Degradation mechanisms of phoxim in river water.
Degradation of phoxim in river water was fully explored in this paper. Effects of pH, temperature, and photoirradiation on the degradation were investigated in detail. The results indicated that the degradation was characterized by a first-order process; UV irradiation and the increase of pH and temperature substantially accelerated the degradation. To fully characterize the degradation mechanism, HPLC-MS/MS was utilized to identify the degradation intermediates. Five intermediates were identified as phoxom, phoxom dimer, O,O,O',O'-tetraethyldithiopyrophosphate, O,O,O'-triethyl-O'-2-hydroxyethyldisulfinylpyrophosphate, and O,O,O'-triethyl-O'-2-hydroxyethyldithiopyrophosphate. On the basis of the results of the intermediate analysis, the degradation pathways of phoxim under the present experimental conditions were proposed. Through conversion of a thiophosphoryl into a phosphoryl group, some phoxim was converted to phoxom, most of which further formed dimer. Another portion of phoxim transformed to O,O,O',O'-tetraethyldithiopyrophosphate via nucleophilic substitution and photolysis. Thereafter, O,O,O',O'-tetraethyldithiopyrophosphate underwent hydroxylation to form O,O,O'-triethyl-O'-2-hydroxyethyldithiopyrophosphate or sulfur oxidation first and then hydroxylation to produce O,O,O'-triethyl-O'-2-hydroxyethyldisulfinylpyrophosphate. The understanding of phoxim's degradation mechanism in this study will be critical to its safety assessment and increase the understanding of the fate of phoxim in environment water.


Strengthening epidemiologic investigation of infectious diseases in Korea: lessons from the Middle East Respiratory Syndrome outbreak.
The recent outbreak of Middle East Respiratory Syndrome (MERS) coronavirus infection in Korea resulted in large socioeconomic losses. This provoked the Korean government and the general public to recognize the importance of having a well-established system against infectious diseases. Although epidemiologic investigation is one of the most important aspects of prevention, it has been pointed out that much needs to be improved in Korea. We review here the current status of the Korean epidemiologic service and suggest possible supplementation measures. We examine the current national preventive infrastructure, including human resources such as Epidemic Intelligence Service officers, its governmental management, and related policies. In addition, we describe the practical application of these resources to the recent MERS outbreak and the progress in preventive measures. The spread of MERS demonstrated that the general readiness for emerging infectious diseases in Korea is considerably low. We believe that it is essential to increase society's investment in disease prevention. Fostering public health personnel, legislating management policies, and establishing research centers for emerging infectious diseases are potential solutions. Evaluating international preventive systems, developing cooperative measures, and initiating improvements are necessary. We evaluated the Korean epidemiologic investigation system and the public preventive measures against infectious diseases in light of the recent MERS outbreak. We suggest that governmental authorities in Korea enforce preventive policies, foster the development of highly qualified personnel, and increase investment in the public health domain of infectious disease prevention.


Pattern Recognition in Vital Signs Using Spectrograms.
Spectrograms visualize the frequency components of a given signal which may be an audio signal or even a time-series signal. Audio signals have higher sampling rate and high variability of frequency with time. Spectrograms can capture such variations well. But, vital signs which are time-series signals have less sampling frequency and low-frequency variability due to which, spectrograms fail to express variations and patterns. In this paper, we propose a novel solution to introduce frequency variability using frequency modulation on vital signs. Then we apply spectrograms on frequency modulated signals to capture the patterns. The proposed approach has been evaluated on 4 different medical datasets across both prediction and classification tasks. Significant results are found showing the efficacy of the approach for vital sign signals. The results from the proposed approach are promising with an accuracy of 91.55% and 91.67% in prediction and classification tasks respectively.


Reactivation of the p90RSK-CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G2-M Arrest and Mediates Acquired Resistance to Ganetespib in KRAS-Mutant NSCLC.
A subset of non-small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations, including the most frequently observed driver mutant KRAS, which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Hsp90 inhibitors appeared to be a promising therapy for KRAS-mutant NSCLC; however, limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib, and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to ganetespib and explored why the combination with docetaxel failed in the clinic. We have not only identified a critical role for the bypass of the G2-M cell-cycle checkpoint as a mechanism of ganetespib resistance (GR) but have also found that GR leads to cross-resistance to docetaxel. Reactivation of p90RSK and its downstream target, CDC25C, was critical for GR and mediated the bypass of a G2-M arrest. Overexpression of either p90RSK or CDC25C lead to bypass of G2-M arrest and induced ganetespib resistance in vitro and in vivo Moreover, resistance was dependent on p90RSK/CDC25C signaling, as synthetic lethality to ERK1/2, p90RSK, or CDC25C inhibitors was observed. Importantly, the combination of ganetespib and p90RSK or CDC25C inhibitors was highly efficacious in parental cells. These studies provide a way forward for Hsp90 inhibitors through the development of novel rationally designed Hsp90 inhibitor combinations that may prevent or overcome resistance to Hsp90i. Mol Cancer Ther; 16(8); 1658-68. ©2017 AACR.


[Treatment of acute cerebrovascular disorders].
Recent advances in technology have improved stroke diagnosis, reduced the risks and increased the frequency of studies of stroke mechanism. Computer-assisted stroke data bank projects have provided new insights into the frequencies of stroke subtypes and the risks for progression and recurrence. A high frequency of strokes due to infarction remain unexplained despite thorough laboratory investigation. These infarcts of undetermined cause suffer recurrence rates almost as high as cardiogenic embolism, forcing a therapeutic decision even in the absence of a demonstrated cause. Stroke from atherosclerosis is far less common than formerly believed but carries the highest risk of worsening and early recurrence, prompting early treatment to attempt to avoid progression. Duplex and transcranial doppler methods of imaging blood vessels and insonating flow have now made it possible non-invasively to follow the course of atheromatous stenosis, embolism and recanalization, development of collateral flow, and vasospasm in ruptured aneurysms and arteriovenous malformations. Extracranial atheromatous disease may progress rapidly from mild to severe stenosis, stabilize at any point; intracranial collateral is not predicted by the degree of extracranial stenosis. Recanalization of cerebral embolism occurs early. Vasospasm after subarachnoid hemorrhage is common and often severe. Where available, magnetic resonance imaging is preferred to CT scanning for the diagnosis of every form of stroke including hemorrhage.


Fatty acids distribution and content in oral squamous cell carcinoma tissue and its adjacent microenvironment.
Squamous cell carcinoma of the oral cavity mucosa grows under conditions of poor oxygenation and nutrient scarcity. Reprogramming of lipid biosynthesis accompanies tumor growth, but the conditions under which it occurs are not fully understood. The fatty acid content of the serum, tumor tissue and adjacent tumor microenvironment was measured by gas chromatography in 30 patients with squamous cell carcinoma grade 1-3. Twenty-five fatty acids were identified; their frequencies and percentages in each of the environments were assessed. Nineteen of the twenty-five fatty acids were found in tumor tissue, tumor adjacent tissue and blood serum. Of them, 8 were found in all thirty patients. Percentages of C16:0 and C18:1n9 were highest in the tumor, C18:1n9 and C16:0 were highest in tumor adjacent tissue, and C16:0 and C18:0 were highest in blood serum. The frequencies and amounts of C22:1n13, C22:4n6, C22:5n3 and C24:1 in tumor adjacent tissues were higher than those in blood serum, independent of the tumor grade. The correlations between the amount of fatty acid and tumor grade were the strongest in tumor adjacent tissues. The correlations between particular fatty acids were most prevalent for grade 1+2 tumors and were strongest for grade 3 tumors. In the adjacent tumor microenvironment, lipogenesis was controlled by C22:6w3. In blood serum, C18:1trans11 limited the synthesis of long-chain fatty acids. Our research reveals intensive lipid changes in oral cavity SCC adjacent to the tumor microenvironment and blood serum of the patients. Increase in percentage of some of the FAs in the path: blood serum-tumor adjacent microenvironment-tumor, and it is dependent on tumor grade. This dependency is the most visible in the tumor adjacent environment.


Giant recurrent fibromatosis of the breast: a case report. Clinical features and implications for treatment.
Fibromatosis of the breast is a benign but locally aggressive neoplasm, which has been described under various names including extra-abdominal desmoid tumour and aggressive fibromatosis. It is a rare condition, accounting for approximately 0.2% of all solid tumours of the breast. Clinically and radiologically the lesion mimics breast cancer and the definitive diagnosis is provided by histology. A high risk of local recurrence is a characteristic of this disease. Radical excision of the tumour with clear histological margins decreases the likelihood of recurrence. The possible association between breast implants and mammary fibromatosis has been reported. In this study we report a case of giant fibromatosis of the breast observed in a young patient and its extensive recurrence, involving all quadrants of the breast, the pectoralis major muscle, the rectus abdominis muscle sheath and the costal layer. The main clinical and pathological characteristics of this rare disease are illustrated, emphasizing the difficulties encountered both in the diagnosis of the primary lesion and in the management of its giant recurrence, particularly as regards the possibility of obtaining a radical surgical excision and the option of performing breast reconstruction.


People Cheat on Task Performance When They Feel Bored: The Mediating Role of State Self-Efficacy.
It is unclear whether the state of boredom is related to morality. The present study investigated how state boredom influenced cheating behaviors on task performance. In Study 1 (N = 104), participants were induced to feel bored, and then reported whether they had finished an anagram task (two sentences in the task were unsolvable). The results found that people with higher boredom showed more cheating behaviors than those with lower boredom on task performance. In Study 2 (N = 139), participants completed the Multidimensional State Boredom Scale, and then completed the same anagram task as in Study 1, as well as a state self-efficacy scale. The results revealed that state self-efficacy mediated the effect of state boredom on cheating behaviors on task performance. In other words, a higher level of state boredom leads to a lower level of state self-efficacy, and the lower state self-efficacy then results in more cheating behaviors. The present study provides empirical evidence that state boredom has its moral function through state self-efficacy.


2006 NOVA Awards.
From projects helping the uninsured in Wisconsin to medical care on wheels in rural Kentucky, these award-winning hospitals share the common goal of improving health care in their own back yards.


Human frequency following responses to iterated rippled noise with positive and negative gain: Differential sensitivity to waveform envelope and temporal fine-structure.
The perceived pitch of iterated rippled noise (IRN) with negative gain (IRNn) is an octave lower than that of IRN with positive gain (IRNp). IRNp and IRNn have identical waveform envelopes (ENV), but differing stimulus waveform fine structure (TFS), which likely accounts for this perceived pitch difference. Here, we examine whether differences in the temporal pattern of phase-locked activity reflected in the human brainstem Frequency Following Response (FFR) elicited by IRNp and IRNn can account for the differences in perceived pitch for the two stimuli. FFRs using a single onset polarity were measured in 13 normal-hearing, adult listeners in response to IRNp and IRNn stimuli with 2 ms, and 4 ms delay. Autocorrelation functions (ACFs) and Fast Fourier Transforms (FFTs) were used to evaluate the dominant periodicity and spectral pattern (harmonic spacing) in the phase-locked FFR neural activity. For both delays, the harmonic spacing in the spectra corresponded more strongly with the perceived lowering of pitch from IRNp to IRNn, compared to the ACFs. These results suggest that the FFR elicited by a single polarity stimulus reflects phase-locking to both stimulus ENV and TFS. A post-hoc experiment evaluating the FFR phase-locked activity to ENV (FFRENV), and TFS (FFRTFS) elicited by IRNp and IRNn confirmed that only the phase-locked activity to the TFS, reflected in FFRTFS, showed differences in both spectra and ACF that closely matched the pitch difference between the two stimuli. The results of the post-hoc experiment suggests that pitch-relevant information is preserved in the temporal pattern of phase-locked activity and suggests that the differences in stimulus ENV and TFS driving the pitch percept of IRNp and IRNn are preserved in the brainstem neural response. The scalp recorded FFR may provide for a noninvasive analytic tool to evaluate the relative contributions of envelope and temporal fine-structure in the neural representation of complex sounds in humans.


"Radical theory" of oxidative phosphorylation and photophosphorylation.
Ketyl radicals of acetone, dihydroxy acetone, and cardiolipin ketone react in 1,2-dimethoxyethane with inorganic phosphate (model: diethyl phosphate) to form phosphate esters of isopropanol, glycerol, or cardiolipin, respectively. After administration of diethyl phosphate to phosphate-impoverished rats, cardiolipin diethyl phosphate (probably as enol phosphate) has been isolated from liver mitochondria. Hence it is assumed that the enol phosphates of cardiolipin or of an analogous compound (mitochondria and chloroplasts) can be considered as high-energy intermediates of both oxidative and photochemical phosphorylation. Moreover, owing to earlier investigations which show that the formation of the phosphoric-acid-anhydride bond occurs proton-catalytically by acidolysis of enol phosphates, it is attempted here to combine the classic theories--"Chemical Coupling", "Chemiosmosis", and "Cooperativity", including the "Collision Hypothesis"--into the "Radical Theory of Oxidative Phosphorylation and Photophosphorylation".


Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases.
The Rho guanosine triphosphatases (GTPases) Rac1 and Rac2 are critical signaling regulators in mammalian cells. The deletion of both Rac1 and Rac2 murine alleles leads to a massive egress of hematopoietic stem/progenitor cells (HSC/Ps) into the blood from the marrow, whereas Rac1-/- but not Rac2-/- HSC/Ps fail to engraft in the bone marrow of irradiated recipient mice. In contrast, Rac2, but not Rac1, regulates superoxide production and directed migration in neutrophils, and in each cell type, the two GTPases play distinct roles in actin organization, cell survival, and proliferation. Thus, Rac1 and Rac2 regulate unique aspects of hematopoietic development and function.


Conjunctival allergenicity-supporting factor (CASF) in DIIIa as the sea squirt antigen capable of inducing asthmatic attack and conjunctival reaction in sea squirt asthma.
Among three glycoproteins, DIIIa, Ei-M, and Gi-rep, isolated from sea squirt as antigens capable of eliciting skin reaction specific to sea squirt allergy, only DIIIa induces asthmatic attack and conjunctival reaction, whereas Ei-M and Gi-rep do not. Periodate oxidation eliminated not only the conjunctival allergenicity but also the skin allergenicity from DIIIa, suggesting that the conjunctival and skin allergenicity could both be ascribed to the epitope residing in the carbohydrate chains of DIIIa. On the other hand, proteolysis with Pronase E and chemical modifications of the carboxyl or amino groups by various methods eliminated the conjunctival allergenicity from DIIIa, whereas the skin allergenicity was still retained. Therefore, the expression of conjunctival reaction was expected to be supported by a relatively small structural factor residing in the protein moiety of DIIIa, which we have tentatively designated as conjunctival allergenicity-supporting factor (CASF). CASF might contribute to the permeability of the antigen into mucosa, enabling the carbohydrate epitope to interact with the allergy-specific IgE distributed in conjunctiva and bronchi . In specificity analysis of a rabbit anti-DIIIa serum, a periodate oxidation- and acid-stable but heat- and alkali-unstable epitope (type gamma) in the protein moiety of DIIIa was also characterized as a useful marker of the antigen. However, the type gamma epitope was apparently independent of CASF that was substantially stable to alkali and heat.


Molecular analysis of norovirus in specimens from children enrolled in a 1982-1986 study in Belém, Brazil: A community-based longitudinal study.
Fecal specimens were collected during a longitudinal, community-based study in the city of Belém, North Brazil, that was conducted over 3 years (October 1982 to March 1986), in which 20 children were included from birth to 3 years of age. A total of 229 fecal samples were screened by real time RT-PCR targeting the junction region (ORF 1/2) of the norovirus (NoV) genome. NoV-positive samples were subjected to PCR and sequencing of the viral polymerase (ORF1) and viral protein 1 (VP1) genes (ORF2). The junction region was also sequenced to assess for recombination when ORF1 and ORF2 genotyping results were dissimilar. Samples classified as GII.P4/GII.4 were further characterized by sequencing the P2 subdomain of the viral capsid to determine possible alterations. An overall positivity of 16.1% (37/229) was observed, including GI (16.2%-6/37) and GII (83.8%-31/37) genogroups. Cases of NoV reinfection in at least 2-month intervals were observed, and 12 children developed at least one case of asymptomatic NoV infection. In total, 48.6% (18/37) NoV-positive samples were subjected to nucleotide sequencing analysis targeting the following polymerase genes: GI.P3 (n = 1), GII.Pa (n = 1), GII.Pc (n = 1), GII.P4 (n = 5), GII.P6 (n = 5), GII.P7 (n = 3), GII.P12 (n = 1), and GII.P22 (n = 1). For the VP1 gene, characterization was performed in 14 (77.8%) samples: GI.3 (n = 1), GII.2 (n = 1), GII.4 (n = 4), GII.6 (n = 4), GII.7 (n = 1), GII.12 (n = 1), GII.14 (n = 1), and GII.23 (n = 1). Recombination events were confirmed in three cases (GII.P12/GII.2, GII.P7/GII.14, and GII.Pa/GII.12), and four samples genotyped as GII.P4/GII.4 were analyzed to identify variants. None had contemporary counterparts. Three children developed consecutive NoV infections by different genotypes. The present report documents the importance of NoV as a cause of childhood infection during a longitudinal study conducted more than 30 years ago.


Effect of prolonged LH-releasing hormone administration on gonadotropin response in patients with hypothalamic and pituitary tumors.
The effect of prolonged administration of synthetic LH-RH (400 mug daily im for 5 days) on gonadotropin response to LH-RH (100 mug single injection iv) was compared in 13 patients with pituitary tumors or suprasellar tumors. No patients with pituitary tumors exhibited an augmented response on serum FSH and LH after prolonged LH-RH administration. A paradoxical fall in response to LH-RH test occurred in 3 patients with pituitary tumors and in a patient with hypothalamic tumor in whom gonadotropin responses were normal on the first LH-RH test. On the other hand, 2 patients with suprasellar tumors with a low response to the initial LH-RH test showed significant increase on a second LH-RHtest after consecutive LH-RH administration. Consecutive administration of LH-RH may help to distinguish between the hypogonadism of pituitary origin and that of hypothalamic origin when the initial LH response to a single dose of LH-RH is subnormal.


Genetic diversity of Mycobacterium bovis evaluated by spoligotyping and MIRU-VNTR in an intensive dairy cattle breeding area in Mexico.
Bovine tuberculosis (bTB) is mainly caused by Mycobacterium bovis. In Mexico, dairy cattle play an important role in the persistence and spread of the bacillus. In order to describe M. bovis genetic diversity, we genotyped a total of 132 strains isolated from slaughtered cattle with bTB suggestive lesions between 2009 and 2010 in Hidalgo, Mexico, using a panel of 9-loci mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) and spoligotyping. We found 21 spoligotypes, and 124 isolates were grouped in 13 clusters. The most frequent spoligotypes were SB0121 (49, 37.1%) and SB0673 (27, 20.5%); three new spoligotypes were reported SB02703, SB02704 and SB02705. We observed 37 MIRU-VNTR patterns, 107 isolates were grouped in 12 clusters and 25 isolates were unique. Spoligotypes SB0121, SB0673, SB0140, SB0145 and SB0120 showed marked subdivision applying MIRU-VNTR method; meanwhile, spoligotypes SB0971 and SB0327 showed single MIRU-VNTR profiles. The Hunter-Gaston discriminatory index (HGDI) was 0.88, 0.78 and 0.90 for 9-loci MIRU-VNTR, spoligotyping and both methods, respectively. Additionally, allelic diversity (h) analysis showed high diversity for QUB3232, QUB26 and QUB11b with h = 0.79, 0.66 and 0.63, respectively. Overall, high genetic variability was observed among M. bovis isolates. Thus, the use of 9-loci MIRU-VNTR panel is enough to describe genetic diversity, evolution and distribution of M. bovis. This study supports the use of these tools for subsequent epidemiological studies in high incidence areas.


In silico modeling of nonspecific binding to human liver microsomes.
Estimation of unbound fraction of substrate in microsomal incubation media is important in accurately predicting hepatic intrinsic clearance and drug-drug interactions. In this study, the unbound fraction of 1223 drug-like molecules in human liver microsomal incubation media has been determined using equilibrium dialysis. These compounds, which include 27 marketed drug molecules, cover a much broader range of physiochemical properties such as hydrophobicity, molecular weight, ionization state, and degree of binding than those examined in previous work. In developing the in silico model, we have used two-dimensional molecular descriptors including cLogP, Kier connectivity, shape, and E-state indices, a subset of MOE descriptors, and a set of absorption, disposition, metabolism, and excretion structural keys used for our in-house absorption, disposition, metabolism, excretion, and toxicity modeling. Hydrophobicity is the most important molecular property contributing to the nonspecific binding of substrate to microsomes. The prediction accuracy of the model is validated using a subset of 100 compounds, and 92% of the variance is accounted for by the model with a root mean square error (RMSE) of 0.10. For the training set of compounds, 99% of variance is accounted for by the model with a RMSE of 0.02. The performance of the developed model has been further tested using the 27 marketed drug molecules with a RMSE of 0.10 between the observed and the predicted unbound fraction values.


Suppression of local invasion of ameloblastoma by inhibition of matrix metalloproteinase-2 in vitro.
Ameloblastomas are odontogenic neoplasms characterized by local invasiveness. This study was conducted to address the role of matrix metalloproteinase-2 (MMP-2) in the invasiveness of ameloblastomas. Plasmids containing either MMP-2 siRNA or tissue inhibitor of metalloproteinase-2 (TIMP-2) cDNA were created and subsequently transfected into primary ameloblastoma cells. Zymography, RT-PCR, and Western blots were used to assess MMP-2 activity and expression of MMP-2 and TIMP-2, as well as protein levels. Primary cultures of ameloblastoma cells expressed cytokeratin (CK) 14 and 16, and MMP-2, but only weakly expressed CK18 and vimentin. MMP-2 mRNA and protein levels were significantly inhibited by RNA interference (P < 0.05). Both MMP-2 siRNA and TIMP-2 overexpression inhibited MMP-2 activity and the in vitro invasiveness of ameloblastoma. These results indicate that inhibition of MMP-2 activity suppresses the local invasiveness of ameloblastoma cells. This mechanism may serve as a novel therapeutic target in ameloblastomas pursuant to additional research.


[Brain imaging of Alzheimer' disease: state of the art and perspectives for clinicians].
To improve the clinical detection of Alzheimer's disease (AD) new diagnostic criteria have been proposed, based on biomarkers of synaptic dysfunction, AD-related neurodegeneration, and Aβ cerebral amyloidosis. Magnetic resonance imaging (MRI) and position emission tomography (PET) neuroimaging can be configured as powerful means for the detection of medial-temporal atrophy, reduced uptake of 18F-FDG PET or and increased retention of Aβ amyloid protein by amyloïd-PET. In this review, we will discuss these promising techniques that allow assessing in vivo AD pathology and help clinicians to better diagnose and follow-up patients, particularly in clinical trials using disease-modifying treatments.


Molecular epidemiology of the endemic multiresistance plasmid pSI54/04 of Salmonella Infantis in broiler and human population in Hungary.
Salmonella Infantis (SI) became endemic in Hungary where the PFGE cluster B, characterized by a large multiresistance (MDR) plasmid emerged among broilers leading to an increased occurrence in humans. We hypothesized that this plasmid (pSI54/04) assisted dissemination of SI. Indeed, Nal-Sul-Tet phenotypes carrying pSI54/04 occurred increasingly between 2011 and 2013 among SI isolates from broilers and humans. Characterization of pSI54/04 based on genome sequence data of the MDR strain SI54/04 indicated a size of ∼277 kb and a high sequence similarity with the megaplasmid pESI of SI predominant in Israel. Molecular characterization of 78 representative broiler and human isolates detected the prototype plasmid pSI54/04 and its variants together with novel plasmid associations within the emerging cluster B. To test in vitro and in vivo pathogenicity of pSI54/04 we produced plasmidic transconjugant of the plasmid-free pre-emergent strain SI69/94. This parental strain and its transconjugant have been tested on chicken embryo fibroblasts (CEFs) and in orally infected day old chicks. The uptake of pSI54/04 did not increase the pathogenicity of the strain SI69/94 in these systems. Thus, dissemination of SI in poultry could be assisted by antimicrobial resistance rather than by virulence modules of the endemic plasmid pSI54/04 in Hungary.


Advances and challenges in the prevention and treatment of Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of dementia and accounts for one-half to three-fourths of all cases of dementia. In the United States, AD is the leading cause of a loss of independent living and subsequent institutionalization. Approximately 4 million Americans are currently diagnosed with Alzheimer's disease-which results in greater than $100 billion dollars in health care costs. This review provides a description of the cognitive and neuropathological features of AD and the challenge that aging populations around the globe pose to health care systems and to societies. A review of new and promising therapeutic strategies for the prevention of AD is discussed which includes estrogen replacement therapy and anti-inflammatory therapeutics. Pharmaceutical approaches that delay the progression of the disease, such as antioxidants, are discussed as well as therapeutic strategies for improvement of cognitive function in AD patients, including the new generation of compounds aimed at enhancing cholinergic function. This section is followed by a review of the current status on nerve growth factor trials. The final section addresses the issue of the genetic linkages of AD, the impact of transgenic and gene knockout mouse models of AD on research in the field and the potential use of gene therapy to treat AD.


The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm.
Mast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by at least 20% of mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 520 μg/L. C-findings were identified in 26 of 28 (93%) patients. Mutations in KIT (D816V, n=19; D816H/Y, n=5; F522C, n=1) were detected in 25 of 28 (89%) patients and prognostically relevant additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naïve patients was 5 of 12 (42%) on midostaurin and 1 of 6 (17%) on cladribine, and after switch 1 of 4 (25%) on midostaurin and 0 of 3 on cladribine, respectively. S/A/Rpos adversely affected response to treatment and progression to secondary mast cell leukemia (n=6) or acute myeloid leukemia (n=3) while on treatment (P<0.05). The median overall survival from mast cell leukemia diagnosis was 17 months as compared to 44 months in a control group of 124 patients with advanced systemic mastocytosis but without mast cell leukemia (P=0.03). In multivariate analyses, S/A/Rpos remained the only independent poor prognostic variable predicting overall survival (P=0.007). In conclusion, the molecular signature should be determined in all patients with mast cell leukemia because of its significant clinical and prognostic relevance.


[Lung ultrasound in COVID-19].
Providing medical care to patients suffering from the coronavirus disease 2019 (COVID-19) pandemic is a major challenge for government healthcare systems around the world. The new coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shows a high organ specificity for the lower respiratory tract. Since there is so far no effective treatment or vaccination against the virus, early diagnostic recognition is of great importance. Due to the specific aspects of the infection, which mainly begins in the peripheral lung parenchyma, lung ultrasonography is suitable as a diagnostic imaging method to identify suspected cases as such in the early stages of the disease. Serial ultrasound examinations on patients with confirmed COVID-19 can promptly detect changes in the affected lung tissue at the bedside. This article summarizes the diagnostic potential of lung ultrasound with respect to screening and therapeutic decision-making in patients with suspected or confirmed SARS-CoV‑2 pneumonia.


The Probiotic VSL#3 Modulates Colonic Macrophages, Inflammation, and Microflora in Acute Trinitrobenzene Sulfonic Acid Colitis.
The probiotic mixture VSL#3 attenuates colitis in patients with Inflammatory Bowel Disease (IBD) and in animal models of this condition, but the mechanisms involved are incompletely understood. VSL#3 alters macrophage morphology and secretory profile in vitro in a polarization-dependent manner. We examined the effect of VSL#3 on macrophages in acute trinitrobenzene sulfonic acid-induced colitis. Rats were randomized to normal, colitis, or colitis+VSL#3 groups. After sacrifice, the colons were evaluated for macroscopic and microscopic damage. Serum cytokine levels were measured, and microbiome analysis undertaken. Total and M1 colonic macrophages, and total and proliferating hepatic macrophages were assessed by double immunofluorescence staining. Colitis+VSL#3 rats had lower macroscopic damage, with less microscopic damage in the proximal colon, compared with colitis alone. Colitis significantly increased colonic macrophage infiltration, which was significantly reduced by VSL#3 treatment. VSL#3 did not decrease the colitis-induced surge of colonic M1 macrophages or hepatic macrophages. VSL#3 reduced colitis-induced serum cytokine levels, and induced restoration of colonic transcript levels for pro-inflammatory, anti-inflammatory, and barrier proteins to, or past, normal levels. Fecal bacteria distribution changed between groups. In summary, the probiotic VSL#3 reduces colitis severity, colonic macrophage infiltration, and serum cytokine levels, but does not dampen the pro-inflammatory phenotype of M1 macrophages.


Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model.
Progranulin (PGRN) promotes cell growth and cell cycle progression in several cell types and contributes to tumorigenesis in diverse cancers. We have recently reported PGRN expression in islets and tumors developed in an MEN1 transgenic mouse. Here we sought to investigate PGRN expression and regulation after exposure to hypoxia as well as its effects on pancreatic islet cells and neuroendocrine tumors (NETs) in MEN1(+/−) mice. Gene and protein expression were analyzed by quantitative polymerase chain reaction, immunohistochemistry, and Western blot. We also investigated PGRN expression in samples from patients carrying pancreatic NETs associated or not with the multiple endocrine neoplasia 1 syndrome, using enzyme-linked immunosorbent assay and immunohistochemistry analysis. Progranulin is upregulated in tumors and islets of the MEN1 mouse as well as in the serum of patients with pancreatic NETs associated with glucagonoma syndrome. In normal mice islets and pancreatic tumors, PGRN expression was strongly potentiated by hypoxia. Progranulin promotes cell proliferation in islet cells and βTC-6 cells, a process paralleled by activation of the mitogen-activated protein kinase signaling cascade. Our findings identify PGRN as an effective inducer of pancreatic islet cell proliferation and a possible important factor for pancreatic endocrine tumor development.


Teamwork in multiteam systems.
The authors examined how networks of teams integrate their efforts to succeed collectively. They proposed that integration processes used to align efforts among multiple teams are important predictors of multiteam performance. The authors used a multiteam system (MTS) simulation to assess how both cross-team and within-team processes relate to MTS performance over multiple performance episodes that differed in terms of required interdependence levels. They found that cross-team processes predicted MTS performance beyond that accounted for by within-team processes. Further, cross-team processes were more important for MTS effectiveness when there were high cross-team interdependence demands as compared with situations in which teams could work more independently. Results are discussed in terms of extending theory and applications from teams to multiteam systems.


Sydenham's Chorea as the First Manifestation of Rheumatic Fever in Two Boys.
Sydenham's chorea is a cardinal manifestation of rheumatic fever, but it is more common in girls. We describe two boys who developed Sydenham's chorea and were successfully treated. A 5-year-old boy started an involuntary movement of his hand, progressing to all the upper limbs, bilaterally. The family observed a deterioration in his handwriting skills. Heart auscultation did not reveal any murmur, and the oropharynx examination was normal. A brain magnetic resonance imaging, cerebrospinal fluid, and echocardiography were interpreted as normal. He was treated with valproate 2.5mL twice a day. Prophylaxis with benzathine penicillin was started using 600,000IU every 21 days. After four months, the patient was asymptomatic, and valproate was tapered off. A 7-year-old boy with a long history of frequent otitis and pharyngitis started involuntary movements of his face and on his upper limbs, and also, his mother noted tics on his face. A brain magnetic resonance imaging and transthoracic echocardiography were normal. He was treated with haloperidol 10 drops (1mg) twice a day, and prophylaxis with benzathine penicillin was started using 600,000IU every 21 days. After three months, the patient was asymptomatic, all chorea manifestations resolved, haloperidol was then tapered off. In conclusion, this study illustrates two uncommon cases of boys who developed Sydenham's chorea and had a good outcome.


Responses of chronically hypoxic rat hearts to ischemia: KATP channel blockade does not abolish increased RV tolerance to ischemia.
Chronic hypoxia may precondition the myocardium and protect from ischemia-reperfusion damage. We therefore examined the recovery of left and right ventricular function after ischemia and reperfusion (15 min each) in isolated blood-perfused working hearts from normoxic (Norm) and hypoxic (Hypo; 14 days, 10.5% O(2)) adult rats. In addition, the mRNA expression of hypoxia-inducible factor (HIF)-1alpha and the protein expression of endothelial nitric oxide synthase (eNOS) were measured. Postischemic left ventricular function recovered to 66 +/- 6% and 67 +/- 5% of baseline in Norm and Hypo, respectively. In contrast, postischemic right ventricular function was 93 +/- 2% of baseline in Hypo vs. 67 +/- 3% in Norm (P < 0.05). Improved postischemic right ventricular function in Hypo (93 +/- 2% and 96 +/- 2% of baseline) was observed with 95% O(2) or 21% O(2) in the perfusate, and it was not attenuated by glibenclamide (5 and 10 micromol/l) (86 +/- 4% and 106 +/- 6% recovery). HIF-1alpha mRNA and eNOS protein expression were increased in both left and right hypoxic ventricles. In conclusion, postischemic right, but not left, ventricular function was improved by preceding chronic hypoxia. ATP-sensitive K(+) channels are not responsible for the increased right ventricular tolerance to ischemia after chronic hypoxia in adult rat hearts.


Astrocyte-derived factors modulate the inhibitory effect of ethanol on dendritic development.
Numerous studies in vivo and in vitro have demonstrated that ethanol disrupts neuromorphogenesis. However, it has not been determined what role, if any, is played by non-neuronal cells in mediating this effect. We recently reported that ethanol inhibits dendritic development in low-density cultures of fetal rat hippocampal pyramidal neurons (Yanni and Lindsley, 2000: Dev Brain Res 120:233-243). In this culture system, cortical astrocytes precondition neuronal culture media for 2 days before the addition of neurons, which then develop on a separate substrate in coculture with the astrocytes. To determine whether astrocyte response to ethanol mediates the effects of ethanol on neurons, the present study compared dendritic development of neurons after 6 days in medium containing 400 mg/dl ethanol in coculture with live astrocytes and in conditioned medium from astrocytes that were never exposed to ethanol. The same experiment was also performed with and without ethanol present during astrocyte preconditioning of the medium. The effects of ethanol differed depending on when it was added to the cultures relative to addition of newly dissociated neurons. However, the effects of ethanol were not related to whether neurons were cocultured with live astrocytes. When astrocytes preconditioned the medium normally, ethanol added at plating inhibited dendritic development of neurons regardless of whether they were maintained in coculture with live astrocytes or in conditioned medium. In surprising contrast, the presence of ethanol during astrocyte preconditioning of the media had a growth promoting effect on subsequent dendrite development despite the continued presence of ethanol in the medium. Thus, astrocytes release soluble factors in response to ethanol that can protect neurons from the inhibitory effects of ethanol on dendritic growth, but the timing of neuronal exposure to these factors, or their concentration, may influence their activity.


Echocardiography and passive leg raising in the postoperative period: A prospective observational study.
Signs of hypovolaemia are frequent in the postoperative period, but not all patients need or respond to fluid administration. An increase in cardiac output (CO) after passive leg raising (PLR) has been demonstrated to be useful as a volume response predictor in non-surgical, spontaneously breathing patients. The objective of this study was to evaluate the accuracy of transthoracic echocardiography after PLR to predict fluid responsiveness in post-surgical patients. A prospective observational study. A tertiary hospital between January and July 2015. Fifty-one spontaneously breathing postoperative patients with suspected hypovolaemia (arterial hypotension, oliguria, tachycardia or delayed capillary refill) were considered for the study. Demographic and personal data were collected, as well as heart rate variations, mean arterial pressure during PLR and after administering 500 ml of Ringer's lactate solution. CO was measured by transthoracic echocardiography. The primary outcome was measurement of CO before and after PLR and Ringer's lactate administration. Forty-one patients were included in the study (six patients were excluded because of a poor echocardiographic window and four because of misalignment of the Doppler and outflow tract of the left ventricle). Twenty-two patients (54%) were considered responders to fluid therapy, with an increase of stroke volume greater than or equal to 15% after 500 ml lactated Ringer's infusion. The highest area under the curve was found for an increase in CO (0.91 ± 0.05; 95% confidence interval 0.78 to 0.97). An increase in CO greater than 11% after the PLR manoeuvre predicts a volume response with 68% sensitivity and 100% specificity. This is the first study showing that measurement of CO after PLR can predict volume response in spontaneously breathing postoperative patients.


Evidence of stress in β cells obtained with laser capture microdissection from pancreases of brain dead donors.
Isolated islets used for transplantation are known to be stressed, which can result from the circumstances of death, in particular brain death, the preservation of the pancreas with its warm and cold ischemia, from the trauma of the isolation process, and the complex events that occur during tissue culture. The current study focused upon the events that occur before the islet isolation procedure. Pancreases were obtained from brain dead donors (n = 7) with mean age 50 (11) and normal pancreatic tissue obtained at surgery done for pancreatic neoplasms (n = 7), mean age 69 (9). Frozen sections were subjected to laser capture microdissection (LCM) to obtain β-cell rich islet tissue, from which extracted RNA was analyzed with microarrays. Gene expression of the 2 groups was evaluated with differential expression analysis for genes and pathways. Marked changes were found in pathways concerned with endoplasmic reticulum stress with its unfolded protein response (UPR), apoptotic pathways and components of inflammation. In addition, there were changes in genes important for islet cell identity. These findings advance our understanding of why islets are stressed before transplantation, which may lead to strategies to reduce this stress and lead to better clinical outcomes.


Deciphering asymmetric charge transfer at transition metal dichalcogenide-graphene interface by helicity-resolved ultrafast spectroscopy.
Transition metal dichalcogenide (TMD)/graphene (Gr) heterostructures constitute a key component for two-dimensional devices. The operation of TMD/Gr devices relies on interfacial charge/energy transfer processes, which remains unclear and challenging to unravel. Fortunately, the coupled spin and valley index in TMDs adds a new degree of freedom to the charges and, thus, another dimension to spectroscopy. Here, by helicity-resolved ultrafast spectroscopy, we find that photoexcitation in TMDs transfers to graphene by asynchronous charge transfer, with one type of charge transferring in the order of femtoseconds and the other in picoseconds. The rate correlates well with energy offset between TMD and graphene, regardless of compositions and charge species. Spin-polarized hole injection or long-lived polarized hole can be achieved with deliberately designed heterostructures. This study shows helicity-resolved ultrafast spectroscopy as a powerful and facile approach to reveal the fundamental and complex charge/spin dynamics in TMD-based heterostructures, paving the way toward valleytronic and optoelectronic applications.


pH-controlled switching of photocurrent direction by self-assembled monolayer of helical peptides.
A novel molecular system, where the photocurrent direction can be reversibly switched by changing the pH of the solution, was prepared on gold from helical peptides carrying a photosensitizer and a carboxyl group at the terminal. Upon photoexcitation of the photosensitizer in an aqueous solution containing an electron donor and acceptor at pH 10, the monolayer generated an anodic photocurrent due to enhancement of the dipole moment by a carboxylate anion, while it generated an opposite cathodic photocurrent at pH 3.4


The delta-opioid receptor participates in T-cell development by promoting negative selection.
The delta-opioid receptor-1 (DOR-1) as well as delta-opioid enkephalin peptides are expressed during maturation of T cells, although the functional significance of their expression remains unclear. Based on results which show that the administration of the highly selective delta-opioid agonist D-Pen2, D-Pen5]enkephalin (DPDPE) induces an altered pattern of T-cell differentiation in fetal thymic organ culture (FTOC), we hypothesized that DOR-1 is involved in the negative selection process. Our results show that superantigen-induced clonal deletion is promoted by DPDPE and significantly impaired in DOR-1-deficient mice. These results suggest that delta-opioids may play a homeostatic role in the negative selection process during T-cell development.


Subtemporal transtentorial approach for recurrent trigeminal neuralgia after microvascular decompression via the lateral suboccipital approach: case report.
Microvascular decompression (MVD) via lateral suboccipital craniotomy is the standard surgical intervention for trigeminal neuralgia (TN). For recurrent TN, difficulties are sometimes encountered when performing reoperation via the same approach because of adhesions and prosthetic materials used in the previous surgery. In the present case report the authors describe the efficacy of the subtemporal transtentorial approach for use in recurrent TN after MVD via the lateral suboccipital approach. An 86-year-old woman, in whom an MVD via a lateral suboccipital craniotomy had previously been performed for TN, underwent surgery for recurrent TN via the subtemporal transtentorial approach, which provided excellent visualization of the neurovascular relationships and the trigeminal nerve without adhesions due to the previous surgery. Her TN disappeared after the MVD. The present approach is ideal for visualizing the trigeminal root entry zone, and the neurovascular complex can be easily dissected using a new surgical trajectory. This approach could be another surgical option for reoperation when the previous MVD had been performed via the suboccipital approach.


Forecasting Hepatocellular Carcinoma Mortality using a Weighted Regression Model to Estimate Cohort Effects in Taiwan.
To eliminate the influence of age and period in age cycle contingency table data, a multistage method was adopted to evaluate the cohort effect. The most general primary malignant tumor of the liver is hepatocellular carcinoma (HCC). HCC is associated with liver cirrhosis with alcohol and viral etiologies. In epidemiology, long-term trends in HCC mortality were delineated (or forecasted) by using an age-period-cohort (APC) model. The HCC deaths were determined for each cohort with its weighted influence. The confidence interval (CI) of the weighted mean is fairly narrow (compared to the equally weighted estimates). Due to the fairly narrow CI with less uncertainty, the weighted mean estimation was used as a means for forecasting. With the multistage method, it is recommended to use weighted mean estimation based on a regression model to evaluate the cohort effect in the age-period contingency table data.


ClpB chaperone passively threads soluble denatured proteins through its central pore.
ClpB disaggregase forms a ring-shaped hexamer that threads substrate proteins through the central pore using energy from ATP. The ClpB protomer consists of an N-terminal domain, a middle domain, and two AAA+ modules. These two AAA+ modules bind and hydrolyze ATP and construct the core of the hexameric ring. Here, we investigated the roles of the two AAA+ modules in substrate threading. BAP is an engineered ClpB that can bind ClpP proteolytic chamber; substrates threaded by BAP are degraded by ClpP. We combined BAP with conserved motif mutations in two AAA+ modules and measured the steady-state rates of threading of soluble denatured proteins by these mutants over a range of substrate concentrations. By fitting the data to the Michaelis-Menten equation, k(cat) and K(m) values were determined. We found that the kinetic parameters of the substrate threading correlate with the type of mutation introduced rather than the ATPase activity of the mutant. Moreover, some mutants having no or marginal ATPase activity could thread denatured proteins significantly. These results indicate that ClpB can passively thread soluble denatured proteins.


Coarse-grained models of tethers for fast self-assembly simulations.
Long molecular ligands or "tethers" play an important role in the self-assembly of many nanoscale systems. These tethers, whose only interaction may be a hard-core repulsion, contribute significantly to the free energy of the system because of their large conformational entropy. Here, we investigate how simple approximate models can be developed and used to quickly determine the configurations into which tethers will self assemble in nanoscale systems. We derive criteria that determine when these models are expected to be accurate. Finally, we propose a generalized two-body approximation that can be used as a toy model for the self-assembly of tethers in systems of arbitrary geometry and apply this to the self-assembly of self-assembled monolayers on a planar surface. We compare our results to those in the literature obtained via atomistic and dissipative particle dynamics simulations.


How Is CDC Funded to Respond to Public Health Emergencies? Federal Appropriations and Budget Execution Process for Non-Financial Experts.
The federal budgeting process affects a wide range of people who work in public health, including those who work for government at local, state, and federal levels; those who work with government; those who operate government-funded programs; and those who receive program services. However, many people who are affected by the federal budget are not aware of or do not understand how it is appropriated or executed. This commentary is intended to give non-financial experts an overview of the federal budget process to address public health emergencies. Using CDC as an example, we provide: (1) a brief overview of the annual budget formulation and appropriation process; (2) a description of execution and implementation of the federal budget; and (3) an overview of emergency supplemental appropriations, using as examples the 2009 H1N1 influenza pandemic, the 2014-15 Ebola outbreak, and the 2016 Zika epidemic. Public health emergencies require rapid coordinated responses among Congress, government agencies, partners, and sometimes foreign, state, and local governments. It is important to have an understanding of the appropriation process, including supplemental appropriations that might come into play during public health emergencies, as well as the constraints under which Congress and federal agencies operate throughout the federal budget formulation process and execution.


Joint keypoint detection and description network for color fundus image registration.
Retinal imaging is widely used to diagnose many diseases, both systemic and eye-specific. In these cases, image registration, which is the process of aligning images taken from different viewpoints or moments in time, is fundamental to compare different images and to assess changes in their appearance, commonly caused by disease progression. Currently, the field of color fundus registration is dominated by classical methods, as deep learning alternatives have not shown sufficient improvement over classic methods to justify the added computational cost. However, deep learning registration methods are still considered beneficial as they can be easily adapted to different modalities and devices following a data-driven learning approach. In this work, we propose a novel methodology to register color fundus images using deep learning for the joint detection and description of keypoints. In particular, we use an unsupervised neural network trained to obtain repeatable keypoints and reliable descriptors. These keypoints and descriptors allow to produce an accurate registration using RANdom SAmple Consensus (RANSAC). We train the method using the Messidor dataset and test it with the Fundus Image Registration Dataset (FIRE) dataset, both of which are publicly accessible. Our work demonstrates a color fundus registration method that is robust to changes in imaging devices and capture conditions. Moreover, we conduct multiple experiments exploring several of the method's parameters to assess their impact on the registration performance. The method obtained an overall Registration Score of 0.695 for the whole FIRE dataset (0.925 for category S, 0.352 for P, and 0.726 for A). Our proposal improves the results of previous deep learning methods in every category and surpasses the performance of classical approaches in category A which has disease progression and thus represents the most relevant scenario for clinical practice as registration is commonly used in patients with diseases for disease monitoring purposes.


Anxiety and Depression in Cancer Patients: The Association with Religiosity and Religious Coping.
There is a lack of studies looking into religiosity and religious coping in cancer patient. In this cross-sectional study, we examined the religiosity using Duke University Religion Index, religious coping using Brief Religious Coping Scale, anxiety and depression based on Hospital Anxiety and Depression Scale among 200 cancer patients. The association between religiosity and religious coping with anxiety and depression was studied. The findings showed that subjects with anxiety or depression used more negative religious coping and had lower non-organization religiosity. Hence, measurements in reducing negative religious coping and encouraging religious activities could help to reduce psychological distress in cancer patients.


Genomic characterization of SARS-CoV-2 isolates from patients in Turkey reveals the presence of novel mutations in spike and nsp12 proteins.
Novel mutations have been emerging in the genome of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2); consequently, the evolving of more virulent and treatment resistance strains have the potential to increase transmissibility and mortality rates. The characterization of full-length SARS-CoV-2 genomes is critical for understanding the origin and transmission pathways of the virus, as well as identifying mutations that affect the transmissibility and pathogenicity of the virus. We present an analysis of the mutation pattern and clade distribution of full-length SARS-CoV-2 genome sequences obtained from specimens tested at Gazi University Medical Virology Laboratory. Viral RNA was extracted from nasopharyngeal specimens. Next-generation sequencing libraries were prepared and sequenced on Illumina iSeq 100 platform. Raw sequencing data were processed to obtain full-length genome sequences and variant calling was performed to analyze amino acid changes. Clade distribution was determined to understand the phylogenetic background in relation to global data. A total of 293 distinct mutations were identified, of which 152 missense, 124 synonymous, 12 noncoding, and 5 deletions. The most frequent mutations were P323L (nsp12), D614G (ORF2/S), and 2421C>T (5'-untranslated region) found simultaneously in all sequences. Novel mutations were found in nsp12 (V111A, H133R, Y453C, M626K) and ORF2/S (R995G, V1068L). Nine different Pangolin lineages were detected. The most frequently assigned lineage was B.1.1 (17 sequences), followed by B.1 (7 sequences) and B.1.1.36 (3 sequences). Sequence information is essential for revealing genomic diversity. Mutations might have significant functional implications and analysis of these mutations provides valuable information for therapeutic and vaccine development studies. Our findings point to the introduction of the virus into Turkey through various sources and the subsequent spread of several key variants.


Patients with the malignant profile within 3 hours of symptom onset have very poor outcomes after intravenous tissue-type plasminogen activator therapy.
The malignant profile has been associated with poor outcomes after reperfusion in the 3- to 6-hour time window. The aim of this study was to estimate the incidence and prognostic implications of the malignant profile, as identified by CT perfusion, in intravenous tissue-type plasminogen activator-treated patients who were imaged <3 hours from stroke onset. The incidence of the malignant profile, based on the previously published optimal perfusion-weighted imaging definition, was assessed in consecutive patients using a fully automated software program (RApid processing of Perfusion and Diffusion [RAPID]). A receiver operating characteristic curve analysis was done to identify time to maximum and core volume thresholds that optimally identify patients with poor outcome (modified Rankin Scale 5-6). Forty-two patients had an interpretable CT perfusion performed within 3 hours of symptom onset. Mean age was 74±14 years and median (interquartile range) National Institutes of Stroke Scale score was 13 (6-19). Four patients (9.5%) met the prespecified criteria for the malignant profile and all 4 had poor outcome. Receiver operating characteristic analysis determined that the best CT perfusion measure to identify patients with poor outcome was a cerebral blood flow based infarct core >53 mL (100% specificity and 67% sensitivity). This criterion identified 5 patients as malignant (12%). The poor outcome rate in these patients was 100% versus 7.1% in the 37 nonmalignant patients (P<0.001). The incidence of the malignant profile on CT perfusion is approximately 10% in tissue-type plasminogen activator-eligible patients imaged within 3 hours of symptom onset. The clinical outcome of these patients is very poor despite intravenous tissue-type plasminogen activator therapy.


Angiopoietin-like protein 3 and adiponectin levels in patients with metabolic syndrome.
To investigate the changes of serum angiopoietin-like protein 3 (Angptl3) and adiponectin levels in patients with metabolic syndrome (MS) in order to understand their association with the MS. Serum Angptl3 and adiponectin levels were measured by sandwich ELISA in a group of 111 patients with MS and 152 normal controls. Serum adiponectin was lower in the MS patients than in the control subjects [4.22(1.01-23.29) microg/mL vs. 5.41(0.97-22.27) microg/mL, P<0.05]. With regard to serum Angptl3, there was no significant difference between the 2 groups(P>0.05). Serum adiponectin was correlated to Angptl3 and high density lipoprotein-cholesterol (HDL-C)(P<0.001) and negatively correlated to body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), triglyceride (TG), fasting plasma glucose (FBG), fasting insulin (FINS) and homeostatic model assessment method-insulin resistance (HOMA-IR) (P<0.001). Serum Angptl3 was positively correlated with adiponectin (P<0.001). Serum adiponectin was found to be independently positive determinant for Angptl3 concentrations (b'=0.256, P<0.001). Adiponectin was inversely correlated with TG and HOMA-IR (b'=-0.234, -0.145, P<0.001). Adiponectin is decreased in MS patients and may be correlated to Angptl3.


Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome.
Pitt-Hopkins syndrome (PTHS) is an emerging condition characterized by severe intellectual disability (ID), typical facial gestalt, and additional features, such as breathing abnormalities. Because of the overlapping phenotype of severe ID with absent speech, epilepsy, microcephaly, large mouth, and constipation, differential diagnosis of PTHS with respect to Angelman, Rett, and Mowat-Wilson syndromes represents a relevant clinical issue, and many patients are currently undergoing genetic tests for different conditions that are assumed to fall within the PTHS clinical spectrum. During a search for TCF4 mutations in 78 patients with a suspected PTHS, haploinsufficiency of TCF4 was identified in 18. By evaluating clinical features of patients with a proven TCF4 mutation with those of patients without, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combination of the following characteristics: ID with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing abnormalities, motor incoordination, ocular anomalies, constipation, seizures, typical behavior, and subtle brain abnormalities. On the basis of these observations, here we propose a clinically based score system as useful tool for driving a first choice molecular test for PTHS. This scoring system is also proposed for a clinically based diagnosis of PTHS in absence of a proven TCF4 mutation.


Salinomycin and Sulforaphane Exerted Synergistic Antiproliferative and Proapoptotic Effects on Colorectal Cancer Cells by Inhibiting the PI3K/Akt Signaling Pathway in vitro and in vivo.
Both salinomycin (SAL) and sulforaphane (SFN) exert their antitumorigenic effects in various types of cancer We investigated whether combining salinomycin (SAL, an antibiotic ionophore) with sulforaphane (SFN, a phytochemical) exerted synergistic antiproliferative and proapoptotic activities in colorectal cancer (CRC) cells in vitro and in vivo by evaluating the proliferative and apoptotic responses of two CRC cell lines. The combination index (CI) was calculated using the Chou-Talalay method, and the effects of the synergistic combination (CI<1) of lower doses of SAL and SFN were selected for further studies. Anti-tumor effect of the combination of SAL and SFN was tested both in vitro and in vivo. Cotreatment effectively inhibited proliferation, migration and invasion and enhanced apoptosis. The xenograft model also showed similar results. Furthermore, we evaluated the molecular mechanism behind SAL- and SFN-mediated CRC cell apoptosis. The combination treatment induced apoptosis in Caco-2 and CX-1 cells by inhibiting the PI3K/Akt pathway, which increased the expression of the tumor suppressor protein p53. The treatment also decreased the expression of the survival protein Bcl-2 and increased the expression of the proapoptotic protein Bax, which increased the Bax/Bcl-2 ratio, as well as enhanced poly ADP-ribose polymerase (PARP) cleavage. Upon inhibiting the PI3K/Akt pathway with LY294002 prior to cotreatment, we detected enhanced PARP cleavage compared to that in the cotreatment only group. We investigated whether the combination of SAL and SFN had antiproliferative and proapoptotic effects in CRC cells both in vitro and in vivo. Cotreatment also significantly decreased migration and invasion compared to that of the control and SAL or SFN monotherapies. This novel combination of SAL and SFN might provide a potential strategy to treat CRC.


Association between chronic diseases and falls among a sample of older people in Finland.
Falls are a major problem for older people and recurrent fallers are especially prone to severe consequences due to falls. This study investigated the association between chronic conditions and falls. Responses from 872 older persons (age 65-98) to a health questionnaire were used in the analyses. Characteristics and disease prevalence between recurrent fallers, one-time fallers and non-fallers were compared. A hierarchical clustering method was applied to find combinations of chronic conditions that were associated with recent recurrent falling. The results showed that recurrent fallers had a higher number of diseases (median 4, interquartile range, IQR = 2.0-5.0) compared to non-fallers (median 2, IQR = 1.0-3.0). Eight clusters were formed based on the data. The participants in the low chronic disease cluster were younger, more physically active, not frail, and had fewer geriatric conditions. Multiple chronic disease cluster participants were older, less physically active, overweight (body mass index, BMI > 30), at risk of malnutrition, and had more geriatric conditions. Significantly increased risk of recurrent falls relative to the low chronic cluster was found for respondents in the osteoporosis cluster and multiple chronic disease cluster (OR = 5.65, 95% confidence interval CI: 1.23-25.85, p = 0.026, and OR = 13.42, 95% CI: 2.47-72.96, p = 0.002, respectively). None of the clusters were associated with increased risk of one-time falling. The results implicate that the number of chronic diseases is related with risk of recurrent falling. Furthermore, the results implicate the potential of identifying certain combinations of chronic diseases that increase fall risk by analyzing health record data, although further studies are needed with a larger population sample.


Regulation and function of lactate oxidation in Streptococcus faecium.
Regulation of the synthesis and function of an l(+)-specific lactate-oxidizing enzyme system found in a homofermentative Streptococcus was investigated. With the exception of fructose, aerobic growth at the expense of a variety of substrates resulted in the formation of a lactate oxidation system; anaerobic growth resulted in a marked reduction or complete loss of lactate-oxidizing activity. Growth on fructose, under aerobic and anaerobic conditions, invariably produced a decrease in the activity of the lactate oxidation system. A negative control, activated by an early intermediate product of glycolysis, appeared to be responsible for repression of the lactate-oxidizing enzyme(s). The enzyme system confers upon the organism the ability to grow aerobically at the expense of l(+)-lactic acid.


Effects of artificial blood (FC-43 emulsion) on myocardial energy metabolism in the rat heart-lung preparation.
We have assessed the effects of artificial blood (FC-43 emulsion) on myocardial energy metabolism in the rat heart-lung preparation. Animals were allocated to four groups (n = 8 each group) according to the ratio of perfusion blood and FC-43 as follows: group 1 = control, perfusion blood only; group 2 = 50% FC-43; group 3 = 75% FC-43; and group 4 = 100% FC-43. Hearts were perfused initially to a cardiac output of 30 ml min-1 and mean arterial pressure of 50 mm Hg. Thirty minutes after perfusion, the hearts were freeze-dried for 6 days. Myocardial high energy phosphates (ATP, ADP and AMP) were measured by high pressure liquid chromatography. Myocardial lactate and glycogen concentrations were measured by enzymatic methods. There were almost no significant differences in cardiac output, systolic pressure, right atrial pressure and heart rate among the groups. Oxygen contents of the perfusate in all FC-43 groups were significantly lower than those in the control group. Myocardial ATP concentrations in rats receiving 50%, 75% and 100% FC-43 were significantly lower than those in the control group. In addition, myocardial ADP and AMP concentrations in rats receiving 75% and 100% FC-43 were significantly higher than those in the control group. Although there is adequate oxygen-carrying capacity in FC-43 to maintain cardiac function during perfusion, the energy levels in the hearts perfused with FC-43 were lower than those in normal hearts.


[Mobile dispersed genetic elements in eukaryotes and their possible relationship to carcinogenesis].
During last three years, the mobile dispersed genetic elements (mdg) were isolated from the genome of Drosophila melanogaster, yeasts and mammals. According to a number of their properties, mdg elements are quite similar to endogenous pro-retroviruses. It is known that in many cases oncogeneity of retroviruses depends on the incorporation of the certain host genes (potential oncogenes) into the viral genome. We suggest that in some cases mdg elements could entrap the potential oncogenes in the course of transposition. As a result, oncogenes become uncontrollable by host regulatory systems and may induce cell transformation. Another possible mechanism underlying switch off of the gene responsible for differentiation control may be mdg transposition to a region in close vicinity of the gene. As transposition of mdg elements seems to occur rather often, they may be regarded as one of the most important factors of genome rearrangements leading to cell transformation.


Characterization of total and active matrix metalloproteinases-1, -3, and -13 synthesized and secreted by anterior cruciate ligament fibroblasts in three-dimensional collagen gels.
Anterior cruciate ligament (ACL) injury and subsequent reconstructive surgery is increasing with an estimated 200,000 reconstructions performed yearly in the United States. Current treatment requires reconstruction with autograft or allograft tissue with inherent disadvantages. The development of tissue-engineered ligament replacements or scaffolds may provide an alternative treatment method minimizing these issues. The study of ligament fibroblast catabolic and anabolic responses to mechanical and biologic stimuli in three-dimensional (3D) cell culture systems is critical to the development of such therapies. A 3D cell culture system was used to measure the total content and active forms of matrix metalloproteinases (MMPs)-1, -3, and -13 to assess the potential role of the mechanical environment in regulation of matrix turnover by ligament fibroblasts. The production, retention, and secretion of MMPs by ACL fibroblasts in 3D culture were measured over a 14-day period. The total MMP content and MMP activity were determined. The level of all MMPs studied increased over 7-10 days and then reached a steady state or decreased slightly in both the collagen gels and the media. This system will now permit the study of externally applied cyclic and static strains, strain deprivation, and the potential combined role of the cytoskeleton and MMPs in matrix turnover in ligaments.


Concerning the potential reversibility of carbometalation in alkoxide-directed Ti(Oi-Pr)4-mediated reductive cross-coupling of homoallylic alcohols with aromatic imines.
In an attempt to understand the nature of selectivity in Ti-mediated reductive cross-coupling between homoallylic alcohols and imines, we investigated whether thermodynamic equilibration of the presumed organometallic intermediate plays a role in selectivity. No evidence could be found for olefin exchange in preformed azatitanacyclopentanes--an observation that is consistent with a model based on kinetically controlled selective carbometalation.


Effect of 24-epibrassinolide on pollen viability during heat-stress in tomato.
Tomato pollen when treated with 24-epibrassinolide (EBR), it was observed that in vitro pollen germination was more tolerant to high temperature. A significantly higher in vitro pollen germination, enhanced tube growth and low pollen bursting were observed in presence of EBR at 35 degrees C. Since a preconditioning treatment of tomato plant was not required for these effects, it is concluded that EBR treatment increased basic thermotolerance of germinating pollen. This study provided the first evidence for EBR induced thermotolerance in germinating pollen.


Arsenic Metabolism and Toxicity Influenced by Ferric Iron in Simulated Gastrointestinal Tract and the Roles of Gut Microbiota.
Iron (Fe) is a common trace element in drinking water. However, little is known about how environmental concentrations of Fe affect the metabolism and toxicity of arsenic (As) in drinking water. In this study, influence of Fe at drinking water-related concentrations (0.1, 0.3, and 3 mg Fe (total)/L) on As metabolism and toxicity, and the roles of gut microbiota during this process were investigated by using in vitro Simulator of the Human Intestinal Microbial Ecosystem (SHIME). Results showed that Fe had ability to decrease bioaccessible As by coflocculation in small intestine. 0.1 and 0.3 mg/L Fe significantly increased As methylation in simulated transverse and descending colon. Gut microbiota played an important role in alteration of As species, and Fe could affect As metabolism by changing the gut microbiota. Bacteroides, Clostridium, Alistipes, and Bilophila had As resistance and potential ability to methylate As. Cytotoxicity assays of effluents from simulated colons showed that the low levels of Fe decreased As toxicity on human hepatoma cell line HepG2, which might be due to the increase of methylated As. When assessing the health risk of As in drinking water, the residual Fe should be considered.


Factors associated with gait speed: results from the RolE of AST120 (Renamezin) in sarCOpenia preVEntion in pRe-dialYsis chronic kidney disease patients (RECOVERY) study.
Gait speed is an important measure of functional ability. This study aimed to investigate the factors associated with gait speed in patients with chronic kidney disease. The study focused on sarcopenic components, plasma uremic or inflammatory marker levels, and quality of life effects. The RolE of AST120 (Renamezin) in sarCOpenia preVEntion in pRe-dialYsis chronic kidney disease patients is a 48-week, randomized controlled, parallel-group, open-label, multicenter trial to determine the role of Renamezin (Daewon Pharmaceutical Co., Ltd.) in patients with chronic kidney disease. The participants were classified into four groups according to gait speed: ≤0.8, 0.8-1.0, ≤1.0-1.3, and ≥1.3 m/sec. Linear regression analysis was performed to identify the factors associated with gait speed. The group with a gait speed of ≤0.8 m/sec was the oldest and had the highest proportion of participants with low education level and medical aid. Participants with a gait speed of ≤0.8 m/sec showed the lowest physical and mental component scale scores. The interleukin-6 (IL-6) level tended to be the higher trend in the lowest gait speed group. In the multivariate linear regression analysis adjusted for age, sex, diabetes mellitus, and estimated glomerular filtration rate, insurance status, handgrip strength, IL-6 level, hemoglobin level, mental component scale score, and physical component scale score were significantly associated with gait speed. In conclusion, gait speed is associated with handgrip strength, IL-6 level, and various components of quality of life in predialysis chronic kidney disease patients.


Recurrent acute primary hyperparathyroidism in an adult male patient.
To report the occurrence of recurrent acute primary hyperparathyroidism (HPT), a rare disorder that occurs in only 1 to 2% of patients with primary HPT. We describe a patient who had two separate episodes of acute primary HPT and discuss the appropriate treatment of parathyroid crisis. In 1990, primary HPT developed in a 41-year-old man, who underwent surgical removal of a parathyroid adenoma. He remained normocalcemic until 1995, when acute primary HPT developed after lithium therapy was initiated because of depression. Calcium and parathyroid hormone (PTH) levels declined after lithium therapy was discontinued, but they remained slightly above the normal range. Nine months later, he was rehospitalized with acute primary HPT. After stabilization, a second parathyroid adenoma was successfully resected, and calcium and PTH levels subsequently remained normal. In this disorder, levels of PTH are increased up to 20 times normal, and the clinical manifestations are similar to parathyroid carcinoma. Treatment involves rehydration, antiresorptive agents, and parathyroidectomy. Our patient initially was thought to have lithium-induced primary HPT, which can occur in up to 10% of patients on long-term lithium therapy. The mechanism is unknown but may be an alteration of the calcium-PTH "set-point." Patients with asymptomatic primary HPT should have close follow-up because of the risk of development of acute primary HPT. Patients at risk, such as those with immobilization or severe illness, should be identified. Drugs known to interfere with calcium metabolism (for example, lithium) should be avoided in patients with primary HPT.


[Characteristic features of autoimmune thyroid disease in children].
The present review discusses in detail the most important problems of autoimmune thyroid disease in children and adolescents. There is a low incidence of autoimmune thyroid disorders in children and adolescents, the most important being Hashimoto's thyroiditis. Painless thyroid enlargement and delayed development are essential symptoms. Patients suffering from hypothyroidism or goitre should be treated with 1-thyroxin. The aim of treatment is to normalise metabolism and TSH levels. Graves' disease in children and adolescents is uncommon, and clinical features may be subtle. Typical eye symptoms are very often not present. Compared to older patients, the duration of symptoms is usually longer and the degree of hyperthyroidism more pronounced. This is why children require more time to achieve remission after anti-thyroid drug treatment. As already indicated, surgery is usually preferred to radioiodine.


"A review and meta-analysis of age-based stereotype threat: Negative stereotypes, not facts, do the damage": Correction to Lamont, Swift, and Abrams (2015).
Reports an error in "A review and meta-analysis of age-based stereotype threat: Negative stereotypes, not facts, do the damage" by Ruth A. Lamont, Hannah J. Swift and Dominic Abrams (Psychology and Aging, 2015[Mar], Vol 30[1], 180-193). In the article, some of the effect sizes in the meta-analysis were mistakenly calculated based on standard error (SE), rather than standard deviation (SD). The authors identified this problem for three of the 32 studies in the analysis. In addition, SE was incorrectly used in one of the original publications (Desrichard & Kopetz, 2005), and amendments have been made based on this also. A table of the recalculated data is provided in the erratum. The recalculations have minimal impact on the meta-analysis conclusions, but effect sizes calculated throughout the article needed to be updated. The meta-analysis still revealed a small-to-medium effect of age-based stereotype threat (ABST; d= .32). Two conclusions have changed from the original moderator analyses. Journal region did not significantly moderate effect sizes of stereotype-based studies conducted within Europe (Qbetween (1) 2.17, p .14). Thus, reassuringly, it cannot be concluded that publication region predicts effect size magnitude or that there are different expectations for effect sizes based on the journal region. Because this issue was slightly peripheral to the central questions for the analysis, the central conclusions of the article remain unaffected. Further, the meta-analysis now supports the authors' initial hypothesis that gender would moderate ABST effects ( β=.36, p< .05), whereby women may experience greater ABST effects. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2015-02669-001.) Stereotype threat effects arise when an individual feels at risk of confirming a negative stereotype about their group and consequently underperforms on stereotype relevant tasks (Steele, 2010). Among older people, underperformance across cognitive and physical tasks is hypothesized to result from age-based stereotype threat (ABST) because of negative age-stereotypes regarding older adults' competence. The present review and meta-analyses examine 22 published and 10 unpublished articles, including 82 effect sizes (N = 3882) investigating ABST on older people's (Mage = 69.5) performance. The analysis revealed a significant small-to-medium effect of ABST (d = .28) and important moderators of the effect size. Specifically, older adults are more vulnerable to ABST when (a) stereotype-based rather than fact-based manipulations are used (d = .52); (b) when performance is tested using cognitive measures (d = .36); and (c) occurs reliably when the dependent variable is measured proximally to the manipulation. The review raises important theoretical and methodological issues, and areas for future research. (PsycINFO Database Record


DCD donor hemodynamics as predictor of outcome after kidney transplantation.
Insufficient hemodynamics during agonal phase-ie, the period between withdrawal of life-sustaining treatment and circulatory arrest-in Maastricht category III circulatory-death donors (DCD) potentially exacerbate ischemia/reperfusion injury. We included 409 Dutch adult recipients of DCD donor kidneys transplanted between 2006 and 2014. Peripheral oxygen saturation (SpO2-with pulse oximetry at the fingertip) and systolic blood pressure (SBP-with arterial catheter) were measured during agonal phase, and were dichotomized into minutes of SpO2 > 60% or SpO2 < 60%, and minutes of SBP > 80 mmHg or SBP < 80 mmHg. Outcome measures were and primary non-function (PNF), delayed graft function (DGF), and three-year graft survival. Primary non-function (PNF) rate was 6.6%, delayed graft function (DGF) rate was 67%, and graft survival at three years was 76%. Longer periods of agonal phase (median 16 min [IQR 11-23]) contributed significantly to an increased risk of DGF (P = .012), but not to PNF (P = .071) and graft failure (P = .528). Multiple logistic regression analysis showed that an increase from 7 to 20 minutes in period of SBP < 80 mmHg was associated with 2.19 times the odds (95% CI 1.08-4.46, P = .030) for DGF. In conclusion, duration of agonal phase is associated with early transplant outcome. SBP < 80 mmHg during agonal phase shows a better discrimination for transplant outcome than SpO2 < 60% does.


Hepatic Epithelioid Hemangioendothelioma.
Epithelioid hemangioendothelioma is a rare vascular tumor, composed of epithelioid and histiocytoid vascular endothelial cells in myxoid or fibrotic stroma, which can arise in multiple locations throughout the body. In the liver, this neoplasm usually presents on imaging as an incidental finding of multifocal, heterogeneously enhancing nodules in both lobes or presents clinically with nonspecific abdominal symptoms. Histologically, the tumor has been mistaken for metastatic carcinoma, angiosarcoma, hepatocellular carcinoma, and cholangiocarcinoma. The neoplasm usually stains positive for vascular markers, such as factor VIII-related antigen, CD31, and CD34, and negative for cytokeratins. The translocation t(1;3)(p36.3;q25), resulting in the CAMTA1- WWTR1 fusion product, is the most commonly identified genetic abnormality with this tumor. Although hepatic epithelioid hemangioendothelioma can have a varied clinical course, it is generally considered less aggressive than angiosarcoma. There is no consensus treatment protocol and techniques including liver transplantation, liver resection, chemotherapy and/or radiation therapy, and surveillance have all been used with varying outcomes.


Pregnancy as a Period of Enhanced Risk for Non-Cavitated Caries Lesions.
To investigate if pregnancy represents a period of increased risk of non-cavitated dental caries related to changes in saliva and oral health behaviours. A non-randomised longitudinal study was performed with 27 pregnant women and 25 non-pregnant women, who were evaluated twice with the same time gap (24 weeks on average). At the first visit sociodemographic and oral health-related behaviours were assessed through a structured questionnaire. At the second visit changes related to eating sweet snacks and oral hygiene habits were also assessed. In both visits the surface-related caries status was evaluated according to ICDAS II criteria. Calculation of D0 (Sound), D1-2 (visual changes) and D3-4 (precavitated caries lesions) Index was based on data collected from clinical examination. Saliva pH and saliva flow rate were also assessed. Throughout pregnancy, a statistically significant increase of eating sweet snacks between main meals was reported, with no effective adaptation of oral hygiene habits. In comparison to the non-pregnant group, pregnant women presented a lower saliva pH at both the first and second visit, p < 0.0005. During the follow-up period, a decrease in the frequency of caries-free surfaces was observed in the pregnant women (p = 0.004) and an increase in precavitated caries lesions (p = 0.011). The main results support the hypothesis that during pregnancy women are prone to enamel demineralisation, namely, to exhibiting additional lesions characterised by precavitated caries lesions.


Polarization modulation imaging ellipsometer.
The polarization modulation technique was successfully combined with parallel synchronous detection using a switching light source and a CCD camera to realize full-frame measurement of ellipsometric parameters. The detected thickness of a monolayer film of n-octadecylsiloxane agreed well with theoretical and reported experimental values. The thickness resolution for imaging and the temporal noise in parallel thickness measurements were smaller than +/-0.1 nm and smaller than +/-0.02 nm, respectively.


Low Sleeping Time, High TV Viewing Time, and Physical Inactivity in School Are Risk Factors for Obesity in Pre-Adolescent Thai Children.
Explore the association between physically active behavior and obesity in 7- to 12-years-old Thai children. As part of SEANUTS Thailand, information on anthropometry, physical activity, and sociodemographic variables were collected in 7- to 12-years-old urban and rural Thai children. Multi-stage sampling technique was used and 1,345 children (32% urban, and 50.3% boys) participated in the study. Anthropometric measurements included weight, height, and BMI-for-age Z-scores (BAZ) using World Health Organization Growth Reference. Obesity was defined as BAZ > 2SD. Physical activity was assessed using a validated physical activity questionnaire (PAQ). The PAQ provided an activity score, activity time in school, sleeping hours, and TV watching time as categorical variable, low, moderate, and high. Chi-square by likelihood ratio test and logistic regression were used to compare obese and non-obese groups. The overall prevalence of overweight and obesity was 10.2 and 10.8% respectively, whereas 8.2% was classified as thin. Maternal education and religion did not differ between obese and non-obese children. However, obese children's family income was higher. After controlling for family income, maternal education, and religion, obese children were significantly less active during break times in school, slept less, and watched more TV than non-obese. However, there was no difference in the activity score of obese and non-obese children. The study showed that physical activity during break time in school, sleep duration, and hours of TV viewing were associated with obesity in pre-adolescent Thai children. It is important to note that activity score was not associated with obesity. One of the most important benefits to be physically active in childhood is the potential to maintain this behavior into adulthood. Therefore, programs that encourage healthy behaviors and address these modifiable risk factors should be incorporated in the school curriculum.


Is functional dyspepsia of particular concern in women? A review of gender differences in epidemiology, pathophysiologic mechanisms, clinical presentation, and management.
Dyspepsia is a remarkably common symptom in the general population. Although multiple definitions have been used to describe the symptom, the most common explanation is that of chronic or recurrent pain or discomfort (a subjective negative feeling that may be associated with early satiety, fullness, bloating, or nausea) centered in the upper abdomen. When a thorough evaluation of a dyspeptic patient fails to identify a cause for her symptoms, the label of nonulcer or functional dyspepsia is applied. Functional dyspepsia is a heterogeneous disorder characterized by relapsing and remitting symptoms. Treatment strategies should focus on alleviating the most bothersome symptom and can be based on the proposed underlying pathophysiology. The effect of gender on mechanisms of disease, symptom presentation, and treatment response is an area of increasing interest and study. As with other functional gastrointestinal disorders, there appear to be some gender-specific features of functional dyspepsia. Specifically, gender-related differences have been observed in some studies of both the prevalence of individual dyspepsia symptoms, and in gastric emptying and proximal gastric motor function. There also appear to be gender differences in the psychosocial realm, with dyspeptic women experiencing a lesser sense of well-being than dyspeptic men, as well as an association of an abuse history with functional dyspepsia. This review will highlight specific gender differences related to the symptom presentation, pathophysiology, and approach to treatment of functional dyspepsia, while noting where differences have not been found and where further investigation is warranted.


Haemolytic uraemic syndrome due to ciprofloxacin-resistant Shigella dysenteriae serotype 1.
A case of haemolytic uraemic syndrome following dysentery due to ciprofloxacin-resistant Shigella dysenteriae serotype 1 is reported for the first time. The increasing resistance of S. dysenteriae serotype 1 to many commonly available antimicrobial agents has implications for the management of dysentery. The choice of antimicrobial treatment for S. dysenteriae serotype 1 infections should take into account widespread drug resistance and the risk of haemolytic uraemic syndrome.


Lamellar macular hole surgery - current concepts, future prospects.
Lamellar macular holes present distinct morphological features including tractional or non-tractional epimacular membranes, foveal tissue alterations, defects of the outer retinal layers, or a separation of the retinal layers. At present, degenerative lamellar holes are differentiated from tractional holes based on the morphological characteristics seen in OCT. The current treatment approach is based on this gross differentiation. Considering the recent developments in high-resolution imaging, this classification needs to be revisited since morphological features may present simultaneously, making it difficult to separate these entities. In addition, a revisited classification may be of value to better standardize the indication for surgical treatment.


Inhibition of autophagy aggravates DNA damage response and gastric tumorigenesis via Rad51 ubiquitination in response to H. pylori infection.
Helicobacter pylori (H. pylori) infection is the strongest known risk factor for the development of gastric cancer. DNA damage response (DDR) and autophagy play key roles in tumorigenic transformation. However, it remains unclear how H. pylori modulate DDR and autophagy in gastric carcinogenesis. Here we report that H. pylori infection promotes DNA damage via suppression of Rad51 expression through inhibition of autophagy and accumulation of p62 in gastric carcinogenesis. We find that H. pylori activated DNA damage pathway in concert with downregulation of repair protein Rad51 in gastric cells, C57BL/6 mice and Mongolian gerbils. In addition, autophagy was increased early and then decreased gradually during the duration of H. pylori infection in vitro in a CagA-dependent manner. Moreover, loss of autophagy led to promotion of DNA damage in H. pylori-infected cells. Furthermore, knockdown of autophagic substrate p62 upregulated Rad51 expression, and p62 promoted Rad51 ubiquitination via the direct interaction of its UBA domain. Finally, H. pylori infection was associated with elevated levels of p62 in gastric intestinal metaplasia and decreased levels of Rad51 in dysplasia compared to their H. pylori- counterparts. Our findings provide a novel mechanism into the linkage of H. pylori infection, autophagy, DNA damage and gastric tumorigenesis.


Collective cell migration of the nephric duct requires FGF signaling.
During the course of development, the vertebrate nephric duct (ND) extends and migrates from the place of its initial formation, adjacent to the anterior somites, until it inserts into the bladder or cloaca in the posterior region of the embryo. The molecular mechanisms that guide ND migration are poorly understood. A novel Gata3-enhancer-Gfp-based chick embryo live imaging system was developed that permits documentation of ND migration at the individual cell level for the first time. FGF Receptors and FGF response genes are expressed in the ND, and FGF ligands are expressed in surrounding tissues. FGF receptor inhibition blocked nephric duct migration. Individual inhibitors of the Erk, p38, or Jnk pathways did not affect duct migration, but inhibition of all three pathways together did inhibit migration of the duct. A localized source of FGF8 placed adjacent to the nephric duct did not affect the duct migration path. FGF signaling acts as a "motor" that is required for duct migration, but other signals are needed to determine the directionality of the duct migration pathway. Developmental Dynamics 244:157-167, 2015. © 2014 Wiley Periodicals, Inc.


Scaling behavior of nonisothermal phase separation.
The phase separation process in a critical mixture of polydimethylsiloxane and polyethylmethylsiloxane (PDMS/PEMS, a system with an upper critical solution temperature) was investigated by time-resolved light scattering during continuous quenches from the one-phase into the two-phase region. Continuous quenches were realized by cooling ramps with different cooling rates kappa. Phase separation kinetics is studied by means of the temporal evolution of the scattering vector qm and the intensity Im at the scattering peak. The curves qm(t) for different cooling rates can be shifted onto a single mastercurve. The curves Im(t) show similar behavior. As shift factors, a characteristic length Lc and a characteristic time tc are introduced. Both characteristic quantities depend on the cooling rate through power laws: Lc approximately kappa(-delta) and tc approximately kappa(-rho). Scaling behavior in isothermal critical demixing is well known. There the temporal evolutions of qm and Im for different quench depths DeltaT can be scaled with the correlation length xi and the interdiffusion coefficient D, both depending on DeltaT through critical power laws. We show in this paper that the cooling rate scaling in nonisothermal demixing is a consequence of the quench depth scaling in the isothermal case. The exponents delta and rho are related to the critical exponents nu and nu* of xi and D, respectively. The structure growth during nonisothermal demixing can be described with a semiempirical model based on the hydrodynamic coarsening mechanism well known in the isothermal case. In very late stages of nonisothermal phase separation a secondary scattering maximum appears. This is due to secondary demixing. We explain the onset of secondary demixing by a competition between interdiffusion and coarsening.


Enzastaurin, an inhibitor of PKCbeta, Enhances Antiangiogenic Effects and Cytotoxicity of Radiation against Endothelial Cells.
Angiogenesis plays an important role in pancreas cancer pathobiology. Pancreatic tumor cells secrete vascular endothelial growth factor (VEGF), activating endothelial cell protein kinase C beta (PKCbeta) that phosphorylates GSK3beta to suppress apoptosis and promote endothelial cell proliferation and microvessel formation. We used Enzastaurin (Enz) to test the hypothesis that inhibition of PKCbeta results in radiosensitization of endothelial cells in culture and in vivo. We measured PKCbeta phosphorylation, VEGF pathway signaling, colony formation, and capillary sprout formation in primary human dermal microvessel endothelial cells (HDMECs) after Enz or radiation (RT) treatment. Microvessel density and tumor volume of human pancreatic cancer xenografts in nude mice were measured after treatment with Enz, RT, or both. Enz inhibited PKCbeta and radiosensitized HDMEC with an enhancement ratio of 1.31 +/- 0.05. Enz combined with RT reduced HDMEC capillary sprouting to a greater extent than either agent alone. Enz prevented radiation-induced GSK3beta phosphorylation of serine 9 while having no direct effect on VEGFR phosphorylation. Treatment of xenografts with Enz and radiation produced greater reductions in microvessel density than either treatment alone. The reduction in microvessel density corresponded with increased tumor growth delay. Enz-induced PKCbeta inhibition radiosensitizes human endothelial cells and enhances the antiangiogenic effects of RT. The combination of Enz and RT reduced microvessel density and resulted in increased growth delay in pancreatic cancer xenografts, without increase in toxicity. These results provide the rationale for combining PKCbeta inhibition with radiation and further investigating such regimens in pancreatic cancer.