Oligomerization-dependent changes in the thermodynamic properties of the TPR-MET receptor tyrosine kinase.
Although oligomerization of receptor tyrosine kinases (RTKs) is necessary for receptor activation and signaling, a quantitative understanding of how oligomerization mediates these critical processes does not exist. We present a comparative thermodynamic analysis of functionally active dimeric and functionally inactive monomeric soluble analogues of the c-MET RTK, which clearly reveal that oligomerization regulates the binding affinity and binding kinetics of the kinase toward ATP and tyrosine-containing peptide substrates. Thermodynamic binding data for oligomeric c-MET were obtained from the dimeric TPR-MET oncoprotein, a functionally active fusion derivative of the c-MET RTK. This naturally occurring oncoprotein contains the cytoplasmic domain of c-MET fused to a coiled coil dimerization domain from the nuclear pore complex. Comparative data were obtained from a soluble monomeric kinase compromising the c-MET cytoplasmic domain (cytoMET). Significantly, under equilibrium binding conditions, the oligomeric phosphorylated kinase showed a significantly lower dissociation constant (K(d,dimer) = 11 microM) for a tyrosine-containing peptide derived from the C-terminal tail of the c-MET RTK when compared to the phosphorylated monomeric kinase cytoMET (K(d,monomer) = 140 microM). Surprisingly, equilibrium dissociation constants measured for the kinase and ATP were independent of the oligomerization state of the kinase (approximately 10 microM). Stopped-flow analysis of peptide substrate binding showed that the association rate constants (k(2)) differed 2-fold and dissociation rate constants (k(-2)) differed 10-fold when phosphorylated TPR-MET was compared to phosphorylated cytoMET. ATP binding abrogated the differences in k(2) rates observed between the two oligomeric states of the c-MET cytoplasmic domain. These results clearly imply that oligomerization induces important thermodynamic and conformational changes in the substrate binding regions of the c-MET protein and provide quantitative mechanistic insights into the necessary role of oligomerization in RTK activation.


Human mesenchymal stem cell (hMSC) differentiation towards cardiac cells using a new microbioanalytical method.
Stem cells (SCs) are more and more often applied in tissue engineering and cell therapies, e.g. in regenerative medicine. Standard methods of SC differentiation are time consuming and ineffective. Therefore, new bioanalytical methods (i.e. Lab-on-a-Chip systems) are develop to improve such type of studies. Although, microtechnology is a rapidly growing research area, there are so far not too many works which present SC differentiation into cardiomyocytes in the microsystems. Therefore, we present new microbioanalytical method of SC differentiation towards cardiac cells using a newly developed digitally controlled microdispenser integrated with a Heart-on-a-chip system. Seven-day culture of human mesenchymal stem cells (hMSCs) and their differentiation using biochemical factors such as 5-AZA (2 μM, 24 h) and VEGF (20 ng ml-1, 72 h) were investigated in the microsystem which was automatically operated using smartphone software. hMSC differentiation into the cardiac cells was confirmed using immunostaining of cardiac markers (α-actinin and troponin T). The usage of the microsystem allowed shortening the time of hMSC differentiation in comparison to macroscale method. We showed that the microsystem, in which the in vivo microenvironment is mimicked and dynamic conditions are provided by a microdispenser, favorably affect hMSC differentiation towards cardiac cells. Based on the presented research we can conclude that the developed digitally controlled microsystem could be successfully utilized as a new microbioanalytical method for stem cells differentiation and analysis of their function under dynamic conditions. In the future, this could be a helpful tool for scientists working on regenerative medicine.


When did oxygenic photosynthesis evolve?
The atmosphere has apparently been oxygenated since the 'Great Oxidation Event' ca 2.4 Ga ago, but when the photosynthetic oxygen production began is debatable. However, geological and geochemical evidence from older sedimentary rocks indicates that oxygenic photosynthesis evolved well before this oxygenation event. Fluid-inclusion oils in ca 2.45 Ga sandstones contain hydrocarbon biomarkers evidently sourced from similarly ancient kerogen, preserved without subsequent contamination, and derived from organisms producing and requiring molecular oxygen. Mo and Re abundances and sulphur isotope systematics of slightly older (2.5 Ga) kerogenous shales record a transient pulse of atmospheric oxygen. As early as ca 2.7 Ga, stromatolites and biomarkers from evaporative lake sediments deficient in exogenous reducing power strongly imply that oxygen-producing cyanobacteria had already evolved. Even at ca 3.2 Ga, thick and widespread kerogenous shales are consistent with aerobic photoautrophic marine plankton, and U-Pb data from ca 3.8 Ga metasediments suggest that this metabolism could have arisen by the start of the geological record. Hence, the hypothesis that oxygenic photosynthesis evolved well before the atmosphere became permanently oxygenated seems well supported.


Terminology of cell-water relations.
Use of the term "water potential" in place of "diffusion pressure deficit" would improve communication between botanists and scientists in other fields because the concept of potential is familiar to most scientists. Water potential, expressed as PsiW, is the difference in free energy or chemical potential per unit molal volume between pure water and water in cells at the same temperature. The potential of pure water is set at zero; hence the potential of water in cells and solutions is less than zero, or negative. The water potential of a cell is numerically equal to its diffusion pressure deficit, but has a negative sign.


Psychometric properties of the emotion awareness questionnaire for children in a French-speaking population.
In this study, we investigated the psychometric properties of the French version of the Emotion Awareness Questionnaire (EAQ30; Rieffe et al., 2008). The EAQ30 was administered to 707 French-speaking children aged 8 to 16 years old. The original 6-factor structure was replicated in our data. The internal consistency coefficients of the EAQ30 subscales were satisfactory. We found small significant differences for gender and age. Regarding convergent validity, we found positive correlations between EAQ30 scores and emotional intelligence and negative correlations between EAQ30 scores and alexithymia. There was preliminary evidence of discriminant validity, with EAQ30 scores being weakly related to school performance, and concurrent validity, with EAQ30 scores being negatively related to somatic complaints, depression, and anxiety. Finally, except for 1 dimension, EAQ30 scores were not susceptible to social desirability. Although some weaknesses of the scale remain to be addressed, these findings support the use of the EAQ30 for research and clinical purposes.


Mathematical aspects of molecular replacement. I. Algebraic properties of motion spaces.
Molecular replacement (MR) is a well established method for phasing of X-ray diffraction patterns for crystals composed of biological macromolecules of known chemical structure but unknown conformation. In MR, the starting point is known structural domains that are presumed to be similar in shape to those in the macromolecular structure which is to be determined. A search is then performed over positions and orientations of the known domains within a model of the crystallographic asymmetric unit so as to best match a computed diffraction pattern with experimental data. Unlike continuous rigid-body motions in Euclidean space and the discrete crystallographic space groups, the set of motions over which molecular replacement searches are performed does not form a group under the operation of composition, which is shown here to lack the associative property. However, the set of rigid-body motions in the asymmetric unit forms another mathematical structure called a quasigroup, which can be identified with right-coset spaces of the full group of rigid-body motions with respect to the chiral space group of the macromolecular crystal. The algebraic properties of this space of motions are articulated here.


Cloning and screening of sequences expressed in a mouse colon tumor.
Polyadenylic acid-containing cytoplasmic RNA was isolated from a dimethylhydrazine-induced mouse transplantable colon carcinoma. Double-stranded complementary DNA synthesized using these molecules was inserted into the HindIII site of pBR322 using HindIII linkers, and the recombinant molecules were cloned in Escherichia coli. Clones were screened with labeled complementary DNA synthesized from the polyadenylic acid-containing cytoplasmic RNA of the tumor or normal mouse colon, liver, or kidney. Of 378 clones screened with the normal colon and tumor probes, seven showed major increases in abundance in the tumor tissue as compared to normal, and one showed a major decrease. Twenty-five other sequences were found which showed smaller increases and 22 showed smaller decreases. Of 373 clones screened with tumor, colon, liver, and kidney probes, 79% exhibited little evidence of tissue specificity in expression. The data for those sequences which do show tissue-specific regulation of expression suggest that the tumor continues to express sequences characteristic of the colon but also shows a loss, or decrease, in other gene products, most of which (19 of 25) are characteristic of the colon. Finally, nine of 10 sequences which increase from low abundance in the normal colon to high abundance in the tumor are found at a moderate to high level in the liver and kidney. On the other hand, 23 of 36 sequences which show more modest increases in the tumor as compared to normal are scarce or absent in the liver and kidney.


Accurate entropy calculation for large flexible hydrocarbons using a multi-structural 2-dimensional torsion method.
Entropy is one of the key thermodynamic parameters in combustion kinetic modeling. Accurate entropy prediction needs to account for the conformational torsional anharmonicity, which could be solved by the state-of-the-art multi-structural torsion (MS-T) method. However, this method is computationally expensive or even not feasible for large flexible molecules. To address this issue, we proposed a multi-structural 2-dimensional torsion (MS-2DT) method that adopts minimally coupled torsions to reduce the computational cost. In this method, a series of 2-dimensional coupled torsion combinations were used to generate an initial conformer space with a size of CN2·9 (N is the number of torsions). The standard entropy (and the heat capacity) values of 18 C6-C8 alkanes with 5-7 torsions were computed at 200-2000 K. The MS-2DT calculation is in good agreement with the benchmark MS-T method: only a small deviation of -0.19 ± 0.15 cal mol-1 K-1 in standard entropy and -0.10 ± 0.21 cal mol-1 K-1 in heat capacity. Additionally, a further application of MS-2DT to n-decane with 9 torsions implies an improved accuracy in entropy (and heat capacity) prediction compared to other conventional simplified treatments. This method provides an affordable and accurate solution to treat the conformational torsional anharmonicity of large flexible alkanes.


Specific downregulation of presenilin 2 gene expression is prominent during early stages of sporadic late-onset Alzheimer's disease.
Mutations in the presenilin genes PS1 and PS2 cause familial Alzheimer's disease (AD). In a previous study, we reported that PS2 mRNA levels are decreased in the hippocampus, frontal cortex and basal forebrain of subjects with late-onset sporadic AD. In this study, we examined whether this downregulation occurs as the disease progresses from mild to severe stages or whether downregulation of PS2 expression is an early event in AD. We used in situ hybridization histochemistry to quantify the level of expression of PS2 message in the hippocampus of normal subjects and subjects with mild, moderate or severe AD. Several regions of the hippocampus which are sequentially susceptible to AD neuropathology as the disease progresses in severity were analyzed. We demonstrate that specific downregulation of PS2 expression is as severe in subjects with mild AD as it is in subjects in late stages of the disease. In addition, we show that hippocampal regions that are relatively free of AD neuropathology during early stages of the disease exhibit severely compromised PS2 mRNA levels even in mild AD cases. In contrast, PS2 is expressed at normal levels in the cerebellum, a region which succumbs to significantly fewer AD-related insults even at very advanced stages of the disease. These results suggest that the specific downregulation of PS2 gene expression is an early event in sporadic late-onset AD.


Incommensurately modulated crystal structure of flamite - natural analogue of \alpha _{\rm H}^{\prime}-Ca2SiO4.
Crystal structures of unquenchable high-temperature polymorphs of Ca2SiO4, important in cement chemistry, have eluded single-crystal X-ray analysis. However, the problem may be addressed by studying chemically stabilized Ca2SiO4 polymorphs at ambient temperature. Here an incommensurately modulated crystal structure of flamite [Pnma(0β0)00s, q = 0.2728 (2)b*, a = 6.8588 (2) Å, b = 5.4301 (2) Å, c = 9.4052 (3) Å] is described. It is a mineral analogue of orthorhombic \alpha _{\rm H}^{\prime}-Ca2SiO4 (stable between 1160 and 1425°C), naturally stabilized by substitution with phosphorus. The incommensurate modulation results from wave-like displacement of cation sites accompanied by tilting of (Si,P)O4 tetrahedra and variation of the Na/(Ca + Na + K) ratio along the modulation period. The studied sample from Hatrurim Basin (Negev Desert, Israel) with composition (Ca1.75K0.12Na0.12)1.99(Si0.74P0.26)1.00O4 also demonstrates pseudomerohedral cyclic twinning around the a axis, which results from pseudohexagonal topology of the crystal structure and complicates the indexing of X-ray diffraction data.


Cyclic nucleotides and lipolysis.
The recent literature regarding the mechanisms of regulation of lipolysis with emphasis on the role of cyclic nucleotides is reviewed. The following conclusions appear warranted at present. (1) Cyclic AMP (cAMP) is a major regulator of lipolysis. However, mechanisms other than the production and catabolism of cAMP also exist. (2) Insulin can lower adipocyte cyclic AMP levels, but this effect cannot explain all aspects of the antilipolytic effect of insulin. (3) Insulin stimulates cyclic AMP phosphodiesterase and inhibits adenylate cyclase in adipocytes. In addition, there are probably other targets of insulin action. The possibilities include cAMP dependent protein kinase, phosphoprotein phosphatase, and triacylglycerol lipase. (4) Cyclic GMP is probably not directly involved in the regulation of lipolysis. (5) Cytosolic Ca2+ probably plays an important role in the regulation of lipolysis. The nature of such a role for Ca2+ and the potential role of calmodulin in the regulation of lipolysis remain to be explored.


CASP microdomain formation requires cross cell wall stabilization of domains and non-cell autonomous action of LOTR1.
Efficient uptake of nutrients in both animal and plant cells requires tissue-spanning diffusion barriers separating inner tissues from the outer lumen/soil. However, we poorly understand how such contiguous three-dimensional superstructures are formed in plants. Here, we show that correct establishment of the plant Casparian Strip (CS) network relies on local neighbor communication. We show that positioning of Casparian Strip membrane domains (CSDs) is tightly coordinated between neighbors in wild-type and that restriction of domain formation involves the putative extracellular protease LOTR1. Impaired domain restriction in lotr1 leads to fully functional CSDs at ectopic positions, forming 'half strips'. LOTR1 action in the endodermis requires its expression in the stele. LOTR1 endodermal expression cannot complement, while cortex expression causes a dominant-negative phenotype. Our findings establish LOTR1 as a crucial player in CSD positioning acting in a directional, non-cell-autonomous manner to restrict and coordinate CS positioning.


Making Your School Nurse Philosophy Visible.
As a school nurse, it can be challenging to make values and philosophy useful in the context of a busy and stressful workday. However, values and philosophy can help guide school nurses in their profession. This article proposes strategies for how school nurses can make their school nurse's values and philosophy visible. The first step in formulating a school nurse philosophy is to identify overall values, such as how one views society and people's equal values. A peer-mentoring group, such as a mastermind group, could offer a place to have philosophical discussions with colleagues.


An ultrasound-controllable ROS-responsive nanoplatform for O2 and NO generation to enhance sonodynamic therapy against multidrug-resistant bacterial infections.
Antimicrobial sonodynamic therapy (SDT) has broad application potential in the eradication of multidrug-resistant (MDR) bacterial infections due to its non-invasiveness, absence of resistance concern, and high cytotoxicity. However, the hypoxic infection microenvironment and the rapid depletion of O2 during SDT severely limit the therapeutic efficacy of SDT. Herein, an ultrasound-controllable ROS-responsive nanoplatform (FOT/Fe3O4@Lipo-ICG) was constructed and prepared by encapsulating FOT and Fe3O4 nanoparticles (Fe3O4 NPs) within sonosensitiser ICG-modified liposomes. Both in vitro and in vivo, we observed that ICG conjugation on the surface of liposomes could effectively maintain good dispersion and prevent ICG aggregates in complex biological matrices. In addition, liposomes could significantly block the catalytic activity of Fe3O4 NPs, as well as the release of FOT, whereas upon US irradiation, the catalytic activity of Fe3O4 NPs was recovered to catalyse the decomposition of endogenous H2O2 into O2 and ˙OH. Meanwhile, the FOT was successfully released to react with endogenous glutathione to sequentially produce NO. Based on the aforementioned advantages, the FOT/Fe3O4@Lipo-ICG demonstrated potent efficacy in eradicating methicillin-resistant Staphylococcus aureus-induced local infection and sepsis resulting from local infection. Thus, the developed US-controllable nanoplatform offers a promising strategy for enhancing SDT for eradicating MDR bacterial infections.


Prognostic Impact of Visceral Pleural Invasion in Resected Solitary Lung Metastases from Gastric Cancer.
Pulmonary resection of metastases from gastric cancer is extremely rare because gastric cancer metastasis to the lungs or thoracic cavity occurs as multiple pulmonary metastases, carcinomatous lymphangitis, or carcinomatous pleurisy. Therefore, the significance of surgery for pulmonary metastasis of gastric cancer remains unclear. This study aimed to investigate the surgical outcomes and prognostic factors for survival after the resection of pulmonary metastases from gastric cancer. From 2007 to 2019, 13 patients with pulmonary metastasis of gastric cancer underwent metastasectomy. Surgical outcomes were analyzed to determine the prognostic factors for recurrence and overall survival (OS). All the patients underwent pulmonary resection for solitary metastases. At the median follow-up time of 45.6 months (range, 4.8-106.8 months), five patients experienced a recurrence of gastric cancer after metastasectomy. The 5-year recurrence-free survival rate was 44.4%, and the 5-year OS rate after pulmonary resection was 45.3%. Univariate analysis revealed that visceral pleural invasion (VPI) was an unfavorable prognostic factor for both recurrence-free and OS. Pulmonary resection of solitary metastases from gastric cancer may be an effective therapeutic option to improve survival. VPI in gastric cancer metastasis is a negative prognostic factor.


Acupuncture accelerates wound healing in burn-injured mice.
The effects of acupuncture on healing of deep second degree burns were compared to the conventional hydrocolloid dressing, Duoderm in mice. The expression level of inflammatory protein-1α (MIP-1α) was significantly reduced in the injured skin and the number of eosinophils in blood decreased significantly following the acupuncture treatment compared to the Duoderm dressing at 7 days after the burn. In addition, the acupuncture treatment was more effective in decreasing the wound size and inducing epidermal regeneration. Histological findings also revealed that there was less leukocyte infiltration and a greater reduction in the immunohistochemical reaction to MIP-2 in the wounds treated with acupuncture versus Duoderm. Furthermore, the numbers of BrdU- and basic fibroblast growth factor (bFGF)-positive cells were significantly increased by the acupuncture treatment, compared to the Duoderm treatment at 7 days. Moreover, in the acupuncture treated mice, the expression of fibronectin was increased and α-SMA was decreased at 7 days. Thus, this present study demonstrates that acupuncture accelerates the skin regeneration process following deep second degree burns.


Rural and urban differences in lifetime occupation and its influence on mortality among Mexican adults.
To determine how primary lifetime occupation type is associated with mortality, and how the relationship varies by rural and urban dwelling. Data come from 2001-2018 Mexican Health and Aging Study (adults aged 50+, n=11 094). We created five occupation categories. Cox proportional hazard models predicted mortality using baseline covariates. In both rural and urban settings, participants with manual jobs, such as agriculture and production/industrial jobs, had an increased risk of mortality compared to those with administrative/professional jobs. In urban settings, participants in the domestic/service and no main job categories had higher risk of mortality than those in the administrative/professional category. For men these differences remained, but not for women. In a context of rural and urban demographic shifts, it is crucial to consider the implications that occupation as a socioeconomic factor can have on health and to identify the most vulnerable groups.


High flow through nasal cannula in exacerbated COPD patients: a systematic review.
Chronic Obstructive Pulmonary Disease (COPD) history is characterized by episodes of exacerbation of varying severity, featured by acute worsening of respiratory symptoms, commonly precipitated by respiratory tract infection. The recent ERS/ATS clinical practice guidelines strongly recommend the application of non invasive ventilation (NIV) for patients with acute respiratory failure (ARF) leading to acute or acute-on-chronic respiratory acidosis (pH 7.35) and not for those patients with acute exacerbation of COPD (AECOPD) and hypercapnia who are not acidotic. In recent years, High-Flow through Nasal Cannula (HFNC) has been introduced in the clinical practice. We designed the present systematic review of the literature to assess all effects of HFNC use reported in exacerbated COPD patients. In this setting, HFNC is able to keep PaCO2 unmodified, while oxygenation slightly deteriorates as opposed to NIV. Furthermore, the work of breathing is reduced with HFNC by a similar extent to NIV, while it increases by 40-50% during conventional oxygen therapy (COT). HFNC is also reported to be more comfortable than COT and NIV. Despite these results, little and limited evidence for improved clinical outcomes is currently available.


Uncovering the Redox Shuttle Degradation Mechanism of Ether Electrolytes in Sodium-Ion Batteries and its Inhibition Strategy.
Ether-based electrolytes exhibit excellent performance when applied in different anode materials of sodium ion batteries (SIBs), but their exploration on cathode material is deficient and the degradation mechanism is still undiscovered. Herein, various battery systems with different operation voltage ranges are designed to explore the electrochemical performance of ether electrolyte. It is found for the first time that the deterioration mechanism of ether electrolyte is closely related to the "redox shuttle" between cathode and low-potential anode. The "shuttle" is discovered to occur when the potential of anodes is below 0.57 V, and the gas products coming from "shuttle" intermediates are revealed by differential electrochemical mass spectrometry (DEMS). Moreover, effective inhibition strategies by protecting low-potential anodes are proposed and verified; ethylene carbonate (EC) is found to be very effective as an additive by forming an inorganics-rich solid electrolyte interphase (SEI) on low-potential anodes, thereby suppressing the deterioration of ether electrolytes. This work reveals the failure mechanism of ether-based electrolytes applied in SIBs and proposes effective strategies to suppress the "shuttle," which provides a valuable guidance for advancing the application of ether-based electrolytes in SIBs.


-Reproductive strategies of two common sympatric Mediterranean sponges: Dysidea avara (Dictyoceratida) and Phorbas tenacior (Poecilosclerida).
Despite their abundance in benthic ecosystems, life cycles and reproductive features of most sponge species remain unknown. We have studied the main reproductive features of two demosponges, Dysidea avara and Phorbas tenacior, belonging to phylogenetically distant groups: Orders Dictyoceratida and Poecilosclerida, respectively. Both sponges are abundant and share habitat in the Mediterranean rocky sublittoral. They brood parenchymella larvae with different morphology and behaviour. Sampling was conducted monthly over a two-year period in a locality where both species coexist. The two species reproduced in spring-summer, and presented species-specific reproductive features despite being subject to the same environmental conditions. D. avara has a shorter reproductive period than P. tenacior, ending before the peak of temperature in summer, while the reproductive period of P. tenacior lasts until beginning of autumn. Brooding larvae were present in June-July in D. avara, and in August-October in P. tenacior. Larval size, reproductive effort and number of larvae produced (measured the month with the maximum production) were significantly higher in D. avara than in P. tenacior. A higher reproductive effort and larval traits point to a more opportunistic life strategy in D. avara than in P. tenacior. A lack of overlap in the timing of larval release, as well as different reproductive traits, may reduce competition and facilitate the coexistence of these two sympatric and abundant sponges.


Patients with coronary heart disease, dilated cardiomyopathy and idiopathic ventricular tachycardia share overlapping patterns of pathogenic variation in cardiac risk genes.
Ventricular tachycardia (VT) is a major cause of sudden cardiac death (SCD). Clinical investigations can sometimes fail to identify the underlying cause of VT and the event is classified as idiopathic (iVT). VT contributes significantly to the morbidity and mortality in patients with coronary artery disease (CAD) and dilated cardiomyopathy (DCM). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility screening for disease-predisposing variants could improve VT diagnostics and prevent SCD in patients. Ninety-two patients diagnosed with coronary heart disease (CHD), DCM, or iVT were included in our study. We evaluated genetic profiles and variants in known cardiac risk genes by targeted next generation sequencing (NGS) using a newly designed custom panel of 96 genes. We hypothesized that shared morphological and phenotypical features among these subgroups may have an overlapping molecular base. To our knowledge, this was the first study of the deep sequencing of 96 targeted cardiac genes in Kazakhstan. The clinical significance of the sequence variants was interpreted according to the guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015. The ClinVar and Varsome databases were used to determine the variant classifications. Targeted sequencing and stepwise filtering of the annotated variants identified a total of 307 unique variants in 74 genes, totally 456 variants in the overall study group. We found 168 mutations listed in the Human Genome Mutation Database (HGMD) and another 256 rare/unique variants with elevated pathogenic potential. There was a predominance of high- to intermediate pathogenicity variants in LAMA2, MYBPC3, MYH6, KCNQ1, GAA, and DSG2 in CHD VT patients. Similar frequencies were observed in DCM VT, and iVT patients, pointing to a common molecular disease association. TTN, GAA, LAMA2, and MYBPC3 contained the most variants in the three subgroups which confirm the impact of these genes in the complex pathogenesis of cardiomyopathies and VT. The classification of 307 variants according to ACMG guidelines showed that nine (2.9%) variants could be classified as pathogenic, nine (2.9%) were likely pathogenic, 98 (31.9%) were of uncertain significance, 73 (23.8%) were likely benign, and 118 (38.4%) were benign. CHD VT patients carry rare genetic variants with increased pathogenic potential at a comparable frequency to DCM VT and iVT patients in genes related to sarcomere function, nuclear function, ion flux, and metabolism. In this study we showed that in patients with VT secondary to coronary artery disease, DCM, or idiopathic etiology multiple rare mutations and clinically significant sequence variants in classic cardiac risk genes associated with cardiac channelopathies and cardiomyopathies were found in a similar pattern and at a comparable frequency.


Synthesis of pro-apoptotic indapamide derivatives as anticancer agents.
4-Chloro-3-({[(substitutedamino)carbonothioyl]amino}sulfonyl)-N-(2-methyl-2,3-dihydro-1H-indole-1-yl)benzamide (1-20) and 4-chloro-3-({[3-(substituted)-4-oxo-1,3-thiazolidine-2-ylidene]amino}sulfonyl)-N-(2-methyl-2,3-dihydro-1H-indole-1-yl)benzamide derivatives (21-31) were synthesized from 4-chloro-N-(2-methyl-2,3-dihydroindol-1-yl)-3-sulfamoylbenzamide (indapamide). 4-Chloro-3-({[(4-chlorophenyl) amino) carbonothioyl]amino}sulfonyl)-N-(2-methyl-2,3-dihydro-1H-indole-1-yl)benzamide 12 demonstrated the highest proapoptotic activity among all synthesized compounds on melanoma cell lines MDA-MB-435 with 3.7% growth inhibition at the concentration of 10 µM. Compound 12 (SGK 266) was evaluated in vitro using the MTT colorimetric method against melanoma cancer cell line MDA-MB435 growth inhibition for different doses and exhibited anticancer activity with IC50 values of 85-95 µM against melanoma cancer cell line MDA-MB435. In addition, this compound was investigated as inhibitors of four physiologically relevant human carbonic anhydrase isoforms, hCA I, II, IX and XII. The compund inhibited these enzymes with IC50 values ranging between 0.72 and 1.60 µM.


Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study.
Carriers of the apolipoprotein A-I(Milano) (apoA-I(M)) mutant present with very low plasma HDL cholesterol and moderate hypertriglyceridemia, apparently not leading to premature coronary heart disease. The objective of this study was to establish whether this high-risk lipid/lipoprotein profile is associated with structural changes in the carotid arteries and heart, indicative of preclinical atherosclerosis. Twenty-one A-I(M) carriers were compared with age- and sex-matched control subjects from the same kindred and with 2 series of matched subjects with primary hypoalphalipoproteinemia (HA). Structural changes in the carotid arteries were defined as the intima-media thickness (IMT) measured by B-mode ultrasound. HA subjects, both recruited among patients attending our Lipid Clinic and blood donors, showed significant thickening of the carotids (average IMT, 0.86+/-0.25 and 0.88+/-0.29 mm, respectively) compared with control subjects (average IMT, 0.64+/-0.12 mm); the apoA-I(M) carriers instead showed normal arterial thickness (average IMT, 0.63+/-0.10 mm). Moreover, a significantly higher prevalence of atherosclerotic plaques was found in patients and blood donors with HA (both 57%) compared with apoA-I(M) carriers (33%) and control subjects (21%). Echocardiographic findings and maximal treadmill ECG did not differ significantly between apoA-I(M) carriers and control subjects, apart from a slight increase in left ventricular end-diastolic dimension in the carriers. Despite severe HA, carriers of the apoA-I(M) mutant do not show structural changes in the arteries and heart, in contrast to HA subjects, who are characterized by a marked increase in carotid IMT and increased prevalence of atherosclerotic plaques.


Peripartum anesthetic management of renal transplant patients--a multicenter cohort study.
As the number and success of renal transplantation has grown, there has been an increase in the number of renal transplant patients giving birth. To date, there has been no data on obstetric anesthesia management of these patients. The purpose of this study was to build an Israeli national database on parturients after renal transplant. A sixteen-year (calendar years 1996-2011) retrospective study was conducted at three major tertiary centers with a combined current birth rate of approximately 25,000 deliveries annually. We found 83 labors in 64 women. Forty-two percent of this population suffered from hypertension while 12.5% had diabetes. Forty-seven percent of women had a vaginal delivery while 53% of women had a cesarean section. The rate of epidural analgesia for labor was 59%, and rate of regional anesthesia during cesarean section was 75%. There were no anesthetic complications in any cases. Standard ASA monitoring was used in all cases except for one woman with severe hypertension who required an arterial line during her cesarean section. Forty-seven percent of newborn were under 37 weeks with average gestational week 36 ± 3 days and birth weight 2.5 ± 0.7 kg. Average Apgar was 8.4 ± 1.3 at one minute and 9.3 ± 0.7 at five minutes. There was one neonatal death in the CS group due to placental abruption. Patients after renal transplant can safely undergo birth and obstetric analgesia.


Structure of EvaA: a paradigm for sugar 2,3-dehydratases.
Unusual deoxysugars found appended to natural products often provide or enhance the pharmacokinetic activities of the parent compound. The preferred carbohydrate donors for the biosynthesis of such glycosylated natural products are the dTDP-linked sugars. Many of the biologically relevant dTDP-deoxysugars are constructed around the 2,6-dideoxyhexoses or the 2,3(4),6-trideoxyhexoses. A key step in the biosynthesis of these sugars is the removal of the hexose C-2' hydroxyl group and the oxidation of the C-3' hydroxyl group to a carbonyl moiety. Enzymes that catalyze these reactions are referred to as 2,3-dehydratases and have been, for the most part, largely uncharacterized. Here we report the first structural analysis of a sugar 2,3-dehydratase. For this investigation, the enzyme, EvaA, was cloned from Amycolatopsis orientalis, and the structure was solved and refined to a nominal resolution of 1.7 Å. On the basis of the resulting model, it is clear that EvaA belongs to the large Nudix hydrolase superfamily and is most similar to GDP-mannose hydrolase. Each subunit of the EvaA dimer folds into two domains that clearly arose via gene duplication. Two dTDP-sugar binding pockets, A and B, are present in each EvaA subunit. On the basis of site-directed mutagenesis experiments and activity assays, it appears that pocket A functions as the active site and pocket B is simply a remnant left behind from the gene duplication event. As 2,3-dehydration is crucial for the biosynthesis of many unusual deoxysugars, this investigation provides key structural insight into this widely conserved reaction.


The role of GSK-3 in synaptic plasticity.
Glycogen synthase kinase-3 (GSK-3), an important component of the glycogen metabolism pathway, is highly expressed in the CNS. It has been implicated in major neurological disorders including Alzheimer's disease, schizophrenia and bipolar disorders. Despite its central role in these conditions it was not known until recently whether GSK-3 has neuronal-specific functions under normal conditions. However recent work has shown that GSK-3 is involved in the regulation of, and cross-talk between, two major forms of synaptic plasticity, N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and NMDAR-dependent long-term depression (LTD). The present article summarizes this recent work and discusses its potential relevance to the treatment of neurological disorders.


Investigation of photocurrents resulting from a living unicellular algae suspension with quinones over time.
Plants, algae, and some bacteria convert solar energy into chemical energy by using photosynthesis. In light of the current energy environment, many research strategies try to benefit from photosynthesis in order to generate usable photobioelectricity. Among all the strategies developed for transferring electrons from the photosynthetic chain to an outer collecting electrode, we recently implemented a method on a preparative scale (high surface electrode) based on a Chlamydomonas reinhardtii green algae suspension in the presence of exogenous quinones as redox mediators. While giving rise to an interesting performance (10-60 μA cm-2) in the course of one hour, this device appears to cause a slow decrease of the recorded photocurrent. In this paper, we wish to analyze and understand this gradual fall in performance in order to limit this issue in future applications. We thus first show that this kind of degradation could be related to over-irradiation conditions or side-effects of quinones depending on experimental conditions. We therefore built an empirical model involving a kinetic quenching induced by incubation with quinones, which is globally consistent with the experimental data provided by fluorescence measurements achieved after dark incubation of algae in the presence of quinones.


Face-to-pubes rotational maneuver for bilateral nuchal arms in a vaginal breech birth, resolved in an upright maternal position: A case report.
A physiological breech birth is one in which the woman is encouraged to remain active throughout her labor and able to assume the position of her choice for the birth. Use of this strategy within the United Kingdom National Health Service has led to the use of innovative maneuvers to relieve obstruction when women give birth in upright positions, for example, kneeling or standing. This includes use of the face-to-pubes rotational maneuver to relieve extended nuchal arm(s). In this paper, we report a case where the face-to-pubes rotational maneuver was used to relieve bilateral nuchal arm entrapment in a breech birth. Single-case study. We aimed to generate an in-depth understanding of how this maneuver works and how professionals decide to use it by exploring its use in a real-life context. The face-to-pubes rotational maneuver appears to be an effective method of relieving nuchal arm entrapment when used by experienced hands. In cases of bilateral nuchal arm entrapment, elevation to a higher station may be necessary to dis-impact the arms above the pelvic inlet before the fetus can be rotated. After face-to-pubes rotation and release of arms, the head should be realigned in an occiput anterior position for delivery. The face-to-pubes rotational maneuver can be taught for resolution of nuchal arms in an upright position. Parents should be informed of the availability or not of a specialist midwife trained in physiological breech birth, as this may be important to their decision-making.


Resolution enhancement of holographic printer using a hogel overlapping method.
We propose a hogel overlapping method for the holographic printer to enhance the lateral resolution of holographic stereograms. The hogel size is directly related to the lateral resolution of the holographic stereogram. Our analysis by computer simulation shows that there is a limit to decreasing the hogel size while printing holographic stereograms. Instead of reducing the size of hogel, the lateral resolution of holographic stereograms can be enhanced by printing overlapped hogels, which makes it possible to take advantage of multiplexing property of the volume hologram. We built a holographic printer, and recorded two holographic stereograms using the conventional and proposed overlapping methods. The images and movies of the holographic stereograms experimentally captured were compared between the conventional and proposed methods. The experimental results confirm that the proposed hogel overlapping method improves the lateral resolution of holographic stereograms compared to the conventional holographic printing method.


Assessment of the quality of reporting in abstracts of randomized controlled trials published in five leading Chinese medical journals.
Clear, transparent and sufficiently detailed abstracts of randomized trials (RCTs), published in journal articles are important because readers will often base their initial assessment of a trial on such information. However, little is known about the quality of reporting in abstracts of RCTs published in medical journals in China. We identified RCTs abstracts from 5 five leading Chinese medical journals published between 1998 and 2007 and indexed in MEDLINE. We assessed the quality of reporting of these abstracts based on the Consolidated Standards of Reporting Trials (CONSORT) abstract checklist. We also sought to identify whether any differences exist in reporting between the Chinese and English language version of the same abstract. We identified 332 RCT abstracts eligible for examination. Overall, the abstracts we examined reported 0-8 items as designated in the CONSORT checklist. On average, three items were reported per abstract. Details of the interventions (288/332; 87%), the number of participants randomized (216/332; 65%) and study objectives (109/332; 33%) were the top three items reported. Only two RCT abstracts reported details of trial registration, no abstracts reported the method of allocation concealment and only one mentioned specifically who was blinded. In terms of the proportion of RCT abstracts fulfilling a criterion, the absolute difference (percentage points) between the Chinese and English abstracts was 10% (ranging from 0 to 25%) on average, per item. The quality of reporting in abstracts of RCTs published in Chinese medical journals needs to be improved. We hope that the introduction and endorsement of the CONSORT for Abstracts guidelines by journals reporting RCTs will lead to improvements in the quality of reporting.


Immunohistochemical localization of mesenchymal stem cells in ossified human spinal ligaments.
Mesenchymal stem cells (MSCs) have been isolated from various tissues and used for elucidating the pathogenesis of numerous diseases. In our previous in vitro study, we showed the existence of MSCs in human spinal ligaments and hypothesized that these MSCs contributed to the pathogenesis of ossification of spinal ligaments. The purpose of this study was to use immunohistochemical techniques to analyze the localization of MSCs in ossified human spinal ligaments in situ. Ossified (OLF) or non-ossified ligamentum flavum (non-OLF) samples from the thoracic vertebra were obtained from patients who had undergone posterior spinal surgery. Serial sections were prepared from paraffin-embedded samples, and double immunofluorescence staining was performed using antibodies against markers for MSCs (CD73, CD90 and CD105), endothelial cells (CD31), pericytes (α-smooth muscle actin), and chondrocytes (S100). Immunolocalization of MSCs was observed in the perivascular area and collagenous matrix in spinal ligaments. Markers for MSCs and pericytes were co-expressed in the perivascular area. Compared with non-OLF, OLF had a large amount of neovascularization in the fragmented ligament matrix, and a high accumulation of MSCs around blood vessels. The prevalence of MSCs in OLF within collagenous matrix was significantly higher than that in non-OLF. Chondrocytes near the ossification front in OLF also presented expression of MSC markers. MSCs may contribute to the ectopic ossification process of OLF through endochondral ossification.


Synthesis and evaluation of 18F-labeled procainamide as a PET imaging agent for malignant melanoma.
Malignant melanoma has an aggressive nature and a high metastatic propensity resulting in the highest mortality rate of any skin cancer. In this study, we synthesized 18F-labeled procainamide (PCA) for detection of melanoma using positron emission tomography (PET), and evaluated its biological characteristics. The non-decay-corrected radiochemical yield of 18F-PCA was 10-15% and its in vitro stability was over 98% for 2 h. At 1 h, cellular uptake of 18F-PCA was 3.8-fold higher in a group with the presence of l-tyrosine than in a non-l-tyrosine-treated group. Furthermore, 18F-PCA permitted visualization of B16F10 (mouse melanoma) xenografts on microPET after intravenous injection, and was retained in the tumor for 60 min, with a high tumor-to-liver uptake ratio. 18F-PCA showed specific melanoma uptake in primary lesions with a high melanin targeting ability in small animal models. 18F-PCA may have potential as a PET imaging agent for direct melanoma detection.


Do assembly history effects attenuate from species to ecosystem properties? A field test with wood-inhabiting fungi.
Assembly history, or the order of species arrival, can have wide-ranging effects on species, communities and ecosystems. However, it remains unclear whether assembly history primarily affects individual species, with effects attenuating at the level of communities and ecosystems or, alternatively, has consistent effect sizes across increasing levels of ecological organisation. We address this question using a field-based manipulation of assembly history of wood-inhabiting fungi. The largest effect sizes were observed for the frequency of some individual species, and mean effect sizes were lower for community metrics of fungi immigrating from the regional species pool. There was little evidence, however, of attenuation in effect sizes at the ecosystem level (carbon, nitrogen, decomposition) in comparison to the species or community level. These results indicate that assembly history can have strong effects on ecosystem properties even under natural levels of environmental variability.


Prostaglandin synthesis in human lymphatics from precursor fatty acids.
(Iso)-eicosanoids appear to play a pivotal role in lymphatic contractility. Because prostaglandin (PG)I2, an arachidonic acid (20:4) metabolite, is a key substance generated by human lymphatics, both from exogenous and endogenous substrates, it is reasonable to assume that altered nutritional intake of precursor fatty acids (FA) influences formation of respective eicosanoids qualitatively and quantitatively, and thereby modify its biological effects on human lymphatics. We, therefore, examined the effect of 2 other FA-precursors, dihomo-gamma-linolenic (20:3) and eicosapentaenoic acid (20:5) on the formation of the respective PG-metabolites in human lymphatics removed from the legs in patients undergoing amputation after traumatic injury. 20:3 and 20:5 were poorer substrates to form PGs. Because these PGs exert different biological actions and their synthesis may be altered by vascular environmental risk factors such as cigarette smoking, diabetes mellitus, hyperlipidemia, and availability of FA precursors and therefore nutrition, PGs may profoundly modulate the lymphatic contractile response under a variety of circumstances. The full effect of all the formed compounds of the 1- and 3-series PGs on lymph vessel contractility, however, still needs to be tested.


Somatic deficiency causes reproductive parasitism in a fungus.
Some multicellular organisms can fuse because mergers potentially provide mutual benefits. However, experimental evolution in the fungus Neurospora crassa has demonstrated that free fusion of mycelia favours cheater lineages, but the mechanism and evolutionary dynamics of this exploitation are unknown. Here we show, paradoxically, that all convergently evolved cheater lineages have similar fusion deficiencies. These mutants are unable to initiate fusion but retain access to wild-type mycelia that fuse with them. This asymmetry reduces cheater-mutant contributions to somatic substrate-bound hyphal networks, but increases representation of their nuclei in the aerial reproductive hyphae. Cheaters only benefit when relatively rare and likely impose genetic load reminiscent of germline senescence. We show that the consequences of somatic fusion can be unequally distributed among fusion partners, with the passive non-fusing partner profiting more. We discuss how our findings may relate to the extensive variation in fusion frequency of fungi found in nature.


Effect of cannabis and subproducts on anthropometric measures: a systematic review and meta-analysis.
Obesity poses a significant public health challenge. Research has examined the impact of cannabis and subproducts on health but varying results have hindered a consensus. This study aimed to evaluated the effects of cannabis and subproducts on body measurements. For searching randomized controlled trials evaluating cannabis and/or subproducts use and changes in anthropometric measures, a systematic search at MEDLINE, Embase, Cochrane Library and Web of Science was conducted until March 2023. The outcomes included changes in body weight, body mass index (BMI) and waist circumference (WC). Meta-analysis was realized using R software (version 4.2.1). In general, cannabis use reduced weight by 1.87 kg (95% CI: -3.71 to -0.03) and WC (mean difference = -2.19, 95% CI: -4.44 to 0.06). When examining subgroups, longer follow-up periods were associated with a more pronounced BMI reduction (mean difference = -1.10, 95% CI: -2.23 to 0.03). Cannabinoid CB1 exhibited an increase in body fat (mean difference = 1.70, 95% CI: 0.66-2.74). These findings suggest that cannabis and subproducts could be considered adjuncts in obesity treatment by helping to reduce relevant anthropometric measurements.


Age differences in strategy selection and risk preference during risk-based decision making.
Studies of the effects of aging on decision making suggest that choices can be altered in a variety of ways depending on the situation, the nature of the outcome and risk, or certainty levels. To better characterize how aging impacts decision making in rodents, young and aged Fischer 344 rats underwent a series of probabilistic discounting tasks in which reward magnitude and probabilities were manipulated. Young rats tended to choose 1 of 2 different strategies: (a) to press for the large/uncertain reward, regardless of the reward probability; or (b) to continually adapt their behavior according to the odds of winning. The first strategy was adopted by about half of the younger rats, the second by the remaining young animals and the entire group of aged rats. Additionally, we found that when the odds of winning were varied from uncertain to certain during a session, aged rats chose most often the lever associated with the small/certain reward. This is consistent with an interpretation of increased risk aversion. When this behavior was further characterized using a lose-shift analysis, it appears that older rats exhibited an increased sensitivity to negative feedback. In contrast, sensitivity to wins was unaltered in aged rats compared with young, suggesting that aging selectively impacts rat's behavior following losses. In line with some human aging studies, it appears that aged rats are either more risk averse or have a greater certainty bias, which may result from age differences in emotion regulation.


[Alternating hemiplegia in young babies].
INTRODUCTION. This paper review the state of the art of alternating hemiplegia of childhood. This entity is a rare neurologic disorder of infancy characterize by transient hemiplegic spells shifting from one side to another, and occasionally affecting to both hemispheres at the same time. Usually start before 18 months, many cases exhibit neonatal symptoms related with the disorder. Early symptomatology include abnormal ocular movements, mainly nystagmus, and tonic or dystonic attacks generally beginning before 6 months of age. These symptoms are frequently misdiagnosis as epilepsy. Typical hemiplegic fits which disappeared when infant felt asleep appeared by 12 months of age. Diagnosis is on clinical basis after excluding any other causes of fluctuating and transitory hemiplegic attacks. Complementary investigations, such as electroencephalograms, TAC, MRI, angiographic MRI, CFS are strictly normal. Cerebral SPECT show controversial abnormalities in some studies. We perform SPECT study in a alert 12 months old girl during an interictal period resulting in a non significant asymmetry, with lesser perfusion in left frontal basal and anterior temporal gyrus. Nevertheless, we observed an striking hyperperfusion in middle occipital area. Treatment is symptomatic with flunarizine. Our patient experience a dramatic decrease in frequency, duration and severity of hemiplegic attacks.


[Recurrent stent thrombosis in a patient with non-ST-segment elevation acute coronary syndrome].
A case of a 64-year-old male with multiple cardiovascular disease risk factors and non-ST segment elevation myocardial infarction complicated by recurrent stent thrombosis is presented. Percutaneous coronary angioplasty with bare metal stent implantation was performed due to critical stenosis of the left circumflex coronary artery. The recovery was complicated by two episodes of stent thrombosis on the 4th and 10th day of in-hospital stay, both treated by subsequent percutaneous coronary interventions. Our hypothesis of resistance to antiplatelet therapy was confirmed by an in vitro test.


[An impact of pronoran on cognitive and affective disorders in Parkinson's disease].
Sixty patients with different types of Parkinson's disease (PD), the disease stage 2.3 +/- 0.08 according to Hoehn&Yahr scale, were treated with Pronoran. Impact of the drug on movement, cognitive and affective disorders assessed by corresponding scales and psychological tests has been studied. Pronoran exerted a positive effect on all the disorders. It improved cognitive function, i.e. reasoning, memory and attention. A more pronounced influence on cognitive function was detected in earlier stages of the disease and for less severity cases of rigid-tremor PD type. A moderate antidepressive effect of Pronoran was found, being more pronounced in the severe PD stages. Emotional disorders were better treated, when Pronoran was used in combination with madopar, and cognitive dysfunction--in case of monotherapy.


Removal of inactivation causes time-invariant sodium current decays.
The kinetic properties of the closing of Na channels were studied in frog skeletal muscle to obtain information about the dependence of channel closing on the past history of the channel. Channel closing was studied in normal and modified channels. Chloramine-T was used to modify the channels so that inactivation was virtually removed. A series of depolarizing prepulse potentials was used to activate Na channels, and a -140-mV postpulse was used to monitor the closing of the channels. Unmodified channels decay via a biexponential process with time constants of 72 and 534 microseconds at 12 degrees C. The observed time constants do not depend upon the potential used to activate the channels. The contribution of the slow component to the total decay increases as the activating prepulse is lengthened. After inactivation is removed, the biexponential character of the decay is retained, with no change in the magnitude of the time constants. However, increases in the duration of the activating prepulse over the range where the current is maximal 1-75 ms) produce identical biexponential decays. The presence of biexponential decays suggests that either two subtypes of Na channels are found in muscle, or Na channels can exist in one of two equally conductive states. The time-invariant decays observed suggest that channel closure does not depend upon their past history.


[Effect of mycoplasma contamination of a human cervical carcinoma cell line M HeLa clone 11 on karyotypic variability].
The karyotypic variability has been investigated for an immortalized human epithelioid cervix carcinoma cell line M HeLa clone 11, cultivated for 15-60 days after contamination with Acholeplasma laidlawii A, strain PG-8, and for 30 days after contamination with Mycoplasma arginini R-16. The character of cell distribution for chromosome number changes in contaminated cells significantly, as compared to the control. So, the frequency of cells with the modal number of chromosomes being equal to 50 decreases significantly, and the range of variability in the number of chromosomes increases. With the prolongation of the term of cultivation in control variants up to 60 days the character of cell distribution for chromosomal number changes, as compared to the preceding terms (15 and 30 days), which is expressed in the extended range of variability in the chromosomal number at the expense of decreased frequency of cells with submodal number of chromosomes equal to 49. But the degree of these changes is significantly smaller than in contaminated variants. The frequency of polyploid cells did not differ in all investigated variants. The number of chromosomal aberrations in cultures contaminated with A. laidlawii (for 15-60 days) and M. arginini (for 30 days) does not differ from that in the corresponding controls. The absence of dicentrics (telomeric association) at a long-term contamination of the human epithelioid cervix carcinoma cell line M HeLa clone 11 having marker chromosomes in karyotype and a comparison of these results with the earlier obtained data on other "marker" and "markerless" cell lines seems to confirm the point of view that dicentrics appear a characteristic feature of karyotypic variability of "markerless" cell lines, mainly with a long-term contamination in different conditions.


Non-ionic Surfactant Based In Situ Forming Vesicles as Controlled Parenteral Delivery Systems.
Non-ionic surfactant (NIS) based in situ forming vesicles (ISVs) present an affordable alternative to the traditional systems for the parenteral control of drug release. In this work, NIS based ISVs encapsulating tenoxicam were prepared using the emulsion method. Tenoxicam-loaded ISVs were prepared using a 22.31 full factorial experimental design, where three factors were evaluated as independent variables; type of NIS (A), molar ratio of NIS to Tween®80 (B), and phase ratio of the internal ethyl acetate to the external Captex® oil phase (C). Percentage drug released after 1 h, particle size of the obtained vesicles and mean dissolution time were chosen as the dependent variables. Selected formulation was subjected to morphological investigation, injectability, viscosity measurements, and solid state characterization. Optimum formulation showed spherical nano-vesicles in the size of 379.08 nm with an initial drug release of 37.32% in the first hour followed by a sustained drug release pattern for 6 days. DSC analysis of the optimized formulation confirmed the presence of the drug in an amorphous form with the nano-vesicles. Biological evaluation of the selected formulation was performed on New Zealand rabbits by IM injection. The prepared ISVs exhibited a 45- and 28-fold larger AUC and MRT values, respectively, compared to those of the drug suspension. The obtained findings boost the use of ISVs for the treatment of many chronic inflammatory conditions.


Social anxiety disorder in callers to the Anxiety Disorders Association of America.
Social anxiety disorder (SAD) is among the most common anxiety disorders with a lifetime prevalence of up to 16%. Among callers to the Anxiety Disorders Association of America (ADAA), we surveyed 1,000 participants using a 97-item questionnaire to understand the characteristics of participants with SAD and subthreshold SAD (SSAD). Current prevalence rates of SAD (n=295) and SSAD (n=41) were 29.5% and 4.1%, respectively. SAD and SSAD participants were more likely to be younger, single, with less education and lower income than their no axis-I-psychiatric-disorder controls (NAC). In addition, they presented with more psychiatric comorbidity, lifetime numbers of trauma, recent psychotropic use and side effects. Increased medical comorbidity, health service utilization, as well as reduced work productivity were also found, particularly among SAD participants. SSAD participants were comparable to SAD participants for most of the measures with a few exceptions, mainly less psychiatric comorbidity, less medication use for panic attack and social fear, and fewer visits to the health professionals. In conclusion, SAD was highly prevalent among callers to the ADAA. SAD participants were particularly impaired and tended to use the health care system extensively. Although SSAD participants were less impaired than those with SAD, they were disadvantaged in many ways. Early diagnosis and better treatment are urged for reducing costs and improving life. An organization such as ADAA can play a vital role in bringing this about.


Screening mammography: factors associated with adherence to recommended age/frequency guidelines.
Examines associations of selected demographic, insurance, health care, health history, and health practice variables with frequency of screening mammograms received during the past 5 years. Telephone interviews were conducted with 350 women aged 40 through 69, never diagnosed with breast cancer, and identified through random digit dialing in Connecticut. Of 10 variables showing bivariate associations with receiving mammograms as frequently as recommended by National Cancer Institute guidelines, younger age, having a first-degree relative with breast cancer, and having annual clinical breast examinations were statistically significant independent predictors in logistic regression analyses of regular utilization of mammography during the past 5 years. In additional logistic analyses, having regular clinical breast exams maintained a strong effect on the odds both of having any mammograms and, among respondents reporting any mammograms, of having the recommended number during the past 5 years. Frequency of breast self-examination was unrelated to frequency of mammograms.


A 41-Year-Old Woman with Excessive Fat of the Lower Body Since Puberty with Progression to Swollen Ankles and Feet Despite Caloric Restriction, Due to Lipedema and Protein-Calorie Malnutrition: A Case of Stage 3 Lipedema.
BACKGROUND Lipedema is a common condition that presents as excessive fat deposition in the extremities, initially sparing the trunk, ankles, and feet, and is found mainly in women, usually occurring after puberty or pregnancy. Lipedema can progress to include lipo-lymphedema of the ankles and feet. This report is of a 41-year old woman with Stage 3 lipedema and lipo-lymphedema with excessive fat of the lower body since puberty, with progression to swollen ankles and feet despite dietary caloric restriction. CASE REPORT A 41-year-old woman noticed increased fat in her legs since age 12. Her weight and leg size increased until age 21, when she reached a maximum weight of 165 kg, and underwent a Roux-En-Y gastric bypass. Over 12 months, she lost 74.8 kg. Her trunk significantly reduced in weight, but her legs did not. Fifteen years later, during recovery from hysterectomy surgery, she became progressively weaker and swollen over her entire body. Laboratory test results showed hypoalbuminemia (2.0 g/dL), lymphopenia, and hypolipoproteinemia. She was diagnosed with protein and calorie malnutrition with marked gut edema requiring prolonged parenteral nutrition. After restoration of normal protein, her health returned and her pitting edema resolved, but her extremities remained enlarged. She was subsequently diagnosed with lipedema. CONCLUSIONS This report demonstrates that early and correct diagnosis of lipedema is important, as women who believe the condition is due to obesity may suffer the consequences of calorie or protein-calorie deficiency in an attempt to lose weight.


Identification of Emerging Macrophage-Tropic HIV-1 R5 Variants in Brain Tissue of AIDS Patients without Severe Neurological Complications.
Untreated HIV-positive (HIV-1+) individuals frequently suffer from HIV-associated neurocognitive disorders (HAND), with about 30% of AIDS patients suffering severe HIV-associated dementias (HADs). Antiretroviral therapy has greatly reduced the incidence of HAND and HAD. However, there is a continuing problem of milder neurocognitive impairments in treated HIV+ patients that may be increasing with long-term therapy. In the present study, we investigated whether envelope (env) genes could be amplified from proviral DNA or RNA derived from brain tissue of 12 individuals with normal neurology or minor neurological conditions (N/MC individuals). The tropism and characteristics of the brain-derived Envs were then investigated and compared to those of Envs derived from immune tissue. We showed that (i) macrophage-tropic R5 Envs could be detected in the brain tissue of 4/12 N/MC individuals, (ii) macrophage-tropic Envs in brain tissue formed compartmentalized clusters distinct from non-macrophage-tropic (non-mac-tropic) Envs recovered from the spleen or brain, (iii) the evidence was consistent with active viral expression by macrophage-tropic variants in the brain tissue of some individuals, and (iv) Envs from immune tissue of the N/MC individuals were nearly all tightly non-mac-tropic, contrasting with previous data for neuro-AIDS patients where immune tissue Envs mediated a range of macrophage infectivities, from background levels to modest infection, with a small number of Envs from some patients mediating high macrophage infection levels. In summary, the data presented here show that compartmentalized and active macrophage-tropic HIV-1 variants are present in the brain tissue of individuals before neurological disease becomes overt or serious.IMPORTANCE The detection of highly compartmentalized macrophage-tropic R5 Envs in the brain tissue of HIV patients without serious neurological disease is consistent with their emergence from a viral population already established there, perhaps from early disease. The detection of active macrophage-tropic virus expression, and probably replication, indicates that antiretroviral drugs with optimal penetration through the blood-brain barrier should be considered even for patients without neurological disease (neuro-disease). Finally, our data are consistent with the brain forming a sanctuary site for latent virus and low-level viral replication in the absence of neuro-disease.


Detection, classification, and management of rejection after lung transplantation.
Rejection is a major complication following lung transplantation. Acute cellular rejection, lymphocytic bronchiolitis, and antibody-mediated rejection (AMR) are all risk factors for the subsequent development of chronic lung allograft dysfunction (CLAD). Acute cellular rejection and lymphocytic bronchiolitis have well defined histopathologic diagnostic criteria and grading. Diagnosis of AMR requires a multidisciplinary approach. CLAD is the major barrier to long-term survival following lung transplantation. The most common phenotype of CLAD is bronchiolitis obliterans syndrome (BOS) which is defined by a persistent obstructive decline in lung function. Restrictive allograft dysfunction (RAS) is a second phenotype of CLAD and is associated with a worse prognosis. This article will review the diagnosis, staging, clinical presentation, and treatment of acute rejection, AMR, and CLAD following lung transplantation.


Brain Oxygenation in Post-concussion Combat Sport Athletes.
Purpose: Investigate the feasibility of a non-invasive method to evaluate the physical and cognitive repercussions of long-lasting post-concussion effects in professional combat sports athletes. To help athletes return to professional combat, there is a need for unbiased objective tools and techniques used as a prognostic method of recovery after Sport Related Concussion (SRC). Methods: Six mild Traumatic Brain Injury (mTBI) athletes, age 20 ÷ 43 yr (1 female, 5 males) and 7 not concussed (NC) participants (amateur), age 24 ÷ 38 yr (3 females, 4 males), were tested Inspired/expired gas concentration, Cerebral changes in oxygenated hemoglobin (Δ[HbO2]) and deoxygenated hemoglobin (Δ[HHb]) were measured using near infrared spectroscopy (NIRS) with a 3-step protocol: rest before maximal oxygen uptake (VO2max) test, hypercapnia, and recovery after VO2max test. The brain oxygenation and respiratory parameters of both sample sets were calculated using a non-parametric test (Mann-Whitney U test). Aerobic fitness outcome was quantified through mean average using the Bruce test. Participants performed Fitt's test using a laptop and analysis of medio-lateral and anterior-posterior range of oscillation was carried out via a force platform Romberg test. Results: mTBI group showed statistically significant differences in saturated hemoglobin Δ[HbO2] (p < 0.001) during rest and recovery phase after maximal incremental exercise, in medio-lateral sway eyes open (p = 0.008, NC 25.35 ± 4.11 mm and mTBI 17.65 ± 4.79 mm). VO2max revealed no significant differences between the two groups: NC 47.47 ± 4.91 mTBI 49.58 ± 5.19 ml/kg/min-1. The 2 groups didn't differ for maximum power output (NC 220 ± 34, mTBI 255 ± 50 W). End-tidal fractional concentration of O2 (FetO2 NC15.20 ± 0.41, mTBI 16.09 ± 0.68) throughout hypercapnia, saturated blood hemoglobin (Δ[HbO2]) revealed significant differences with the mTBI group. No differences emerged from Fitt's test. Conclusions: It emerges that NIRS is able to reveal differences in long time outcomes of mTBI. The medio-lateral variations cannot be considered as a marker of long-term damage in athletes specifically trained for balance.


Associations Between Trajectories of Leisure-Time Physical Activity and Television Viewing Time Across Adulthood: The Cardiovascular Risk in Young Finns Study.
The purpose of this study was to examine trajectories of leisure-time physical activity (LTPA) and television-viewing (TV) time and their associations in adults over 10 years. The sample comprised 2934 participants (men, 46.0%) aged 24-39 years in 2001 and they were followed up for 10 years. LTPA and TV time were assessed using self-report questionnaires in 2001, 2007, and 2011. Longitudinal LTPA and TV-time trajectories and their interactions were analyzed with mixture modeling. Three LTPA (persistently highly active, 15.8%; persistently moderately active, 60.8%; and persistently low active, 23.5%) and 4 TV time (consistently low, 38.6%; consistently moderate, 48.2%; consistently high, 11.7%; and consistently very high, 1.5%) trajectory classes were identified. Persistently highly active women had a lower probability of consistently high TV time than persistently low-active women (P = .02), whereas men who were persistently highly active had a higher probability of consistently moderate TV time and a lower probability of consistently low TV time than their persistently low-active counterparts (P = .03 and P = .01, respectively). Maintaining high LTPA levels were accompanied by less TV over time in women, but not in men. The associations were partially explained by education, body mass index, and smoking.


[Study of the effect of the fungicide zineb on microorganisms].
Changes in yeast cells induced by the fungicide zineb were studied using biochemical, genetic techniques and electron microscopy. The primary changes involved anabolic processes since RNA and protein content increased in the cells. The data were consistent with a larger size of mitochondria. The oxidative-reductive activity of cell extracts did not change under the action of the fungicide. Zineb at a concentration of 0.5 to 50 mg/litre exerted a genetic activity towards indicator microorganisms. The changes in the morphophysiological characteristics of yeast growth under the action of zineb are presumed to be of a protective nature. Zineb traces in soil must be controlled in terms of the microbiological index.


Vestibular deficits do not underlie looping behavior in achiasmatic fish.
Zebrafish belladonna (bel) mutants carry a mutation in the lhx2 gene that encodes a Lim domain homeobox transcription factor, leading to a defect in the retinotectal axon pathfinding. As a result, a large fraction of homozygous bel mutants is achiasmatic. Achiasmatic bel mutants display ocular motor instabilities, both reserved optokinetic response (OKR) and spontaneous eye oscillations, and an unstable swimming behavior, described as looping. All these unstable behaviors have been linked to the underlying optic nerve projection defect. Looping has been investigated under different visual stimuli and shown to be vision dependent and contrast sensitive. In addition, looping correlates perfectly with reversed OKR and the spontaneous oscillations of the eyes. Hence, it has been hypothesized that looping is a compensatory response to the perception of self-motion induced by the spontaneous eye oscillations. However, both ocular and postural instabilities could also be caused by a yet unidentified vestibular deficit. Here, we performed a preliminary test of the vestibular function in achiasmatic bel larval mutants in order to clarify the potential role of a vestibular deficit in looping. We found that the vestibular ocular reflex (VOR) is normally directed in both bel mutants and wild types and therefore exclude the possibility that nystagmus and looping in reverse to the rotating optokinetic drum can be attributed to an underlying vestibular deficit.


Fatty liver is associated with transcriptional downregulation of stearoyl-CoA desaturase and impaired protein dimerization.
We evaluated the modulation of liver stearoyl-CoA desaturase-1 (Scd1) by dietary factors and insulin resistance (IR) in two experimental models of high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). The first model included Sprague Dawley (SD) rats that developed NAFLD without IR, and the second one included a rat model of genetic IR and cardiovascular disease, the spontaneously hypertensive rats (SHR) and its normotensive, insulin-sensitive control Wistar-Kyoto (WKY). The adult rats were given standard chow diet (CD) or HFD for 10 weeks. In all the animals, we explored the hepatic Scd1 transcriptional activity and protein levels. HFD-fed rats of both strains developed severe NAFLD. Liver abundance of Scd1 mRNA was significantly decreased in HFD-fed rats regardless of the strain; SD-CD: 235±195 vs. SD-HFD 4.5±2.9, p<0.0004, and SHR-CD: 75.6±10.8 vs. SHR-HFD: 4.48±17.4, and WKY-CD: 168.7±17.4 vs. WKY-HFD: 12.9±17.4, p<0.000001 (mean±SE, ANCOVA adjusted by HOMA). Analysis of liver Scd1 protein expression showed a particular pattern in the HFD groups, characterized by the presence of high levels of a monomeric protein band (32.2-36.6 Kda, p<0.003) and decreased levels of a dimeric protein band (61.9-66.1 Kda, p<0.02) regardless of the rat strain. Pharmacologic intervention with the peroxisome proliferator-activated receptor α agonist clofibrate reverted the liver phenotype and significantly modified the hepatic Scd1 transcriptional activity and protein expression. Diet-induced fatty liver is associated with the downregulation of hepatic Scd1 transcript and de-dimerization of the protein, and these changes were not much affected by the status of peripheral IR.


Mesenchymal Stem Cells: Time to Change the Name!
Mesenchymal stem cells (MSCs) were officially named more than 25 years ago to represent a class of cells from human and mammalian bone marrow and periosteum that could be isolated and expanded in culture while maintaining their in vitro capacity to be induced to form a variety of mesodermal phenotypes and tissues. The in vitro capacity to form bone, cartilage, fat, etc., became an assay for identifying this class of multipotent cells and around which several companies were formed in the 1990s to medically exploit the regenerative capabilities of MSCs. Today, there are hundreds of clinics and hundreds of clinical trials using human MSCs with very few, if any, focusing on the in vitro multipotential capacities of these cells. Unfortunately, the fact that MSCs are called "stem cells" is being used to infer that patients will receive direct medical benefit, because they imagine that these cells will differentiate into regenerating tissue-producing cells. Such a stem cell treatment will presumably cure the patient of their medically relevant difficulties ranging from osteoarthritic (bone-on-bone) knees to various neurological maladies including dementia. I now urge that we change the name of MSCs to Medicinal Signaling Cells to more accurately reflect the fact that these cells home in on sites of injury or disease and secrete bioactive factors that are immunomodulatory and trophic (regenerative) meaning that these cells make therapeutic drugs in situ that are medicinal. It is, indeed, the patient's own site-specific and tissue-specific resident stem cells that construct the new tissue as stimulated by the bioactive factors secreted by the exogenously supplied MSCs. Stem Cells Translational Medicine 2017;6:1445-1451.


Extremotolerant tardigrade genome and improved radiotolerance of human cultured cells by tardigrade-unique protein.
Tardigrades, also known as water bears, are small aquatic animals. Some tardigrade species tolerate almost complete dehydration and exhibit extraordinary tolerance to various physical extremes in the dehydrated state. Here we determine a high-quality genome sequence of Ramazzottius varieornatus, one of the most stress-tolerant tardigrade species. Precise gene repertoire analyses reveal the presence of a small proportion (1.2% or less) of putative foreign genes, loss of gene pathways that promote stress damage, expansion of gene families related to ameliorating damage, and evolution and high expression of novel tardigrade-unique proteins. Minor changes in the gene expression profiles during dehydration and rehydration suggest constitutive expression of tolerance-related genes. Using human cultured cells, we demonstrate that a tardigrade-unique DNA-associating protein suppresses X-ray-induced DNA damage by ∼40% and improves radiotolerance. These findings indicate the relevance of tardigrade-unique proteins to tolerability and tardigrades could be a bountiful source of new protection genes and mechanisms.


Frequent expression of beta-human chorionic gonadotropin (beta-hCG) in squamous cell carcinoma of the cervix.
Human chorionic gonadotropin (beta-hCG) has been detected within tissue homogenates, culture fluid, and sera of patients with squamous cell carcinoma of the cervix. Studies regarding in vivo localization of beta-hCG in squamous cell carcinoma of the cervix are scant and conflicting. Cervical samplings (biopsy and/or curettage specimens) of 63 cases of poorly differentiated invasive squamous cell carcinoma of the cervix were initially stained by the immunoperoxidase technique for the presence of beta-hCG and human placental lactogen (hPL). Based on beta-hCG reactivity, patients were divided into beta-hCG-positive and beta-hCG-negative groups. Thirty-three of the 63 (52%) cases showed localization of beta-hCG in tumor cells. Subsequent specimens of patients, who underwent surgical treatment, were likewise examined for beta-hCG reactivity. These surgical specimens showed focal beta-hCG reactivity in the beta-hCG-positive group only. The beta-hCG reactivity was seen in both high-grade SIL (CIN III), invasive squamous cell carcinoma, and its metastases. The focal beta-hCG reactivity was predominantly confined to the peripheral tumor cells at the stromal-epithelial interface in noninvasive and invasive lesions. Intensity of immunostaining was moderate to strong. The beta-hCG staining was observed in different cancer stages and in various age groups. No hPL reactivity was seen in any cases. Poorly differentiated squamous cell carcinoma of uterine cervix showing immunoreactivity for beta-hCG should be distinguished from choriocarcinoma and other trophoblastic tumors.


The BioCassava plus program: biofortification of cassava for sub-Saharan Africa.
More than 250 million Africans rely on the starchy root crop cassava (Manihot esculenta) as their staple source of calories. A typical cassava-based diet, however, provides less than 30% of the minimum daily requirement for protein and only 10%-20% of that for iron, zinc, and vitamin A. The BioCassava Plus (BC+) program has employed modern biotechnologies intended to improve the health of Africans through the development and delivery of genetically engineered cassava with increased nutrient (zinc, iron, protein, and vitamin A) levels. Additional traits addressed by BioCassava Plus include increased shelf life, reductions in toxic cyanogenic glycosides to safe levels, and resistance to viral disease. The program also provides incentives for the adoption of biofortified cassava. Proof of concept was achieved for each of the target traits. Results from field trials in Puerto Rico, the first confined field trials in Nigeria to use genetically engineered organisms, and ex ante impact analyses support the efficacy of using transgenic strategies for the biofortification of cassava.


[Effect of miR-204-5p on the proliferation, migration, and invasion on tongue squamous cell carcinoma SCC25 cells by targeting bromodomain-containing protein 4].
This study aimed to explore the target relationship between miR-204-5p and bromodomain-containing protein (BRD) 4, as well as their effects on cell proliferation, migration, and invasion in tongue squamous cell carcinoma SCC25. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to detect miR-204-5p and BRD4 expression levels in tongue squamous cell carcinoma and different cell lines. TargetScan and dual luciferase reporter assay were used to confirm the target relationship between miR-204-5p and BRD4. The effects of miR-204-5p on SCC25 cell proliferation were examined by cell counting kit (CCK) 8 assay, whereas those on SCC25 cell migration and invasion were determined by Transwell assay. RT-qPCR and Western blot were used to detect the effects of miR-204-5p mimics and inhibitors on BRD4 expression. Transwell and CCK8 assays were used to detect the effects of miR-204-5p on proliferation, migration, and invasion through BRD4 regulation. miR-204-5p was significantly downregulated in the tissues and cells of squamous cell carcinoma, and BRD4 showed the opposite result. The increase in miR-204-5p expression can inhibit the proliferation, migration, and invasion of SCC25 cells. TargetScan and luciferase test confirmed that miR-204-5p and BRD4 had a negative regulatory relationship with BRD4, respectively. Moreover, miR-204-5p mimics can inhibit BRD4 expression, and miR-204-5p inhibitors can promote BRD4 expression upregulation. When miR-204-5p and BRD4 were overexpressed in SCC25 cells, BRD4 can make up for the inhibitory effect of miR-204-5p on SCC25 cells. miR-204-5p could inhibit proliferation, migration and invasion in tongue squamous cell carcinoma SCC25 cells by targeting BRD4 gene.


Interactions between Rickettsia prowazekii and rabbit polymorphonuclear leukocytes: rickettsiacidal and leukotoxic activities.
Rickettsia prowazekii was assessed for in vitro susceptibility to phagocytosis by rabbit polymorphonuclear leukocytes. [alpha-32P]adenosine triphosphate-labeled rickettsiae were used to determine phagocytosis and adsorption quantitatively. R. prowazekii was less susceptible to phagocytosis than were Escherichia coli and Neisseria gonorrhoeae. Although R. prowazekii was similar to E. coli in susceptibility to superoxide and activated halide, few phagocytized rickettsial cells were inactivated after being ingested by polymorphonuclear leukocytes, and rickettsiae were observed free in polymorphonuclear leukocyte cytoplasm. At low ratios of rickettsiae to polymorphonuclear leukocytes, PMN phagocytosis increased as a linear function of time, but at high ratios (multiplicity of infection, 50) rickettsiae were phagocytized during only the first 10 min of incubation. Polymorphonuclear leukocytes were damaged in the presence of high rickettsial multiplicities such that they released lactate dehydrogenase into the medium and lost the ability to phagocytize both rickettsiae and E. coli. The amount of leukotoxic activity in a given rickettsial sample correlated with the relative hemolytic activity of that sample. The rickettsial leukotoxin was probably not a soluble product, was active in the absence of phagocytosis, and was inhibited by inactivation of the rickettsiae or by incubation at 4 degrees C.


The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease.
The foot deformities in CMT follow certain general patterns; however, like the underlying motor failures that cause them, the deformities present in each patient are unique, and care must be individualized. There is no simple algorithm that can be applied to all patients. The hindfoot, forefoot, and toe deformities in CMT all ultimately are interconnected. As a general rule, it makes sense to address the plantar fascia, then proceed from the hindfoot to the forefoot in analyzing the deformities and in surgery. Releasing the plantar fascia may alter the amount of bony correction required in any concomitant hindfoot procedure. Likewise, only after the heel is realigned can any residual forefoot valgus be assessed, and a hindfoot procedure may alter the resting tension of the digital flexors and extensors. Finally, if a patient has purely dynamic clawtoes preoperatively, the toes may appear perfectly normal in the operating room with the ankle plantar flexed. Tightness of the flexor digitorum longus should be elicited by bringing the ankle up to neutral as a final check. The variety of foot deformities in CMT present a unique challenge to the orthopedic foot and ankle surgeon. It is vital for the patient and physician to remember that CMT is an inexorably progressive disease, and an initially good result can deteriorate with changing motor function. With meticulous attention to the neurologic examination and the balance of supple and fixed deformities in the foot, very satisfying outcomes usually can be obtained.


Laser damage resistance of hafnia thin films deposited by electron beam deposition, reactive low voltage ion plating, and dual ion beam sputtering.
A comparative study is made of the laser damage resistance of hafnia coatings deposited on fused silica substrates with different technologies: electron beam deposition (from Hf or HfO(2) starting material), reactive low voltage ion plating, and dual ion beam sputtering. The laser damage thresholds of these coatings are determined at 1064 and 355 nm using a nanosecond pulsed YAG laser and a one-on-one test procedure. The results are associated with a complete characterization of the samples: refractive index n measured by spectrophotometry, extinction coefficient k measured by photothermal deflection, and roughness measured by atomic force microscopy.


Modifying the electronic health record to facilitate the implementation and evaluation of a bundled care program for intensive care unit delirium.
Electronic health records (EHRs) have been promoted as a key driver of improved patient care and outcomes and as an essential component of learning health systems. However, to date, many EHRs are not optimized to support delivery of quality and safety initiatives, particularly in Intensive Care Units (ICUs). Delirium is a common and severe problem for ICU patients that may be prevented or mitigated through the use of evidence-based care processes (daily awakening and breathing trials, formal delirium screening, and early mobility-collectively known as the "ABCDE bundle"). This case study describes how an integrated health care delivery system modified its inpatient EHR to accelerate the implementation and evaluation of ABCDE bundle deployment as a safety and quality initiative. In order to facilitate uptake of the ABCDE bundle and measure delivery of the care processes within the bundle, we worked with clinical and technical experts to create structured data fields for documentation of bundle elements and to identify where these fields should be placed within the EHR to streamline staff workflow. We created an "ABCDE" tab in the existing patient viewer that allowed providers to easily identify which components of the bundle the patient had and had not received. We examined the percentage of ABCDE bundle elements captured in these structured data fields over time to track compliance with data entry procedures and to improve documentation of care processes. Modifying the EHR to support ABCDE bundle deployment was a complex and time-consuming process. We found that it was critical to gain buy-in from senior leadership on the importance of the ABCDE bundle to secure information technology (IT) resources, understand the different workflows of members of multidisciplinary care teams, and obtain continuous feedback from staff on the EHR revisions during the development cycle. We also observed that it was essential to provide ongoing training to staff on proper use of the new EHR documentation fields. Lastly, timely reporting on ABCDE bundle performance may be essential to improved practice adoption and documentation of care processes. The creation of learning health systems is contingent on an ability to modify EHRs to meet emerging care delivery and quality improvement needs. Although this study focuses on the prevention and mitigation of delirium in ICUs, our process for identifying key data elements and making modifications to the EHR, as well as the lessons learned from the IT components of this program, are generalizable to other health care settings and conditions.


[Differences in the prognosis according to the periods of diagnosis in ulcerative colitis].
Infliximab was approved for the treatment of ulcerative colitis (UC) in 2006 and has recently been used as rescue therapy in steroid-refractory UC. The aim of this study was to investigate the differences of medication use and prognosis in UC patients according to the periods of diagnosis. From 1987 to 2012, a total of 1,422 patients with UC were retrospectively reviewed in 12 hospitals. The study population was divided into two groups according to the periods of diagnosis as follows; group A: 1987-2005, group B: 2006-2012. Analyzed variables were compared by using chi-square test and logistic regression analysis. Mean age of the subjects was 42.2 years, and the mean follow-up period was 4.7 years. In univariate analysis, the use of infliximab in group B was significantly higher than group A (4.5% vs. 7.6%, p=0.016), and UC-related hospitalization (45.8% vs. 40.1%, p=0.031) and UC-related surgery (6.4% vs. 3.5%, p=0.010) in group B was significantly lower than that of group A. The use of oral steroid in surgery group was significantly higher than non-surgery group in multivariate analysis (OR 1.85, 95% CI 1.03-3.30, p=0.039). Infliximab might play an important role for the treatment of steroid-refractory UC. Well-designed prospective trials based on the efficacy and safety of infliximab are required in the future.


Nox4 NAD(P)H oxidase mediates Src-dependent tyrosine phosphorylation of PDK-1 in response to angiotensin II: role in mesangial cell hypertrophy and fibronectin expression.
Activation of glomerular mesangial cells (MCs) by angiotensin II (Ang II) leads to hypertrophy and extracellular matrix accumulation. Here, we demonstrate that, in MCs, Ang II induces an increase in PDK-1 (3-phosphoinositide-dependent protein kinase-1) kinase activity that required its phosphorylation on tyrosine 9 and 373/376. Introduction into the cells of PDK-1, mutated on these tyrosine residues or kinase-inactive, attenuates Ang II-induced hypertrophy and fibronectin accumulation. Ang II-mediated PDK-1 activation and tyrosine phosphorylation (total and on residues 9 and 373/376) are inhibited in cells transfected with small interfering RNA for Src, indicating that Src is upstream of PDK-1. In cells expressing oxidation-resistant Src mutant C487A, Ang II-induced hypertrophy and fibronectin expression are prevented, suggesting that the pathway is redox-sensitive. Ang II also up-regulates Nox4 protein, and siNox4 abrogates the Ang II-induced increase in intracellular reactive oxygen species (ROS) generation. Small interfering RNA for Nox4 also inhibits Ang II-induced activation of Src and PDK-1 tyrosine phosphorylation (total and on residues 9 and 373/376), demonstrating that Nox4 functions upstream of Src and PDK-1. Importantly, inhibition of Nox4, Src, or PDK-1 prevents the stimulatory effect of Ang II on fibronectin accumulation and cell hypertrophy. This work provides the first evidence that Nox4-derived ROS are responsible for Ang II-induced PDK-1 tyrosine phosphorylation and activation through stimulation of Src. Importantly, this pathway contributes to Ang II-induced MC hypertrophy and fibronectin accumulation. These data shed light on molecular processes underlying the oxidative signaling cascade engaged by Ang II and identify potential targets for intervention to prevent renal hypertrophy and fibrosis.


A Process Evaluation of an HIV/STI Intervention for Rural African American Youth.
We evaluated the fidelity and implementation of an HIV/AIDS and sexually transmitted infections intervention for rural African American youth. Using a community-based evaluation approach, community partners and researchers monitored four core process-evaluation components: reach, fidelity, dose delivered, and dose received. Researchers collected evaluation data through session observations, facilitator debriefing interviews, a youth focus group, and a satisfaction survey. For reach, more than half of the participants attended the 13 sessions. Participation varied between 62% and 100%. For fidelity, not all sessions were implemented as intended; multiple modifications occurred across sessions. For dose delivered, some lessons were missing materials and content was omitted; facilitators omitted content when there was insufficient time to complete a lesson. For dose received, engagement varied across lessons but youth reported high levels of satisfaction with the intervention. This formative process evaluation enabled us to identify and address multiple challenges to implementation.


Total thyroidectomy. The preferred option for multinodular goiter.
Total thyroidectomy is an operation that has generally been reserved for the management of differentiated thyroid carcinoma. Over the last decade total thyroidectomy has become used increasingly and is now the preferred option in the authors' unit for the management of multinodular goiter affecting the entire gland. Over the period from 1975 to 1985, 853 thyroidectomies have been performed for multinodular goiter; of these, 115 have been total thyroidectomies. During that time, the incidence of total thyroidectomy for multinodular goiter has increased in percentage terms from 9% in 1975 to 50% in 1985. There have been two cases of permanent hypoparathyroidism and one case of permanent recurrent laryngeal nerve injury, and these occurred in patients who had less than total thyroidectomy. Total thyroidectomy is an appropriate operation for the management of diffuse multinodular goiter where the entire gland is involved because it precludes patients from requiring further surgery for recurrent disease, with its high associated risks. It must be emphasized, however, that protection of the recurrent laryngeal nerve and parathyroid glands must still be paramount in dealing with benign thyroid disease.


Double Flow Bioreactor for In Vitro Test of Drug Delivery.
In this work, double-structured polymeric scaffolds were produced, and a double flow bioreactor was designed and set up in order to create a novel system to carry out advanced in vitro drug delivery tests. The scaffolds, consisting of a cylindrical porous matrix, are able to host cells, thus mimicking a three-dimensional tumor mass: moreover, a "pseudo-vascular" structure was embedded into the matrix, with the aim of allowing a flow circulation. The structure that emulates a blood vessel is a porous tubular-shaped scaffold prepared by Diffusion Induced Phase Separation (DIPS), with an internal lumen of 2 mm and a wall thickness of 200 micrometers. The as-prepared vessel was incorporated into a three-dimensional matrix, prepared by Thermally Induced Phase Separation (TIPS), characterized by a high porosity (about 95%) and pore size adequate to accommodate tumor cells and/or mesenchymal cells. The morphology of the multifunctional scaffolds is easy-tunable in terms of pore size, porosity and thickness and therefore adaptable to various cell or tissue types. At the same time, a double flow bioreactor was designed and built up, in order to be able to carry out biological tests on the scaffold under dynamic conditions. The device allows a separate control of the two flows (one for the tubular scaffold, one for the porous matrix) through the scaffolds. Preliminary characterizations and tests carried out suggest the presented system as a candidate to suitably "in vitro" assess the effects of different drugs on various cell populations.