-mEPO injection in subtotally nephrectomized rats improved the anemic status induced by surgery. HD Ad vectors are thus excellent tools for EPO gene therapy.


An emerging map of glutamate delta 1 receptors in the forebrain.
Glutamate delta 1 (GluD1) and glutamate delta 2 (GluD2) form the delta family of ionotropic glutamate receptors; these proteins plays widespread roles in synaptic architecture, motor behavior, and cognitive function. Though the role of GluD2 at cerebellar parallel fiber-Purkinje cell synapses is well established, attention now turns to the function of GluD receptors in the forebrain. GluD1 regulates synaptic assembly and modulation in multiple higher brain regions, acting as a postsynaptic cell adhesion molecule with effects on both excitatory and inhibitory transmission. Furthermore, variations and mutations in the GRID1 gene, which codes for GluD1, and in genes which code for proteins functionally linked to GluD1, are associated with mental disorders including autism, schizophrenia, bipolar disorder, and major depression. Cerebellin (Cbln) family proteins, the primary binding partners of delta receptors, are secreted C1q-like proteins which also bind presynaptic neurexins (NRXNs), forming a tripartite synaptic bridge. Published research explores this bridge's function in regions including the striatum, hippocampus, cortex, and cerebellum. In this review, we summarize region- and circuit-specific functions and expression patterns for GluD1 and its related proteins, and their implications for behavior and disease.


Harvey and Gurvir's Law: The Need for Accurate Information Balanced Against Avoiding Unnecessary Restrictions on Autonomous Decision Making.
Decision making during reproduction is complex for a variety of medical and social reasons. Anyone who has had a conversation with a family member about the "best time" to have a baby can attest to this - there is no "best time" or "best way." Multiple pressures from any number of sources combine in a minefield of hazards made ever more complicated by restrictive laws in the US. Add to this a screening result of potential chromosomal aneuploidy and decision making becomes ever more complex. Societal stigma and lack of adequate and accurate information during counseling certainly plays a role in the high number of terminations in the setting of diagnosed chromosomal aneuploidy, yet other factors also push families in this direction including medical considerations and the abysmal lack of social support programs.


Indole-3-carbinol inhibits prostate cancer cell migration via degradation of beta-catenin.
We determined whether indole-3-carbinol (I3C) could affect DU145 human prostate carcinoma cell migration to prevent the development and progression of prostate cancer. Although previous studies have shown anticancer properties of I3C in various cancer cell lines, it has not been determined how I3C regulates epidermal growth factor (EGF)-induced migration and related signaling pathways. DU145 cells were treated with I3C (100 microM) in the absence or presence of EGF (10 ng/ml). Our results showed that I3C significantly inhibited DU145 cell migration with and without EGF stimulation. It has been reported that the beta-catenin signaling pathway controls androgen receptor (AR)-mediated prostate cancer progression, which plays a key role in the metastasis of prostate cancer. Western blot analysis demonstrated that I3C led to the phosphorylation of beta-catenin and subsequent degradation of beta-catenin in the absence and presence of EGF. In contrast, I3C did not have any effect on the expression of beta-catenin mRNA. From these results, we suggest that I3C inhibits EGF (dependent or independent)-induced DU145 cell migration through beta-catenin degradation.


FcgammaRIII is protective against Pseudomonas aeruginosa pneumonia.
Defenses against bacterial infections involve activation of multiple systems of innate immunity, including complement, Toll-like receptors, and defensins. Reactions to chronic infections bring adaptive immune mechanisms into play as well, with the introduction of modulatory interactions between the two. In humans with chronic lung infections, the severity of inflammation and disease correlate with elevated levels of pathogen-specific immune complexes and complement activation. In mice with genetic deficiency in C5, or targeted deletion of the C5a receptor, Pseudomonas lung infections reveal a role for the C5a anaphylatoxin in disease severity. Deficient animals exhibit significantly reduced survival and clearance of infecting bacteria, simultaneous with greatly increased pulmonary influx of inflammatory cells. Among the actions of C5a on inflammatory cells mediated through the C5a receptor is a shift in the relative expression of Fcgamma receptors to increase FcgammaRIII relative to FcgammaRII. This shift may significantly impact defenses against chronic infection, reflecting the cellular activation profiles of these IgG receptors. We addressed the role of FcgammaRIII in defense against Pseudomonas lung infection, and found that, like C5aR-deficient mice, animals with targeted deletion of FcgammaRIII are more susceptible to mortality upon infection and exhibit reduced clearance of the pathogen. Pseudomonas infection was associated with an increase in the FcgammaRIII/FcgammaRII ratio in wild-type mice, and the data support its role as an additional mechanism of host defense against bacterial infection.


Examining the association between social health insurance participation and patients' out-of-pocket payments in China: the role of institutional arrangement.
Previous work on the relationship between social health insurance (SHI) participation and patients' out-of-pocket payments (OOP) in China has overlooked the mediating mechanisms of the institutional arrangement. This study establishes a conceptual framework involving the reimbursement, behavior management and purchasing mechanisms to elaborate on the institutional arrangement of SHI in China. Using structural equation modeling, data on 1645 hospitalized patients obtained from a nationally representative survey in China are analyzed. The results show that the behavior management and purchasing mechanisms of SHI perform poorly, undermining the function of the reimbursement mechanism and mitigating the association between SHI participation and OOP. As a result, SHI participation has a weak negative or even no significant association with the OOP of hospitalized patients. This seems to contradict the principles of SHI, which aims to reduce people's OOP and enhance their wellbeing. These findings are expected to provide valuable insights to the ongoing healthcare reform process in China.


[A PARADIGM SHIFT IN THE PERCEPTION OF HEALTH MAINTENANCE FROM INCREASING PHYSICAL ACTIVITY TO DECREASING PHYSICAL INACTIVITY].
Modern man spends most of his waking hours (50-70%) in one form or another of sedentary behavior, defined as activity conducted in a sitting or reclining position involving low energy expenditure. The remaining waking hours are spent performing low intensity physical activity (25-45%) and medium-high intensity physical activity (less than 5%): Despite this distribution, medical research has focused on the impact of increasing medium-high intensity physical activity and many health organizations' recommendations are in accordance. In recent years, research conducted has begun to examine the effect inactivity has on health and has shown that excess sedentary behaviour is an independent risk factor for a wide range of medical problems such as obesity, metabolic syndrome, poor cardiovascular health profile, diabetes mellitus, and possibly cancer. Although the higher risk brought on by sedentary behaviour is partially reduced by increasing medium-high intensity physical activity, it is not completely neutralized. One way to diminish the harm caused by long hours of sitting is to take short breaks during periods of prolonged sitting in order to walk. According to these findings, it is worthwhile to recommend reducing the hours spent in sedentary behaviour, or at least to take frequent short breaks ("activity snacks") during periods of prolonged sitting to get up and walk around.


Differences between dentitions with palatally and labially located maxillary canines observed in incisor width, dental morphology and space conditions.
To analyze the interrelationship between incisor width, deviations in the dentition and available space in the dental arch in palatally and labially located maxillary ectopic canine cases. Size: On dental casts from 69 patients (mean age 13 years 6 months) the mesiodistal widths of each premolar, canine and incisor were measured and compared with normal standards. Dental deviations: Based on panoramic radiographs from the same patients the dentitions were grouped accordingly: Group I: normal morphology; Group IIa: deviations in the dentition within the maxillary incisors only; Group IIb: deviations in the dentition in general. Descriptive statistics for the tooth sizes and dental deviations were presented by the mean and 95% confidence limits for the mean and the p-value for the T-statistic. Space: Space was expresses by subtracting the total tooth sizes of incisors, canines and premolars from the length of the arch segments. Size of lateral maxillary incisor: The widths of the lateral incisors were significantly different in groups I, IIa and IIb (p=0.016) and in cases with labially located ectopic canines on average 0.65 (95% CI:0.25-1.05, p=0.0019) broader than lateral incisors in cases with palatally located ectopic canines. Space: Least available space was observed in cases with labially located canines. The linear model did show a difference between palatally and labially located ectopic canines (p=0.03). Space related to deviations in the dentition: When space in the dental arch was related to dental deviations (groups I, IIa and IIb), the cases in group IIb with palatally located canines had significantly more space compared with I and IIa. Two subgroups of palatally located ectopic maxillary canine cases based on registration of space, incisor width and deviations in the morphology of the dentition were identified.


Treatment of bimaxillary protrusion with temporary anchorage devices.
For treatment of severe bimaxillary protrusion in adults, a condition known to be among the most difficult to manage, both the maxillary and mandibular anterior teeth must be fully retracted using all the extraction space available. This article reports the treatment of an adult with severe high-angle bimaxillary protrusion. To correct the protrusion of the anterior teeth, orthodontic anchor screws (OASs) were used to provide absolute anchorage during anterior retraction. Acceptable occlusion, facial profile, and balance were achieved. OASs appear to be very useful for treatment of severe bimaxillary protrusion in adults.


Extracellular HIV-1 Tat induces human beta-defensin-2 production via NF-kappaB/AP-1 dependent pathways in human B cells.
Defensins, a family of antimicrobial peptides, are one of the first lines of host defense. Human beta-defensins (hBD) such as hBD-2 and -3 have anti-HIV activity. Previous studies have shown that HIV-1 virion can induce the expression of hBD, although the exact components of HIV-1 virion that are responsible for hBD expression have not yet been elucidated. In this study, we examined the effect of HIV-1 Tat on the expression of hBD in B cells. Stimulation of B cells with HIV-1 Tat protein significantly increased the mRNA and protein levels of hBD-2. HIV-1 Tat also induced the activation of a reporter gene for hBD-2 in a dose-dependent manner in B cells. Pretreatment of B cells with a JNK inhibitor suppressed HIV-1 Tat-induced hBD-2 expression. Pretreatment of B cells with AP-1 inhibitors or NF-κB inhibitors led to a decrease in HIV-1 Tat-induced protein and mRNA expression of hBD-2. Taken together, our results indicate that HIV-1 Tat can up-regulate the expression of hBD-2 via JNK-NF-κB/AP-1-dependent pathways in human B cells.


Reelin Signaling Controls the Preference for Social Novelty in Zebrafish.
Reelin (Reln) is an extracellular glycoprotein that is important for brain patterning. During development Reln coordinates the radial migration of postmitotic cortical neurons, cerebellar and hippocampal neurons, whereas it promotes dendrite maturation, synaptogenesis, synaptic transmission, plasticity and neurotransmitter release in the postnatal and adult brain. Genetic studies of human patients have demonstrated association between the RELN locus and autism spectrum disorder, schizophrenia, bipolar disorder, and Alzheimer's disease. In this study we have characterized the behavioral phenotype of reelin (reln) mutant zebrafish, as well as two canonical signaling pathway targets DAB adaptor protein 1a (dab1a) and the very low density lipoprotein receptor (vldlr). Zebrafish reln-/- mutants display a selective reduction in preference for social novelty that is not observed in dab1a-/- or vldlr-/- mutant lines. They also exhibit an increase in 5-HT signaling in the hindbrain that parallels but does not underpin the alteration in social preference. These results suggest that zebrafish reln-/- mutants can be used to model some aspects of human diseases in which changes to Reln signaling alter social behavior.


Two patients with Kabuki syndrome presenting with endocrine problems.
A 4 year-old boy with mental retardation and seizures presented to the pediatric endocrinology clinic because of a history of hypoglycemia; a 16 month-old girl with developmental delay presented with bilateral breast tissue enlargement; in both, a diagnosis of Kabuki syndrome was made because of typical facial features, neurodevelopmental delay and other stigmata consistent with Kabuki syndrome. Kabuki syndrome is a mental retardation-malformation syndrome affecting multiple organ systems with a broad spectrum of abnormalities. The facial features of the syndrome are specific and independent of ethnic origin. In addition to presenting with endocrine problems, the patients reported here exhibit some novel findings such as congenital alopecia areata and hyperpigmented skin lesion. The diagnosis of Kabuki syndrome should be considered in patients with hypoglycemia or premature thelarche when associated with developmental delay and a peculiar facies.


Gastrointestinal cancer risk in patients with a family history of gastrointestinal cancer.
This study was performed to evaluate the relationship between family history of gastrointestinal (GI) cancers and incidence of any GI cancer in the Korean population. Between January 2015 and July 2016, 711 GI cancer patients and 849 controls in 16 hospitals in Korea were enrolled. Personal medical histories, life styles, and family history of GI cancers were collected via questionnaire. There was a significant difference in the incidence of family history of GI cancer between GI cancer patients and controls (p=0.002). Patients with family history of GI cancer tended to be diagnosed as GI cancer at younger age than those without family history (p=0.016). The family members of GI cancer patients who were diagnosed before 50 years of age were more frequently diagnosed as GI cancer before the age of 50 years (p=0.017). After adjusting for major confounding factors, age (adjusted odds ratio [AOR] 1.065, 95% confidence interval [CI]; 1.053-1.076), male gender (AOR 2.270, 95% CI; 1.618-3.184), smoking (AOR 1.570, 95% CI; 1.130-2.182), and sibling's history of GI cancer (AOR 1.973, 95% CI; 1.246-3.126) remained independently associated with GI cancers. GI cancer patients tended to have a first relative with a history of concordant GI cancer. Personal factors (old age and male) and lifestyle (smoking) contribute to the development of GI cancer, independently. Individuals with high risk for GI cancers may be advised to undergo screening at an earlier age.


Association between socioeconomic status (SES), mental health and need for long-term care (NLTC)-A Longitudinal Study among the Japanese Elderly.
This study was carried out to explore the relationship between the SES, mental health and the NLTC of the Japanese elderly, with the aim of providing useful information to lower the NLTC. A longitudinal survey was carried out in Tama City, Tokyo in 2001 and 2004. Data were collected from the urban-dwelling older adults, aged 65 years old and above, through self-reported questionnaires, which was participated by 7905 respondents (47.6% male and 52.4% female). Chi-square test, Kendall tau-b correlation analysis and structural equation modeling (SEM) were used to identify the association between SES, mental health and NLTC. The results of the SEM analysis indicated that mental health would exert a negative effect on NLTC for both the elderly men and the elderly women, while the effect was stronger for the elderly women; SES was significantly and negatively associated to NLTC, both for the elderly men and elderly women; a significant and positive relationship was observed between SES and mental health for both genders, but slightly stronger for the elderly men. These findings have implications for targeting the interventions that are aimed to delaying the NLTC and the financing of LTC system.


Good and bad molecular fingerprints for human rhinovirus 3C protease inhibition: identification, validation, and application in designing of new inhibitors through Monte Carlo-based QSAR study.
HRV 3 C protease (HRV 3Cpro) is an important target for common cold and upper respiratory tract infection. Keeping in view of the non-availability of drug for the treatment, newer computer-based modelling strategies should be applied to rationalize the process of antiviral drug discovery in order to decrease the valuable time and huge expenditure of the process. The present work demonstrates a structure wise optimization using Monte Carlo-based QSAR method that decomposes ligand compounds (in SMILES format) into several molecular fingerprints/descriptors. The current state-of-the-art in QSAR study involves the balance of correlation approach using four different sets: training, invisible training, calibration, and validation. The final models were also validated through mean absolute error, index of ideality of correlation, Y-randomization and applicability domain analysis. R2 and Q2 values for the best model were 0.8602, 0.8507 (training); 0.8435, 0.8331 (invisible training); 0.7424, 0.7020 (calibration); 0.5993, 0.5216 (validation), respectively. The process identified some molecular substructures as good and bad fingerprints depending on their effect to increase or decrease the HRV 3Cpro inhibition. Finally, new inhibitors were designed based on the fundamental concept to replace the bad fragments with the good fragments as well as including more good fragments into the structure. The study points out the importance of the fingerprint based drug design strategy through Monte Carlo optimization method in the modelling of HRV 3Cpro inhibitors.


Longitudinal 3T MRI T2 * mapping of Juvenile osteochondritis dissecans (JOCD) lesions differentiates operative from non-operative patients-Pilot study.
Juvenile osteochondritis dissecans (JOCD) is an orthopedic joint disorder of children and adolescents that can lead to premature osteoarthritis. Thirteen patients (mean age: 12.3 years, 4 females), 15 JOCD-affected and five contralateral healthy knees, that had a baseline and a follow-up magnetic resonance imaging (MRI) (mean interval of 8.9 months) and were treated nonoperatively during this interval were included. Retrospectively, patients were assigned to operative or nonoperative groups based on their electronic medical records. Volumetric mean T2 * values were calculated within regions of interest (progeny lesion, interface, parent bone) and region matched control bone in healthy contralateral knees and condyles. The normalized percentage difference of T2 * between baseline and follow up MRI in nonoperative patients significantly increased in progeny lesion (-47.8%, p < 0.001), parent bone (-13.9%, p < 0.001), and interface (-32.3%, p = 0.011), whereas the differences in operative patients were nonsignificant and below 11%. In nonoperative patients, the progeny lesion (p < 0.001) and interface T2 * values (p = 0.012) were significantly higher than control bone T2 * at baseline, but not at follow-up (p = 0.219, p = 1.000, respectively). In operative patients, the progeny lesion and interface T2 * values remained significantly elevated compared to the control bone both at baseline (p < 0.001, p < 0.001) and follow-up (p < 0.001, p < 0.001), respectively. Clinical Significance: Longitudinal T2 * mapping differentiated nonhealing from healing JOCD lesions following initial nonoperative treatment, which may assist in prognosis and improve the ability of surgeons to make recommendations regarding operative versus nonoperative treatment.


Cross-sex genetic correlations for fitness and fitness components: Connecting theoretical predictions to empirical patterns.
Sex differences in morphology, physiology, development, and behavior are widespread, yet the sexes inherit nearly identical genomes, causing most traits to exhibit strong and positive cross-sex genetic correlations. In contrast to most other traits, estimates of cross-sex genetic correlations for fitness and fitness components ( r W fm ) are generally low and occasionally negative, implying that a substantial fraction of standing genetic variation for fitness might be sexually antagonistic (i.e., alleles benefitting one sex harm the other). Nevertheless, while low values of r W fm are often regarded as consequences of sexually antagonistic selection, it remains unclear exactly how selection and variation in quantitative traits interact to determine the sign and magnitude of r W fm , making it difficult to relate empirical estimates of cross-sex genetic correlations to the evolutionary processes that might shape them. We present simple univariate and multivariate quantitative genetic models that explicitly link patterns of sex-specific selection and trait genetic variation to the cross-sex genetic correlation for fitness. We show that r W fm provides an unreliable signal of sexually antagonistic selection for two reasons. First, r W fm is constrained to be less than the cross-sex genetic correlation for traits affecting fitness, regardless of the nature of selection on the traits. Second, sexually antagonistic selection is an insufficient condition for generating negative cross-sex genetic correlations for fitness. Instead, negative fitness correlations between the sexes ( r W fm < 0 ) can only emerge when selection is sexually antagonistic and the strength of directional selection on each sex is strong relative to the amount of shared additive genetic variation in female and male traits. These results imply that empirical tests of sexual antagonism that are based on estimates of r W fm will be conservative and underestimate its true scope. In light of these theoretical results, we revisit current data on r W fm and sex-specific selection and find that they are consistent with the theory.


[Individualization of immunosuppressive treatment in patients with HCV infection after transplantation].
The number of patients with HCV infection is increasing in Georgia. High number of infection is noticeable in patients on hemodialysis. 60-70% of them needs renal transplantation. This makes the problem more acute especially among the organ recipients with HCV infection, who are receiving immunosuppressive treatment. The aim of the survey was to work out optimal protocol of immunosuppressive treatment for patients after renal transplantation. There were clinically observed 39 patients after renal transplantation. They were divided into four groups according to the clinical data (serology, replication of HCV and different schemes of immunosuppressive treatment). It was shown that immunosuppressive treatment carried out among patients with HCV infection after transplantation is effective and safe. Consideration of the data leads us to the statement that there is no risk of losing transplanted organ in case of individualization and minimization of immunosuppressive treatment. Periodic control of blood HCV RNA is reasonable during the pre and post operation period.


Use of Anal Acoustic Reflectometry in the Evaluation of Men With Passive Fecal Leakage.
Men with passive fecal leakage represent a distinct clinical entity in which the pathophysiology remains unclear. Standard anorectal investigations fail to demonstrate consistent abnormalities in this group. Anal acoustic reflectometry is a new test of anal sphincter function with greater sensitivity and discriminatory ability than conventional anal manometry. The aim of this study was to determine whether men with fecal leakage have an abnormality in anal sphincter function that is detectable by anal acoustic reflectometry. This was an age-matched study of continent and incontinent men. The study was conducted at a university teaching hospital. Male patients with isolated symptoms of fecal leakage were recruited. Anal acoustic reflectometry, followed by conventional anal manometry, was performed. Results were then compared with those from an age-matched group of men with no symptoms of anal incontinence or anorectal pathology. Variables measured with anal acoustic reflectometry and anal manometry in the incontinent and continent men were compared. Thirty subjects were recruited, of whom 15 were men with fecal leakage and 15 were continent men. There was a significantly higher incidence of previous anorectal surgery in the men with leakage. The anal acoustic reflectometry variables of opening and closing pressure were significantly lower in leakers compared with continent subjects (p = 0.003 and p = 0.001). Hysteresis was significantly greater in the male leaker group (p = 0.026). No difference was seen in anal manometry. With a larger sample size, the effect of previous anorectal surgery and the presence of an anal sphincter defect could be clarified. Anal acoustic reflectometry is a sensitive test of anal sphincter function and, unlike anal manometry, can discriminate male leakers from continent subjects. An identifiable abnormality has been detected using anal acoustic reflectometry, which may further our understanding of the pathogenesis in this group.


Flow cytometry for clinical estimation of circulating hematopoietic progenitors for autologous transplantation in cancer patients.
Optimum methods of harvesting circulating hematopoietic progenitors for autologous transplantation to support myeloablative cancer therapy are still uncertain, mostly because of the lack of an assay for marrow-repopulating stem cells. The CFU-GM assay, the commonly used indirect indicator of the quality of the graft, is poorly standardized and provides results evaluable only retrospectively. Based on the knowledge that hematopoietic progenitors express CD34 and CD33 differentiation antigens, we developed a dual-color direct immunofluorescence flow cytometry assay with the aim of replacing the CFU-GM assay advantageously. For this purpose, we applied both assays to 157 blood samples obtained daily throughout 20 different recoveries from pancytopenia induced by high-dose cyclophosphamide or etoposide cancer therapy with or without recombinant human GM colony-stimulating factor (rhGM-CSF). The appearance of CD34+ cells in the circulation indicated that hematopoietic progenitors had increased to more than 500 CFU-GM/mL, a level clinically adequate for large-scale harvest by leukapheresis. Total CD34+ cells correlated well with CFU-GM (r = .89), and data could be fitted by a linear regression line described by the equation y = 388.3 + 64.0x, where y = CFU-GM/mL and x = CD34+ cells per microliter. Moreover, in a series of six patients treated with myeloablative chemoradiotherapy, early hematopoietic recovery of marrow functions was predicted more accurately by the number of transplanted CD34+/CD33+ cells than by either total nucleated cells, CFU-GM, CD34+/CD33- cells, or CD34-/CD33+ cells. Data presented in this article favor clinical use of the CD34/CD33 flow cytometry assay to guide harvesting of circulating hematopoietic progenitors for autologous transplantation and contribute to better understanding of the role played by circulating hematopoietic progenitor cell subsets in marrow recovery after myeloablative cancer therapy.


The role of glycolytic metabolic pathways in cardiovascular disease and potential therapeutic approaches.
Cardiovascular disease (CVD) is a major threat to human health, accounting for 46% of non-communicable disease deaths. Glycolysis is a conserved and rigorous biological process that breaks down glucose into pyruvate, and its primary function is to provide the body with the energy and intermediate products needed for life activities. The non-glycolytic actions of enzymes associated with the glycolytic pathway have long been found to be associated with the development of CVD, typically exemplified by metabolic remodeling in heart failure, which is a condition in which the heart exhibits a rapid adaptive response to hypoxic and hypoxic conditions, occurring early in the course of heart failure. It is mainly characterized by a decrease in oxidative phosphorylation and a rise in the glycolytic pathway, and the rise in glycolysis is considered a hallmark of metabolic remodeling. In addition to this, the glycolytic metabolic pathway is the main source of energy for cardiomyocytes during ischemia-reperfusion. Not only that, the auxiliary pathways of glycolysis, such as the polyol pathway, hexosamine pathway, and pentose phosphate pathway, are also closely related to CVD. Therefore, targeting glycolysis is very attractive for therapeutic intervention in CVD. However, the relationship between glycolytic pathway and CVD is very complex, and some preclinical studies have confirmed that targeting glycolysis does have a certain degree of efficacy, but its specific role in the development of CVD has yet to be explored. This article aims to summarize the current knowledge regarding the glycolytic pathway and its key enzymes (including hexokinase (HK), phosphoglucose isomerase (PGI), phosphofructokinase-1 (PFK1), aldolase (Aldolase), phosphoglycerate metatase (PGAM), enolase (ENO) pyruvate kinase (PKM) lactate dehydrogenase (LDH)) for their role in cardiovascular diseases (e.g., heart failure, myocardial infarction, atherosclerosis) and possible emerging therapeutic targets.


Rheumatoid arthritis synovial macrophages express the Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein and are refractory to Fas-mediated apoptosis.
The chronic inflammation and progressive joint destruction observed in rheumatoid arthritis (RA) are mediated in part by macrophages. A paucity of apoptosis has been observed in RA synovial tissues, yet the mechanism remains unknown. The present study sought to characterize the expression of Fas, Fas ligand (FasL), and Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (FLIP), and to quantify the apoptosis induced by agonistic anti-Fas antibody, using mononuclear cells (MNC) isolated from the peripheral blood (PB) and synovial fluid (SF) of RA patients. The expression of Fas, FasL, and FLIP and apoptosis induced by agonistic anti-Fas antibody in MNC from the PB and SF of RA patients were determined by flow cytometry. Immunohistochemistry employing a monospecific anti-FLIP antibody was performed on RA and osteoarthritis (OA) synovial tissue. CD14-positive monocyte/macrophages from normal and RA PB and from RA SF expressed equivalent levels of Fas and FasL. Furthermore, unlike the CD14-positive PB monocytes, RA SF monocyte/macrophages were resistant to the addition of agonistic anti-Fas antibody. In contrast, both CD14-positive PB and SF monocyte/macrophages were sensitive to apoptosis mediated by a phosphatidylinositol 3-kinase inhibitor. Intracellular staining of the caspase 8 inhibitor, FLIP, in CD14-positive SF monocyte/macrophages revealed a significant up-regulation of FLIP compared with normal and RA PB monocytes. Immunohistochemical analysis of synovial tissue from RA and OA patients revealed increased FLIP expression in the RA synovial lining compared with the OA synovial lining. Furthermore, FLIP expression was observed in the CD68positive population in the RA synovial lining. Forced reduction of FLIP by a chemical inhibitor resulted in RA SF macrophage apoptosis that was enhanced by agonistic anti-Fas antibody, indicating that FLIP is necessary for SF macrophage survival. These data suggest that up-regulation of FLIP in RA macrophages may account for their persistence in the disease. Thus, the targeted suppression of FLIP may be a potential therapeutic strategy for the amelioration of RA.


High-level activation of transcription of the yeast U6 snRNA gene in chromatin by the basal RNA polymerase III transcription factor TFIIIC.
Transcription of the U6 snRNA gene (SNR6) in Saccharomyces cerevisiae by RNA polymerase III (pol III) requires TFIIIC and its box A and B binding sites. In contrast, TFIIIC has little or no effect on SNR6 transcription with purified components in vitro due to direct recognition of the SNR6 TATA box by TFIIIB. When SNR6 was assembled into chromatin in vitro by use of the Drosophila melanogaster S-190 extract, transcription of these templates with highly purified yeast pol III, TFIIIC, and TFIIIB displayed a near-absolute requirement for TFIIIC but yielded a 5- to 15-fold-higher level of transcription relative to naked DNA (>100-fold activation over repressed chromatin). Analysis of chromatin structure demonstrated that TFIIIC binding leads to remodeling of U6 gene chromatin, resulting in positioning of a nucleosome between boxes A and B. The resulting folding of the intervening DNA into the nucleosome could bring the suboptimally spaced SNR6 box A and B elements into greater proximity and thus facilitate activation of transcription. In the absence of ATP, however, the binding of TFIIIC to box B in chromatin was not accompanied by remodeling and the transcription activation was approximately 35% of that seen in its presence, implying that both TFIIIC binding and ATP-dependent chromatin remodeling were required for the full activation of the gene. Our results suggest that TFIIIC, which is a basal transcription factor of pol III, also plays a direct role in remodeling chromatin on the SNR6 gene.


Effect of the excitation source on the quantum-yield measurements of rhodamine B laser dye studied using thermal-lens technique.
A dual-beam transient thermal-lens technique was employed for the determination of absolute fluorescence quantum-yield measurements of Rhodamine B laser dye in different solvents. We investigated the effect of excitation on the absolute fluorescence quantum yield of Rhodamine B. 514 nm radiation from an argon ion laser was used as a cw excitation source and 532 nm pulses from a Q-switched Nd:YAG laser were used as a pulsed excitation source. The fluorescence quantum-yield values were found to be strongly influenced by environmental effects as well as the transient nature of the excitation beam. Our results also indicate that parameters, like the concentration of the dye solution, aggregate formation and excited state absorption, affect the absolute values of the fluorescence yield significantly.


Side chain metabolism of 25-hydroxy-[26,27-14C] vitamin D3 and 1,25-dihydroxy-[26,27-14C] vitamin D3 in vivo.
Radioactive CO2 was detected in expired air after the administration of 25-hydroxy-[26,27-14C] vitamin d3 to vitamin D-deficient hypocalcemic rats; 14co2 was also detected after the administration of 1,25-dihydroxy-[26,27-14C] vitamin D3 to rats raised on the same diet. Nephretcomy totally abolished 14CO2 formation after administration of 25-hydroxy-[26,27-14C] vitamin D3 but not after the administration of 1,25-dihydroxy-[26,27-14C] vitamin D3. The production of 14CO2 commenced within 4 hours after injection of 1,25-dihydroxy-[26,27-14C] vitamin D3, suggesting a possible relevance of this reaction to the function of 1,25-dihydroxyvitamin D3. These results at least demonstrate a new metabolic pathway of vitamin D3 metabolism involving the oxidation of a portion of the side chain of 1,25-dihydroxyvitamin D3 to CO2.


[Bioelectric activity of the brain and glucocorticoid production in patients with hematologic malignancies].
A parallel study of bioelectrical activity of the brain and urine excretion of 17-hydroxycorticosteroids was carried out in 107 patients with various malignant tumors of hemopoietic tissue before, during and after treatment. In all of them, electroencephalography showed excitation of the hypothalamus, the central component of the hypothalamo-pituitary-adrenal system. Moreover, the patients revealed a significant increase in the excretion of 17-hydroxycorticosteroids that pointed to the activation of the peripheral component--the adrenal cortex. Activation of both central and peripheral components suggests that its intermediate component--the pituitary--is activated in patients with hemopoietic system neoplasms, too.


Incidence and risk factors for epidural morphine induced pruritus in parturients receiving cesarean section: A prospective multicenter observational study.
This study is designed to clarify the incidence of epidural morphine induced pruritus (EMIP) in Chinese Han and Tibetan parturients after cesarean section (CS) and to identify the correlated risk factors.This is a prospective multicenter observational study. Follow-up evaluations were performed at 3 hours, 6 hours, 12 hours, 24 hours, and 48 hours after morphine administration. The primary outcome was EMIP incidence. Other details were also recorded for risk factor screening.Totally 284 parturients receiving CS were enrolled and 247 completed the study. The overall incidence of EMIP was 18.6% (46 in 247). The onset of pruritus was 5.6 ± 4.8 hours (mean ± SD) after morphine administration and the duration of pruritus was 14.0 ± 8.8 hours. Logistic regression models was built with 5 variables, history of allergy, serotonin receptor antagonist administration, I.V. fentanyl administration, epidural morphine volume and VAS pain score. Results of showed that 2 of the variables, history of allergy (P < .001) and serotonin receptor antagonist (P < .05), were significantly correlated with incidence of EMIP.In conclusion, EMIP incidence in our study was 18.6%. Positive medical history of allergy and not using serotonin receptor antagonist were potential risk factors of EMIP development.Trial registration: ChiCTR-OPC-17012345.


A new promising oncogenic target (p.C382R) for treatment with pemigatinib in patients with cholangiocarcinoma.
Point mutations of the fibroblast growth factor receptor (FGFR)2 receptor in intrahepatic cholangiocarcinoma (iCC) are mainly of unknown functional significance compared to FGFR2 fusions. Pemigatinib, a tyrosine kinase inhibitor, is approved for the treatment of cholangiocarcinoma with FGFR2 fusion/rearrangement. Although it is hypothesized that FGFR2 mutations may cause uncontrolled activation of the signaling pathway, the data for targeted therapies for FGFR2 mutations remain unclear. In vitro analyses demonstrated the importance of the p.C382R mutation for ligand-independent constitutive activation of FGFR2 with transforming potential. The following report describes the clinical case of a patient diagnosed with an iCC carrying a FGFR2 p.C382R point mutation which was detected in liquid, as well as in tissue-based biopsies. The patient was treated with pemigatinib, resulting in a sustained complete functional remission in fluorodeoxyglucose-positron emission tomography/computed tomography over 10 months to date. The reported case is the first description of a complete functional remission under the treatment with pemigatinib in a patient with p.C383R mutation.


Physician practice variation under orthopedic bundled payment.
To describe the extent of and longitudinal changes in physician practice variation with respect to implant costs, institutional postacute care (PAC) provider utilization, and total episode payments, as well as to evaluate the association between physician volume and quality and these outcomes. Observational study. We combined claims and internal hospital cost data for 34 physicians responsible for 3614 joint replacement episodes under bundled payment at Baptist Health System (BHS). Multilevel multivariable generalized linear models were employed and the intraclass correlation (ICC) was used to quantify between-physician variation. There was significant between-physician variation in implant costs, institutional PAC provider utilization, and total episode payments not explained by observable variables (P <.001 for all). Over 5 years, the ICC decreased from 0.26 to 0.06, 0.15 to 0.13, and 0.12 to 0.10 for implant costs, institutional PAC provider utilization, and total episode payments, respectively, but differences were not statistically significant. Both higher physician case volume and quality were associated with decreased total episode payments and institutional PAC provider utilization, but not with changes in implant costs. Considerable physician practice variation was observed under bundled payment at BHS and decreased to a greater degree for implant costs than institutional PAC provider utilization or total episode payments. Institutional PAC provider utilization and total episode payments were associated with physician volume and quality. Although some organizational strategies achieve gains by reducing physician practice variation, variation reduction is not an absolute requisite for success under bundled payment.


Feeding patterns of S. crassicaudata (Marsupialia:Dasyuridae): role of gender, photoperiod, and fat stores.
Little is known about feeding regulation in marsupials. Sminthopsis crassicaudata is a small nocturnal marsupial, whose tail contains approximately 25% total body fat. We have characterized the effect of gender, photoperiod, food deprivation, and tail removal (lipectomy) on food intake in S. crassicaudata. Males and females maintained in captivity on long-day (LD, 16:8-h light-dark cycle) and short-day (SD, 9:15-h light-dark cycle) light regimens were studied. Feeding patterns under LD and SD photoperiods were initially measured under conditions of ad libitum food supply and then in groups of animals exposed to 24- and 36-h periods of food deprivation. Feeding occurred predominantly in the dark. Females maintained on SD photoperiods for 5 wk ate less (P < 0.005) than females on LD or males on either SD or LD, but this reduction in food intake was not associated with a decrease either in body weight or tail width. After both 24- and 36-h fasts, total food intake in the subsequent 24 h increased (P < 0.001) up to 100% in all groups, with no gender or photoperiod effect. SD females, however, ate less (P < 0.05) than LD females in the first 6 h after refeeding. Tail width decreased (P < 0.05) in all groups of animals after the 36-h fast but only in LD animals after the 24-h fast (P < 0.05). Body weight decreased similarly in all groups of animals after fasting. The effect of tail removal was studied in LD males. The procedure, which was well tolerated, resulted in an initial decrease in body weight (P < 0.005), which recovered within 3 wk. On day 45 in the animals whose tails were removed, body fat was approximately 30% greater than body fat of controls (P < 0.02). No significant increase in food intake occurred after tail removal. These data demonstrate in Sminthopsis crassicaudata 1) a photoperiod and gender-dependent effect on food intake, 2) the ability to regulate the amount and distribution of total body fat, and 3) a dissociation between the regulation of food intake and changes in body fat stores, which suggest alterations in energy expenditure.


Erythropoietin reduces the degree of arthritis caused by type II collagen in the mouse.
Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells, and its expression is enhanced by hypoxia. The aim of this study was to investigate the effect of EPO on collagen-induced arthritis (CIA) in the mouse. CIA was induced by intradermal injection of bovine type II collagen (CII) and Freund's complete adjuvant. Starting on day 25, some of the mice with CIA received daily subcutaneous injections of EPO (1,000 units/kg). Two other groups of mice received sham treatment alone or sham treatment followed by EPO treatment, respectively. Arthritis was assessed clinically, radiologically, and histologically. Cytokine and chemokine levels were measured, and neutrophil infiltration into inflamed joints was quantitated. Immunohistochemistry studies were performed to measure protein nitrosylation. Chondrocyte apoptosis was assessed by TUNEL assay. Macroscopic clinical evidence of CIA first appeared as periarticular erythema and edema in the hind paws. The incidence of CIA was 100% by day 27 in the CII-challenged mice, and the severity of CIA progressed over a 35-day period, with radiographic evaluation revealing focal resorption of bone. Histopathologic features of CIA included erosion of the cartilage at the joint margins. Treatment with EPO starting at the onset of arthritis (day 25) ameliorated the clinical signs on days 26-35 and improved histologic status in the joints and paws. The degree of oxidative and nitrosative damage was significantly reduced in EPO-treated mice as indicated by decreased nitrotyrosine formation and poly(ADP-ribose) polymerase activation. Plasma levels of the proinflammatory cytokine tumor necrosis factor alpha were also significantly reduced by EPO treatment. In addition, EPO reduced the levels of apoptosis in chondrocytes in articular cartilage, as indicated by decreased TUNEL staining. These findings demonstrate that EPO exerts an antiinflammatory effect during chronic inflammation and is able to ameliorate the tissue damage associated with CIA.


The high incidence of tuberculosis among renal transplant recipients in India.
Tuberculosis is an important infection encountered after renal transplantation in third-world countries. Over an 8-year period, 36 cases of tuberculosis were encountered in 305 renal transplant recipients (11.8%) with grafts functioning for more than 3 months followed up at our center. The infection was limited to the thoracic cavity in 41.7% and a single extrapulmonary site in 11.1%, and it was disseminated in 27.8% cases. In 19.4% of cases, the disease appeared as pyrexia of unknown etiology and the diagnosis was confirmed by a good therapeutic response to antitubercular therapy. Tuberculosis was diagnosed within 1 year of transplantation in 58.3% of cases. There was no significant difference in the incidence of tuberculosis in patients on different immunosuppressive regimens. The Mantoux test was positive in 33.3% patients. A total of 23 patients were treated with isoniazid and rifampicin, with the addition of a third drug for the first 2 months. Treatment was continued for 9 months in 11 cases with isolated pleuropulmonary disease and for 12-15 months in the other 12 patients. The other 13 were on cyclosporine and were given isoniazid, pyrazinamide, and ethambutol for 18 months. Two patients died of fulminant disease and five more died from unrelated causes. No recurrence of disease has been noted in any of the patients after a mean follow-up of 14.6 months. We conclude that the incidence of tuberculosis in renal allograft recipients in third world countries is much higher than that seen in the western world. Most of the cases are encountered in the first posttransplant year. Tuberculosis must be considered seriously in all patients who have prolonged fever of undetermined etiology. Treatment with isoniazid and rifampicin for 9 months is adequate for patients with localized pleuropulmonary disease. In patients on cyclosporine to whom rifampicin cannot be given because of economic considerations, treatment with isoniazid, pyrazinamide, and ethambutol should be given for 18 months.


Plasma membrane microdomains: organization, function and trafficking.
The plasma membrane consists of a mosaic of functional microdomains facilitating a variety of physiological processes associated with the cell surface. In most cells, the majority of the cell surface is morphologically featureless, leading to difficulties in characterizing its organization and microdomain composition. The reliance on indirect and perturbing techniques has led to vigorous debate concerning the nature and even existence of some microdomains. Recently, increasing technical sophistication has been applied to study cell surface compartmentalization providing evidence for small, short-lived clusters that may be much less than 50 nm in diameter. Lipid rafts and caveolae are cholesterol-dependent, highly ordered microdomains that have received most attention in recent years, yet their precise roles in regulating functions such as cell signalling remain to be determined. Endocytosis of lipid rafts/caveolae follows a clathrin-independent route to both early endosomes and non-classical caveosomes. The observation that a variety of cellular pathogens localize to and internalize with these microdomains provides an additional incentive to characterize the organization, dynamics and functions of these domains.


[Mechanical instrumentation of the root canals. A study using SEM and computerized image analysis].
The effectiveness of ultrasonic and sonic instrumentation in eliminating the smear layer from instrumented root channels. The results were examined with S.E.M. and the effective areas of dental diffusion were calculated using the computerized image analyzer. The agents used: citric acid at concentrations of 10, 25 and 50% as well as 15% EDTA, proved their efficiency with both types of mechanical instrumentation. However, the area of diffusion found was always greater using the ultrasonic instrumentation technique as opposed to the sonic instrumentation technique. 1, 2.5 and 5.25% sodium hypochlorite, as well as 10 volume hydrogen peroxide were not effective in eliminating the smear layer using both types of instrumentation.


Deep Learning-Based Recognition of Periodontitis and Dental Caries in Dental X-ray Images.
Dental X-ray images are important and useful for dentists to diagnose dental diseases. Utilizing deep learning in dental X-ray images can help dentists quickly and accurately identify common dental diseases such as periodontitis and dental caries. This paper applies image processing and deep learning technologies to dental X-ray images to propose a simultaneous recognition method for periodontitis and dental caries. The single-tooth X-ray image is detected by the YOLOv7 object detection technique and cropped from the periapical X-ray image. Then, it is processed through contrast-limited adaptive histogram equalization to enhance the local contrast, and bilateral filtering to eliminate noise while preserving the edge. The deep learning architecture for classification comprises a pre-trained EfficientNet-B0 and fully connected layers that output two labels by the sigmoid activation function for the classification task. The average precision of tooth detection using YOLOv7 is 97.1%. For the recognition of periodontitis, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve is 98.67%, and the AUC of the precision-recall (PR) curve is 98.38%. For the recognition of dental caries, the AUC of the ROC curve is 98.31%, and the AUC of the PR curve is 97.55%. Different from the conventional deep learning-based methods for a single disease such as periodontitis or dental caries, the proposed approach can provide the recognition of both periodontitis and dental caries simultaneously. This recognition method presents good performance in the identification of periodontitis and dental caries, thus facilitating dental diagnosis.


Miconazole nitrate vaginal suppository 1,200 mg versus oral fluconazole 150 mg in treating severe vulvovaginal candidiasis.
Miconazole is a synthetic imidazole antifungal that has a broad spectrum of activity against Candida albicans and non-albicans Candida species. The aim of this study was to evaluate the efficacy and safety of miconazole nitrate vaginal suppository and oral fluconazole in treating severe vulvovaginal candidiasis (SVVC). In this prospective, randomized case control study, 577 cases of consecutive patients with SVVC were studied at the Gynecological Clinic of Peking University Shenzhen Hospital from January 1, 2009 through December 31, 2010. Patients with SVVC were treated with two doses of miconazole nitrate vaginal suppository 1,200 mg or two doses of fluconazole 150 mg. The patients were followed up for 7-14 and 30-35 days following the second dose of therapy. The mycological cure rates of the patients on days 7-14 of follow-up were 75.9% (220/290) and 84.0% (241/287) in the miconazole and fluconazole groups, respectively (p < 0.05). The mycological cure rates of the patients at the second follow-up were 64.8% (188/290) and 69.7% (200/287), respectively, in the two groups (p > 0.05). The study demonstrated that two doses of miconazole nitrate vaginal suppository 1,200 mg were as effective as two doses of an oral fluconazole 150 mg regimen in the treatment of patients with SVVC.


Pathobiological implications of the d16HER2 splice variant for stemness and aggressiveness of HER2-positive breast cancer.
We have previously shown that the d16HER2 splice variant is linked to HER2-positive breast cancer (BC) tumorigenesis, progression and response to Trastuzumab. However, the mechanisms by which d16HER2 contributes to HER2-driven aggressiveness and targeted therapy susceptibility remain uncertain. Here, we report that the d16HER2-positive mammary tumor cell lines MI6 and MI7, derived from spontaneous lesions of d16HER2 transgenic (tg) mice and resembling the aggressive features of primary lesions, are enriched in the expression of Wnt, Notch and epithelial-mesenchymal transition pathways related genes compared with full-length wild-type (WT) HER2-positive cells (WTHER2_1 and WTHER2_2) derived from spontaneous tumors arising in WTHER2 tg mice. MI6 cells exhibited increased resistance to anoikis and significantly higher mammosphere-forming efficiency (MFE) and self-renewal capability than the WTHER2-positive counterpart. Furthermore, d16HER2-positive tumor cells expressed a higher fraction of CD29High/CD24+/SCA1Low cells and displayed greater in vivo tumor engraftment in serial dilution conditions than WTHER2_1 cells. Accordingly, NOTCH inhibitors impaired mammosphere formation only in MI6 cells. A comparative analysis of stemness-related features driven by d16HER2 and WTHER2 in ad hoc engineered human BC cells (MCF7 and T47D) revealed a higher MFE and aldehyde dehydrogenase-positive staining in d16HER2- vs WTHER2-infected cells, sustaining consistent BC-initiating cell enrichment in the human setting. Moreover, marked CD44 expression was found in MCF7_d16 and T47D_d16 cells vs their WTHER2 and Mock counterparts. Clinically, BC cases from two distinct HER2-positive cohorts characterized by high levels of expression of the activated-d16HER2 metagene were significantly enriched in the Notch family and signal transducer genes vs those with low levels of the metagene.