Ophthalmic beta-blockers: determination of plasma and aqueous humor levels by a radioreceptor assay following multiple doses.
We determined the binding affinities of multiple doses of four ophthalmic beta-blockers, timolol, betaxolol, levobunolol and carteolol, to the beta-1 and beta-2 receptors. With a Ki value of 0.39 nM and 0.36 nM for the beta-1 and beta-2 receptors, respectively, levobunolol shows the highest binding affinity to both beta receptors. The Ki values of timolol (1.97 nM for the beta-1 receptor and 2.0 nM for the beta-2 receptor) and of carteolol (0.83 nM and 0.85 nM for the beta-1 and beta-2 receptors, respectively) are characteristic of a nonspecific beta-blocker. On the contrary, betaxolol is a beta-1 specific antagonist (Ki of 23.33 nM) and has a very low binding affinity to the beta-2 receptor (Ki of 200.00 nM). With a radioreceptor assay, levels of beta-antagonist were measured in the plasma and aqueous humor 1 hour and 12 hours after instillation of 50 microliters of 0.5% or 2% each of the four beta-blockers into the rabbit eye. At 1 hour after administration, the plasma levels of timolol, levobunolol, and carteolol are 9.89 ng/ml, 1.60 ng/ml and 8.00 ng/ml, respectively; such levels of 11.82 to 29.22 times the respective Ki values cause a virtually total blockade of both beta-1 and beta-2 receptors and suggest significant systemic absorption. Betaxolol has a peak 1 hour plasma level of 22.28 ng/ml, which is equivalent to only 3.08 times its Ki for the beta-1 receptor and 0.36 times its Ki for the beta-2 receptor; it has less systemic beta-1 blocking activity than the other three drugs and very minimal systemic beta-2 blocking activity. Peak aqueous humor concentrations of all 4 beta-blockers are extremely elevated at 1 hour after administration (timolol 1613.58 ng/ml; betaxolol 866.06 ng/ml; levobunolol 750.89 ng/ml; and carteolol 859.18 ng/ml). Such levels of 14 to 7192 times the respective Ki values should cause a virtually complete blockade of both beta-1 and beta-2 receptors in the iris-ciliary body complex. At 12 hours after administration, plasma levels of all four beta blockers remain moderately elevated (timolol 0.94 ng/ml; betaxolol 9.43 ng/ml; levobunolol 0.66 ng/ml; and carteolol 1.61 ng/ml). Trough aqueous humor levels of levobunolol (43.38 ng/ml) and carteolol (92.81 ng/ml) remain elevated at least 300 times their Ki value. On the contrary, 12-hour trough aqueous humor levels of timolol (33.67 ng/ml) and betaxolol (94.86 ng/ml) have decreased to 2 to 40 times their Ki value, which may explain their requirement for twice daily administration clinically.


[Airway Management in Thoracic Anesthesia with Double-Lumen Tube].
Lung separation and isolation with accomplished one-lung ventilation plays a key role in the airway management for thoracic surgery. Spectrum of indication contains thoracic surgery, procedure- and patient-dependent factors. Usually lung isolation is achieved with a double-lumen tube or a bronchial blocker. Knowledge in tracheobronchial anatomy is routinely requested for anesthesiologists just as the standard use of flexible fibreoptic bronchoscope. This review would give an overview and discussion about the airway management in patients during thoracic anesthesia with double-lumen tubes and recommendations for the clinical routine.


Multicolor three-photon fluorescence imaging with single-wavelength excitation deep in mouse brain.
Multiphoton fluorescence microscopy is a powerful technique for deep-tissue observation of living cells. In particular, three-photon microscopy is highly beneficial for deep-tissue imaging because of the long excitation wavelength and the high nonlinear confinement in living tissues. Because of the large spectral separation of fluorophores of different color, multicolor three-photon imaging typically requires multiple excitation wavelengths. Here, we report a new three-photon excitation scheme: excitation to a higher-energy electronic excited state instead of the conventional excitation to the lowest-energy excited state, enabling multicolor three-photon fluorescence imaging with deep-tissue penetration in the living mouse brain using single-wavelength excitation. We further demonstrate that our excitation method results in ≥10-fold signal enhancement for some of the common red fluorescent molecules. The multicolor imaging capability and the possibility of enhanced three-photon excitation cross section will open new opportunities for life science applications of three-photon microscopy.


Phytochemicals from Camellia nitidissima Chi Flowers Reduce the Pyocyanin Production and Motility of Pseudomonas aeruginosa PAO1.
Camellia nitidissima Chi, known as a medicinal and edible plant in China, exhibits multiple bioactivities, especially antibacterial activity. In this study, we investigated the inhibitory effects of the dichloromethane fraction (DF) of C. nitidissima Chi flowers on the pyocyanin production, swarming motility, and swimming motility of Pseudomonas aeruginosa PAO1, at sub-minimum inhibitory concentrations. Results showed that the DF had a remarkable inhibitory effect on pyocyanin production without influencing P. aeruginosa PAO1 growth, and concentration-dependent inhibitory effects on swarming and swimming motility. The half maximal inhibitory concentrations (IC50) were 0.158 ± 0.009, 0.139 ± 0.004, and 0.334 ± 0.049 mg/mL for pyocyanin production, swarming motility, and swimming motility, respectively. Real-time RT-PCR showed that the DF significantly down-regulated the expressions of lasR (p < 0.05) and rhlR (p < 0.01). In addition, gallic acid, catechin, ellagic acid, chlorogenic acid, quercetin, and kaempferol were identified in the DF by HPLC Triple TOF MS/MS analysis. All six identified compounds showed inhibitory effects on pyocyanin production, swarming motility, and swimming motility, though ellagic acid showed the strongest effects, with IC50 values of 0.067 ± 0.002, 0.024 ± 0.008, and 0.020 ± 0.003 mg/mL, respectively. Thus, the inhibitory effects on P. aeruginosa PAO1 virulence factors might be attributable to these six and/or other compounds in the DF of C. nitidissima Chi flowers. Consequently, the C. nitidissima Chi flower, especially the DF, might be a potential quorum sensing inhibitor of P. aeruginosa PAO1.


SbHPO3F: 2D van der Waals Layered Phosphite Exhibiting Large Birefringence.
A novel antimony(III)-based phosphite, SbHPO3F, featuring a unique two-dimensional (2D) van der Waals layered structure, has been successfully designed and synthesized via the simultaneous employment of optically active moieties including SbO3F seesaw and tetrahedral HPO3 groups. Its optimized layered arrangement formed by the alternating connection of 4-membered rings (4-MRs) and 8-MRs endows the title compound with desirable optical properties including a large birefringence and short ultraviolet (UV) cutoff edge, implying that it is a potential UV birefringent material.


Increased cardiac sympathetic drive in renovascular hypertension.
Patients with renovascular hypertension (RVH) have high cardiovascular mortality and morbidity. In these patients, overall sympathetic nerve activity is increased. It is unknown, however, whether this increase also involves the heart. We tested the hypothesis that cardiac sympathetic activity is increased in patients with hypertension and renal artery stenosis. A total of 14 patients with hypertension were studied before angioplasty of angiographically identified renal artery stenosis. Nine out of 14 patients had renovascular hypertension proven at the 1-year follow-up visit. A total of 19 healthy subjects served as a control group. A right heart catheterization, including the positioning of a coronary sinus thermodilution catheter was performed for hemodynamic recordings and blood sampling. Using a radiotracer dilution technique with infusion of tritiated noradrenaline ([3H]NA) and adrenaline ([3H]A), fractional extraction and clearance were calculated. Total body and cardiac NA spillovers were used as indices of systemic and cardiac sympathetic nervous activity. The study group had normal left ventricular ejection fraction and cardiac pressures. Cardiac NA spillover was increased by 127% in the hypertensive patients compared with healthy subjects (200 +/- 53 versus 88 +/- 10 pmol/min in controls, P < 0.05). Total body NA spillover was similar in both groups. Cardiac fractional extraction of [3H]NA and [3H]A was decreased by 26 and 47%, respectively, compared with normotensive subjects (P < 0.01 for both). Patients with renovascular hypertension have altered cardiac sympathetic function with increased sympathetic drive and impaired catecholamine extraction. The increased cardiac sympathetic drive may have adverse long-term effects on prognosis in this patient group with high cardiovascular mortality.


Clinical and immunological features of systemic lupus erythematosus complicated by Jaccoud's arthropathy.
Abstract This work was undertaken to evaluate clinical and immunological features in patients with systemic lupus erythematosus (SLE) complicated by Jaccoud's arthropathy. Patients diagnosed with SLE between 1985 and 1999, and who met the criteria of Villiaumey et al., were checked for Jaccoud's arthropathy. Clinical features were retrospectively analysed for patients with both diseases. Sjögren's syndrome and human leukocyte antigens (HLA) in these patients were evaluated. Jaccoud's arthropathy was found in 15 (4.4%) of 340 patients with SLE. The mean age at the time of SLE diagnosis was significantly higher in these patients than in our control SLE patients, which was 51.2 ± 13.0 years (n = 15) and 29.6 ± 13.0 years (n = 222) (p = 2.1 × 10(-8)). Sjögren's syndrome was diagnosed according to the European Community Study Group's criteria in 10 (91%) of 11 patients examined. The incidence of HLA-A11 (5/9, 55%) and -B61(40) (5/9, 55%) in patients with Jaccoud's arthropathy was higher in the Japanese population (A11, 17.4%, p < 0.05; B61, 17.5%, p < 0.057. Jaccoud's arthropathy in patients with SLE is associated with Sjögren's syndrome, elderly SLE, HLA-A11, and HLA-B61. These clinical features might be characteristic of patients with Jaccoud's arthropathy and SLE.


(Bio)chemical Strategies To Modulate Amyloid-β Self-Assembly.
Amyloid plaques are one of the two hallmarks of Alzheimer's disease (AD). They consist mainly of fibrils made of self-assembled amyloid-β (Aβ) peptides. Aβ is produced in healthy brains from proteolytic cleavage of the amyloid precursor protein. Aβ aggregates, in particular smaller, soluble aggregates, are toxic to cells. Hence, modulating the self-assembly of Aβ became a very active field of research, with the aim to reduce the amount of the toxic aggregates of Aβ or to block their toxic action. A great variety of molecules, chemical and biological, are able to modify the aggregation of Aβ. Here we give an overview of the different mechanistic ways to modulate Aβ aggregation and on which step in the self-assembly molecules can interfere. We discuss the aggregation modulators according to different important parameters, including the type of interaction (weak interaction, coordination or covalent bonds), the importance of kinetics and thermodynamics, the size of the modulating molecules, and binding specificity.


Recombinant IgE antibody engineering to target EGFR.
Monoclonal antibodies have become a mainstay for the targeted treatment of cancer today. Some of the most successful targets of monoclonal antibodies are constituted by the epidermal growth factor receptor family spearheaded by the epidermal growth factor receptor (EGFR). Prompted by studies indicating that IgE compared to IgG may harness alternate effector functions to eradicate malignant cells, we addressed the establishment, engineering, and the potential tumoricidal effects of recombinant anti-EGFR IgE. Therefore, two different therapeutic EGFR-specific antibodies, 225 and 425, were chosen for re-cloning into different chimeric IgE and IgG formats and produced in human cells. Simultaneous antibody binding to the sEGFR demonstrated accessibility of both epitopes for recombinant IgE. Proliferation and cytotoxicity assays demonstrated signal blocking and effector mediating capability of IgE isotypes. Pronounced degranulation in the presence of sEGFR upon activation exclusively with two IgE antibodies verified the epitope proximity and provides evidence that tumor-targeting by anti-EGFR IgE is safe with regard to soluble target structures. Degranulation mediated by tumor cells expressing EGFR could be demonstrated for singular and combined IgE antibodies; however, use of two IgE specificities was not superior to use of one IgE alone. The data suggest that the surface distribution of EGFR is optimally suited to mount a robust effector cell trigger and corroborate the potential and specificity of the IgE/IgE receptor network to react to xenobiotic or pathogenic patterns for targeting malignancies.


Blood pressure in rural and urban adult healthy females of Jat Sikh community in Punjab, North India: an epidemiologic profile.
Blood pressure readings were collected from 1042 adult females of rural and urban Jat Sikh community of Punjab, a north Indian State. Anthropometric measurements like height, weight and skinfold thickness were also collected. The difference between rural and urban females in systolic, diastolic and mean arterial blood pressure was found to be statistically significant. All anthropometric variables and age have a significant positive association with blood pressure. The effects of anthropometric variables on blood pressure were assessed simultaneously through stepwise multiple regression analysis. All 'F' ratios have been found highly significant (p < 0.001) among both rural and urban female population.


Triploidy in rainbow trout determined by computer-assisted analysis.
This study was designed to assess the use of a computer-assisted system based on erythrocyte measurements as a possible alternative to flow cytometry for identifying triploid rainbow trout (Oncorhynchus mykiss). Blood smears were prepared from 26 triploid and 26 diploid specimens, as determined by flow cytometry after staining blood cells with propidium iodide. The cell and nucleus lengths of 10 erythrocytes were determined in each fish. This was followed by discriminatory analysis to distinguish between diploids and triploids based on their score profiles. Triploid trout showed significantly larger erythrocyte cell and nucleus measurements than their diploid counterparts (N=52; P<0.0001). Erythrocyte length correctly identified 100% of the fish specimens as diploid or triploid, while nucleus length was a less accurate predictor of the level of ploidy. Our findings validate the potential use of computer-assisted analysis for this purpose.


[Homocystein--an independent risk factor for cardiovascular and thrombotic diseases].
Over the last 20 years homocysteine has taken on increasing importance as an independent, potentially modifiable risk factor for various forms of vascular disease including peripheral and cerebral vascular disease, coronary heart disease and thrombosis. This association has been ascertained in many retrospective and prospective studies but the strength of risk is not yet firmly established although it is clearly dependent on several modifying factors such as other risk factors, nutrition and genetic polymorphisms. Generally it is estimated that hyperhomocysteinaemia is responsible for about 10% of all risks. Homocysteine is formed from the dietary amino acid methionine and plays a pivotal role in folate metabolism and methyl group transfer. Its concentrations in tissues and plasma are influenced by many genetic and environmental factors, especially vitamins such as folate, B12 and B6 as well as certain medications and even life style factors. Nowadays the measurement of plasma homocysteine is freely available although care has to be taken in sample handling and interpretation of results. Final proof that homocysteine is a causal agent and not just a marker for cardiovascular disease and that reduction of plasma homocysteine by vitamin treatment reduces risk of cardiovascular disease is still awaited. Therefore at the present time neither wide-scale screening for homocysteine levels nor general prophylaxis with high dose vitamins is justified. However most experts recommend homocysteine determination in individuals with existing or high risk for arterial or venous blood vessel disease and their relatives. Elevated homocysteine can be lowered in such cases with a combination of folic acid, vitamin B12 vitamin B6. The results of ongoing trials on the impact of such treatment on risk of vascular disease are awaited with great interest.


Increase of striatal Met5-enkephalin-Arg6-Phe7 (YGGFMRF) content elicited by long-term treatment with haloperidol.
In rats, daily doses of haloperidol repeated for various time periods increase striatal Met5-enkephalin-Arg6-Phe7 (YGGFMRF) immunoreactivity in a time- and dose-dependent manner. This increase occurred also in other dopamine-rich brain areas. After intraventricular captopril (0.5 mg), the accumulation rate of immunoreactive YGGFMRF was greater in haloperidol- than in saline-injected rats. Intraventricular captopril inhibits the YGGFMRF degradation; hence the greater accumulation rate of YGGFMRF caused by captopril in haloperidol-treated rats suggests that this drug increases the YGGFMRF biosynthesis. A slower rate of YGGFMRF release in haloperidol-treated rats can be excluded as a cause for the drug-induced increase in striatal content of this peptide because the release rates of YGGFMRF elicited by K+ were similar in striatal slices of haloperidol- and saline-treated rats. The similarities between the accumulation rate of immunoreactive YGGFMRF and of Met5-enkephalin induced by haloperidol suggest that haloperidol increases the biosynthesis of the specific messenger RNA for preproenkephalin, an opioid peptide precursor, which contains one copy of YGGFMRF and several copies of Met5-enkephalin.


Validation performance comparison for finite element models of the human brain.
The objective of this study was to compare the performance of six validated brain finite element (FE) models to localized brain motion validation data in five experimental configurations. Model performance was measured using the objective metric CORA (CORrelation and Analysis), where higher ratings represent better correlation. The KTH model achieved the highest average CORA rating, and the ABM received the highest average rating among models robustly validated against five cadaver impacts in three directions. This technique can be more frequently employed to build better models and, when associated limitations are well understood, to compare inter-model performance under similar conditions.


Enhancement of Wound Healing Efficacy by Increasing the Stability and Skin-Penetrating Property of bFGF Using 30Kc19α-Based Fusion Protein.
The instability of recombinant basic fibroblast growth factor (bFGF) is a major disadvantage for its therapeutic use and means frequent applications to cells or tissues are required for sustained effects. Originating from silkworm hemolymph, 30Kc19α is a cell-penetrating protein that also has protein stabilization properties. Herein, it is investigated whether fusing 30Kc19α to bFGF can enhance the stability and skin penetration properties of bFGF, which may consequently increase its therapeutic efficacy. The fusion of 30Kc19α to bFGF protein increases protein stability, as confirmed by ELISA. 30Kc19α-bFGF also retains the biological activity of bFGF as it facilitates the migration and proliferation of fibroblasts and angiogenesis of endothelial cells. It is discovered that 30Kc19α can improve the transdermal delivery of a small molecular fluorophore through the skin of hairless mice. Importantly, it increases the accumulation of bFGF and further facilitates its translocation into the skin through follicular routes. Finally, when applied to a skin wound model in vivo, 30Kc19α-bFGF penetrates the dermis layer effectively, which promotes cell proliferation, tissue granulation, angiogenesis, and tissue remodeling. Consequently, the findings suggest that 30Kc19α improves the therapeutic functionalities of bFGF, and would be useful as a protein stabilizer and/or a delivery vehicle in therapeutic applications.


The early and late effects of surgical closure of ventricular septal defects on pulmonary vascular dynamics.
In sixty patients who underwent closure of ventricular septal defect (VSD), cardiac catheterizations were performed before and late after surgery together with pressure measurements immediately after closure of the VSD during surgery. Pulmonary arterial mean pressure (PAm), pulmonary arterial systolic pressure to systemic arterial systolic pressure ratio (Pp/Ps), and pulmonary vascular resistance to systemic vascular resistance ratio (Rp/Rs) were measured and calculated. The patients were classified into 5 groups according to the preoperative Rp/Rs and Qp/Qs as was reported by Nakada: Group A: Rp/Rs less than 0.15, Qp/Qs larger than or equal to 1.8, Group B: Rp/Rs less than 0.15, Qp/Qs less than 1.8, Group C: 0.15 less than or equal to Rp/Rs less than 0.50, Group D: 0.50 less than or equal to Rp/Rs less than 0.85, Group E: 0.85 less than or equal to Rp/Rs. These groups were further divided into 3 groups respectively according to age at operation (less than or equal to 2 years, 3 or 4 years, 5 years less than or equal to). The averages of PAm, Pp/Ps, and Rp/Rs were within the normal range in Group A and B patients (normal pulmonary vascular resistance groups) irrespective to the age at operation except the average of PAm before surgery. In Group C, D and E patients (elevated pulmonary vascular resistance group), these variables decreased immediately after closure of VSD, and further decreases were noted at the time of late catheterization. These variables, however, did not completely normalize even at that time. Among the patients operated upon at 2 years of age or less, the averages of these variables normalized immediately after closure of the VSD. When operated upon at 3 or 4 years of age, these variables decreased but did not normalize immediately after closure of the VSD and were found to be within the normal range at the time of late catheterization. When operated upon at 5 years of age or more, these variables decreased immediately after closure of the VSD, and further decrease was found at the time of late catheterization but mostly remained in the abnormal range even at this time. From the data obtained herein, the factors producing the pulmonary vascular resistances in respective age groups were discussed. The closure of VSD in patients with elevated pulmonary vascular resistance is recommended at the latest 4 years of age and preferably at 2 years of age or less, in order to obtain normal pulmonary circulatory dynamics after surgery.


Early intervention of atopic dermatitis as a preventive strategy for progression of food allergy.
Atopic diseases, such as atopic dermatitis (AD) and food allergy (FA), have increased in prevalence in industrialized countries during the past few decades and pose a significant health burden. They appear to have a common underlying mechanism and a natural disease progression. AD is generally the first atopic disease to manifest followed by other atopic diseases, such as FA, allergic rhinitis, or allergic asthma suggesting that they are likely different manifestations of the same disease. BODY: Evidence suggests that allergic sensitization occurs through an impaired skin barrier, while consumption of these foods at an early age may actually result in tolerance. This has been termed the Dual-Allergen-Exposure hypothesis. Loss of barrier integrity has been hypothesized to enable penetration of allergens, pollutants, and microbes and initiation of an inflammatory immune cascade of events leading to sensitization. The immune dysfunction is thought to further exacerbate the impaired skin barrier to form a vicious cycle. There is much interest in preventing or protecting the skin barrier from developing a proinflammatory atopic state, which may potentially lead to the development of AD and subsequently, FA. Research on preventing or treating skin barrier dysfunction is ongoing. A number of studies have evaluated the efficacy of emollients in preventing AD and FA with mixed results. Studies have differed in the study design, population characteristics, emollients type, and frequency, duration, and area of application. Emollient type has varied widely from oils, creams, petrolatum-based lotions, and trilipid creams. Current research is directed towards the use of trilipid emollients that are similar to the skin's natural lipid composition with a 3:1:1 ratio of ceramides, cholesterol and free fatty acids and a pH that is similar to that of skin to determine their effectiveness for skin barrier repair and prevention of AD and FA.


A Case Series of Ketoacidosis After Coronavirus Disease 2019 Vaccination in Patients With Type 1 Diabetes.
We report a case series of severe ketoacidosis after COVID-19 vaccination in a type 1 diabetes patients treated with insulin and an SGLT-2 inhibitor. We present two cases of type 1 diabetes mellitus. One patient was treated with insulin therapy and an SGLT-2 inhibitor, and the other patient was treated with insulin therapy alone. Both patients became ill after coronavirus disease-2019 vaccination, making it difficult to continue their diet or insulin injections. On admission, they developed severe diabetic ketoacidosis. This is the first report of ketoacidosis after coronavirus disease-2019 vaccination. The vaccine should be carefully administered to type 1 diabetes patients receiving intensive insulin therapy and a sodium-glucose transporter due to the high risk ketoacidosis. It is important to instruct patients to drink sufficient fluids and to continue insulin injections when they become sick.


Augmentation with amisulpride for schizophrenic patients non-responsive to risperidone monotherapy.
The combination of antipsychotic drugs is a therapeutic resource in clinical practice. This study aimed to evaluate the efficacy and security of adding amisulpride in patients who at least partially responded to risperidone. A 3-month, open, observational study was undertaken to evaluate the effectiveness of adding amisulpride in subjects who scored at least 25 on the brief psychiatric rating scale (BPRS) after risperidone monotherapy. Patients were evaluated with BPRS, the Clinical Global Impressions Severity of Illness scale (CGI-S) and the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (UKU) at baseline, 1 and 3 months. Coadjuvant treatment with amisulpride achieves a statistically significant improvement in mental status over a period of 3 months when measured with BPRS, CGI and UKU scales. The response rate was 70 (45%) in the oral risperidone and 74 (28%) in the parenteral risperidone groups. The addition of amisulpride could lead to an improvement in schizophrenia symptoms in patients that do not, or only partially, respond to risperidone. Further research is required into alternative therapies for poor responders.


Polymerization/depolymerization of actin cooperates with the morphology and stability of cell-sized droplets generated in a polymer solution under a depletion effect.
Intercellular fluids in living organisms contain high concentrations of macromolecules such as nucleic acid and protein. Over the past few decades, several studies have examined membraneless organelles in terms of liquid-liquid phase separation. These studies have investigated aggregation/attraction among a rich variety of biomolecules. Here, we studied the association between the polymerization/depolymerization of actin, interconversion between monomeric (G-actin) and filamentous states (F-actin), and water/water phase separation in a binary polymer solution using polyethylene glycol (PEG) and dextran (DEX). We found that actin, which is a representative cytoskeleton, changes its distribution in a PEG/DEX binary solution depending on its polymerization state: monomeric G-actin is distributed homogeneously throughout the solution, whereas polymerized F-actin is localized only within the DEX-rich phase. We extended our study by using fragmin, which is a representative actin-severing and -depolymerizing factor. It took hours to restore a homogeneous actin distribution from localization within the DEX-rich phase, even with the addition of fragmin in an amount that causes complete depolymerization. In contrast, when actin that had been depolymerized by fragmin in advance was added to a solution with microphase-separation, F-actin was found in DEX-rich phase droplets. The micro-droplets tended to deform into a non-spherical morphology under conditions where they contained F-actin. These findings suggest that microphase-separation is associated with the dynamics of polymerization and localization of the actin cytoskeleton. We discuss our observations by taking into consideration the polymer depletion effect.


Inhibition of mitochondrial complex 1 by the S6K1 inhibitor PF-4708671 partly contributes to its glucose metabolic effects in muscle and liver cells.
mTOR complex 1 (mTORC1) and p70 S6 kinase (S6K1) are both involved in the development of obesity-linked insulin resistance. Recently, we showed that the S6K1 inhibitor PF-4708671 (PF) increases insulin sensitivity. However, we also reported that PF can increase glucose metabolism even in the absence of insulin in muscle and hepatic cells. Here we further explored the potential mechanisms by which PF increases glucose metabolism in muscle and liver cells independent of insulin. Time course experiments revealed that PF induces AMP-activated protein kinase (AMPK) activation before inhibiting S6K1. However, PF-induced glucose uptake was not prevented in primary muscle cells from AMPK α1/2 double KO (dKO) mice. Moreover, PF-mediated suppression of hepatic glucose production was maintained in hepatocytes derived from AMPK α1/2-dKO mice. Remarkably, PF could still reduce glucose production and activate AMPK in hepatocytes from S6K1/2 dKO mice. Mechanistically, bioenergetics experiments revealed that PF reduces mitochondrial complex I activity in both muscle and hepatic cells. The stimulatory effect of PF on glucose uptake was partially reduced by expression of the Saccharomyces cerevisiae NADH:ubiquinone oxidoreductase in L6 cells. These results indicate that PF-mediated S6K1 inhibition is not required for its effect on insulin-independent glucose metabolism and AMPK activation. We conclude that, although PF rapidly activates AMPK, its ability to acutely increase glucose uptake and suppress glucose production does not require AMPK activation. Unexpectedly, PF rapidly inhibits mitochondrial complex I activity, a mechanism that partially underlies PF's effect on glucose metabolism.


A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF.
Despite the widespread use of continuous renal replacement therapy in critically ill patients with acute renal failure (ARF), there are few data supporting its benefits over conventional intermittent hemodialysis (IHD). We sought to analyze differences in survival between modalities in a study that compared continuous venovenous hemodialysis (CVVHD) with IHD. Eighty critically ill patients with ARF requiring dialysis were randomized after stratification by severity of illness to treatment with CVVHD or IHD. There were no differences in survival or renal recovery between groups. In patients who died, mean survival time was 10.7 +/- 11.2 days for the IHD group versus 14.3 +/- 16.1 days for the CVVHD group (P = not significant). There was greater net volume removal in the CVVHD group during 72 hours. Declines in urine output during 72 hours were similar between groups. Mean arterial pressure off and on dialysis therapy was analyzed retrospectively. There was a significant decrease in mean arterial pressure for patients on IHD therapy not seen in those on CVVHD therapy, but this did not lead to a survival advantage. Despite greater volume control, CVVHD did not lead to an improvement in survival, preservation of urine output, or renal recovery compared with IHD in patients with ARF.


Human protein S cleavage and inactivation by coagulation factor Xa.
Human factor Xa specifically cleaves the anticoagulant protein S within the thrombin-sensitive domain. Amino-terminal amino acid sequencing of the heavy chain cleavage product indicates cleavage of protein S by factor Xa at Arg60, a site that is distinct from those utilized by alpha-thrombin. Cleavage by factor Xa is unaffected by the presence of hirudin and is completely blocked by tick-anticoagulant-peptide and D-Glu-Gly-Arg-chloromethyl ketone, the latter two being specific inhibitors of factor Xa. The cleavage requires the presence of phospholipid and Ca2+, and is markedly inhibited by the presence of factor Va. Factor Xa-cleaved protein S no longer possesses its activated protein C-dependent or -independent anticoagulant activity, as measured in a factor VIII-based activated partial thromboplastin time clot assay. The apparent binding constant for protein S binding to phospholipid (Kd approximately 4 nM +/- 1.0) is unaffected by factor Xa or thrombin cleavage, suggesting that the loss of anticoagulant activity resulting from cleavage is not primarily due to the loss of membrane binding ability. Cleavage and inactivation of protein S by factor Xa may be an additional way in which factor Xa exerts its procoagulant effect, after the initial stages of clot formation.


Comparison between Wound Closure Methods in the Reversal of Diverting Ileostomy.
The objective of this study was to determine the more appropriate wound-closure method by comparing the effectiveness of two methods in a group of patients who underwent ileostomy repair. The study conducted after obtaining the approval of the Institutional Review Board (IRB) included 58 patients ≥19 years of age who underwent ileostomy at the Department of Surgery at the Presbyterian Medical Center. This was a retrospective, single-center trial. Patients who underwent ileostomy closure between January 2011 and September 2017 were assigned to the primary wound-closure (PC, n=25) group and the purse-string wound-closure (PSC, n=33) group. Post-repair complications, such as wound infection, delayed healing, and patient satisfaction related to wound management, were investigated and compared according to the wound-closure method. The PSC group had a significantly lower surgical site infection rate than the PC group (0% vs. 44%, p<0.001). The wound-healing period was also significantly different between the PC and PSC groups (mean 27.18 days vs. 20.96 days, p=0.023). However, the postoperative wound-healing delay of >30 days was not significantly different (39% vs. 20%, p=0.114). In addition, there were no significant differences in the response to questionnaires on patient satisfaction between the two groups. PSC has a lower surgical site infection rate and the wound-healing delay was not very different from that of PC. Therefore, if patients are at risk of wound infection, such as in severe wound contamination, long operating time, and immunocompromised conditions, we should consider PSC as a wound closure method of choice.


[Different gene gun-mediated plasmid DNA transfection of eukaryotic cell lines in vitro experimental study].
To establish a preparation method of cartridge for gene gun and different gene transfection to MVF-7 cell lines in vitro. The cartridge was prepared by precipitation method of spermidine and calcium chloride.using gene gun method, respectively, the eukaryotic expression plasmid pEGFP, Pmcherry transfected with the control group and experimental group MCF-7 cells 24 h after transfection. The preparation of the gene-gun bullets, gene gun-mediated pEGFP, Pmcherry be able to separate and co-transfected into cultured MCF-7 cells, 24 h after transfection could be detected in red, green fluorescence, while the control group there was no fluorescent protein expression. Gene gun can be effectively mediated gene transfer and be able to achieve a common transfer of two genes. The report gene can be expressed through gene gun-transfected MCF-7 cells.


The Incidence of Cranial Arteriovenous Shunts in Patients With Pulsatile Tinnitus: A Prospective Observational Study.
Finding the underlying cause for pulsatile tinnitus can be challenging. We aimed to determine the incidence of arteriovenous shunts, i.e., arteriovenous malformations (AVMs) or dural arteriovenous fistulas (dAVFs), in patients referred for catheter angiography (digital subtraction angiography [DSA]). Furthermore, we assessed which clinical features were predictive for the presence of such a lesion. Fifty-one patients with pulsatile tinnitus, who were referred to us for DSA to exclude an arteriovenous shunt, were enrolled, prospectively. DSA determined the presence of a dAVF or AVM. Clinical characteristics were recorded systematically and all patients underwent a physical examination. Fifty patients were included in the final analyses. While no AVMs were found, a dAVF was found in 12 cases (24%). Three of these demonstrated cortical venous reflux, thus requiring treatment due to the risk of hemorrhage. In three cases (6%), DSA demonstrated a non-arteriovenous-shunt abnormality, likely causing the tinnitus. The odds of having a dAVF were significantly raised by unilaterality, objective bruit, and the ability to influence the tinnitus with compression. Unilaterality even had a negative predictive value of 1 and, if used as selection criterion, would have raised dAVF prevalence from 24 to 32%. In a tertiary care setting, the prevalence of dAVFs in patients with pulsatile tinnitus is not negligible. Thus, patients with unilateral pulsatile tinnitus should be offered dynamic vascular imaging to rule out a dAVF. Especially, since some of these patients are at risk of intracranial hemorrhage and treatment options exist.


Economic and technological drivers of generic sterile injectable drug shortages.
Over the past few years, an increasing number of critically needed medicines have been in short supply. Using economic theory to frame the drug-shortage problem, this paper explores why and how manufacturing-quality problems could combine with other economic and technological factors to result in shortages of generic sterile injectable drugs. The fundamental problem we identify is the inability of the market to observe and reward quality. This lack of reward for quality can reinforce price competition and encourage manufacturers to keep costs down by minimizing quality investments. The US Food and Drug Administration's (FDA's) need to use its regulatory flexibility, on behalf of patients, to avoid shortages of medically necessary drugs may further strengthen the incentive to "push the envelope" on quality. These dynamics may have produced a market situation in which quality problems have become sufficiently common and severe to result in drug shortages.


SOCS and diabetes--ups and downs of a turbulent relationship.
Diabetes mellitus is one of the most emerging diseases threatening the present world. Thus, intensive investigations are carried out to better understand the mechanisms occurring in type 1 (T1D) and 2 (T2D) diabetes, and to elaborate more potent methods to fight the disease. In this aspect, the suppressors of cytokine signalling (SOCS) are one of the most studied factors of recent years. SOCS proteins have been discovered as cytokine pathway inhibitors; however, presently, their influence seems wider. Most of the known SOCS proteins are involved in the modulation of the development of insulin resistance, β-cell failure and eventually T1D and T2D. They are also involved in complications related with diabetes, such as retinopathy, nephropathy and cardiomyopathy. In T1D, SOCS proteins regulate β-cell mass, mediate resistance to damaging factors and improve pancreatic islet graft survival. Regarding insulin resistance and T2D, SOCS proteins take part in mediating signals produced by diabetogenic substances and regulate insulin receptor functioning, affecting insulin sensitivity. However, not all of the present data are consistent, and thus, further studies are required. Finally, for several pharmacologically active substances of importance regarding the treatment of diabetes, SOCS-modulating properties have already been described. Here, we review the findings of SOCS-diabetes relations of the last decade.


Impact of postharvest methyl jasmonate treatment on the volatile composition and flavonol content of strawberries.
Although strawberry aroma is very complex, certain compounds have been described as main contributors, i.e. furanones, aldehydes, alcohols, sulfur compounds and particularly methyl and ethyl esters. In addition, strawberries possess potent antioxidant activity because of their high content of phenolic compounds. Among them, flavonols are highlighted as important antioxidant compounds in strawberry. The objective of this study was to assess the effect of methyl jasmonate (MJ) on the composition of the major contributors to aroma and on the content of certain flavonols in strawberry fruits. The levels of all studied volatile compounds were significantly affected by MJ treatment, though the individual effect differed according to the specific compound considered. Most of them increased significantly (P < 0.05), except methyl butanoate, which always showed higher levels in untreated strawberries. In contrast to aroma compounds, the change in the concentration of flavonols (i.e. myricetin, quercetin and kaempferol) was not significant in MJ-treated strawberries. Considering the health-promoting activity of these compounds, further investigations on the experimental conditions related to the treatment are required to control flavonol bioformation by means of MJ. The exogenous application of MJ vapour to strawberry enhances, in general, the production of the most relevant aroma-active compounds. On the contrary, MJ treatment does not appear to influence the levels of myricetin, quercetin and kaempferol. Thus postharvest MJ treatment is proposed as an approach to obtain improved strawberry fruits in terms of sensory quality and health-promoting properties.


The first successful elective laparotomy.
The first time the abdomen was opened at an elective operation, the pathology excised and made a smooth recovery was not, as you might guess, performed in some famous university hospital in the British Isles or mainland Europe about a hundred years ago, but in a private house in the backwoods of Kentucky in 1807, and the story is a fascinating one.


Molecular tailoring approach for geometry optimization of large molecules: energy evaluation and parallelization strategies.
A linear-scaling scheme for estimating the electronic energy, gradients, and Hessian of a large molecule at ab initio level of theory based on fragment set cardinality is presented. With this proposition, a general, cardinality-guided molecular tailoring approach (CG-MTA) for ab initio geometry optimization of large molecules is implemented. The method employs energy gradients extracted from fragment wave functions, enabling computations otherwise impractical on PC hardware. Further, the method is readily amenable to large scale coarse-grain parallelization with minimal communication among nodes, resulting in a near-linear speedup. CG-MTA is applied for density-functional-theory-based geometry optimization of a variety of molecules including alpha-tocopherol, taxol, gamma-cyclodextrin, and two conformations of polyglycine. In the tests performed, energy and gradient estimates obtained from CG-MTA during optimization runs show an excellent agreement with those obtained from actual computation. Accuracy of the Hessian obtained employing CG-MTA provides good hope for the application of Hessian-based geometry optimization to large molecules.


Sexual trauma increases the risk of developing psychosis in an ultra high-risk "prodromal" population.
Studies indicate a high prevalence of childhood trauma in patient cohorts with established psychotic disorder and in those at risk of developing psychosis. A causal link between childhood trauma and development of psychosis has been proposed. We aimed to examine the association between experience of childhood trauma and the development of a psychotic disorder in a large "Ultra High Risk" (UHR) for psychosis cohort. The data were collected as part of a longitudinal cohort study of all UHR patients recruited to research studies at the Personal Assessment and Clinical Evaluation clinic between 1993 and 2006. Baseline data were collected at recruitment to these studies. The participants completed a comprehensive follow-up assessment battery (mean time to follow-up 7.5 years, range 2.4-14.9 years), which included the Childhood Trauma Questionnaire (CTQ), a self-report questionnaire that assesses experience of childhood trauma. The outcome of interest was transition to a psychotic disorder during the follow-up period. Data were available on 233 individuals. Total CTQ trauma score was not associated with transition to psychosis. Of the individual trauma types, only sexual abuse was associated with transition to psychosis (P = .02). The association remained when adjusting for potential confounding factors. Those with high sexual abuse scores were estimated to have a transition risk 2-4 times that of those with low scores. The findings suggest that sexual trauma may be an important contributing factor in development of psychosis for some individuals.


Toxicity and repellency of compounds from clove (Syzygium aromaticum) to red imported fire ants Solenopsis invicta (Hymenoptera: Formicidae).
The toxicity and repellency of the bioactive chemicals of clove (Syzygium aromaticum) powder, eugenol, eugenol acetate, and beta-caryophyllene were evaluated against workers of the red imported fire ant, Solenopsis invicta Buren. Clove powder applied at 3 and 12 mg/cm2 provided 100% ant mortality within 6 h, and repelled 99% within 3 h. Eugenol was the fastest acting compound against red imported fire ant compared with eugenol acetate, beta-caryophyllene, and clove oil. The LT50 values inclined exponentially with the increase in the application rate of the chemical compounds tested. However, repellency did not increase with the increase in the application rate of the chemical compounds tested, but did with the increase in exposure time. Eugenol, eugenol acetate, as well as beta-caryophyllene and clove oil may provide another tool for red imported fire ant integrated pest management, particularly in situations where conventional insecticides are inappropriate.


Psoralen plus ultraviolet A irradiation-induced lentigines arising in vitiligo: involvement of vitiliginous and normal appearing skin.
Psoralen plus ultraviolet A irradiation (PUVA therapy) is commonly used for the management of vitiligo in which perifollicular repigmentation is the usual response pattern. However, excessive PUVA therapy may be associated with adverse effects. We report a case of generalized vitiligo that has been extensively treated with topical and systemic PUVA therapy for several years with the development of extensive and widespread stellate and irregularly shaped black and brown macules (lentigines). Interestingly, the lentigines were observed not only in the normally pigmented skin but also within the depigmented lesions that were lacking the perifollicular response pattern. The lesions developed in the exposed and unexposed skin areas. No evidence of skin malignancy was observed clinically and no melanocyte atypia was detected histopathologically. Cryotherapy may be used in the management of the lentigines; however, because of the extent of lesions this was impractical in our case.


Flash signal evolution, mate choice, and predation in fireflies.
Many key advances in our understanding of firefly biology and signaling have been made over the past two decades. Here we review this recent research, which includes new phylogenetic results that shed light on the evolution of courtship signal diversity within the family Lampyridae, new insights into firefly flash control, and the discovery of firefly nuptial gifts. We present a comprehensive overview of sexual selection in lampyrids, including evidence from Photinus fireflies that females choose their mates on the basis of male flash signals, and discuss the importance of examining both precopulatory and postcopulatory sexual selection in this group. Finally, we review recent findings on firefly chemical defenses, and discuss their implications for flash signal evolution in response to generalist predators as well as specialist predatory fireflies. This review provides new insight into how firefly flash signals have been shaped by the dual evolutionary processes of sexual selection (mate choice) and natural selection (predation), and proposes several exciting directions for future research.


Optimal Scheme to Achieve Energy Conservation in Induced Dipole Models.
Induced dipole models have proven to be effective tools for simulating electronic polarization effects in biochemical processes, yet their potential has been constrained by energy conservation issue, particularly when historical data is utilized for dipole prediction. This study identifies error outliers as the primary factor causing this failure of energy conservation and proposes a comprehensive scheme to overcome this limitation. Leveraging maximum relative errors as a convergence metric, our data demonstrates that energy conservation can be upheld even when using historical information for dipole predictions. Our study introduces the multi-order extrapolation method to quicken induction iteration and optimize the use of historical data, while also developing the preconditioned conjugate gradient with local iterations to refine the iteration process and effectively remove error outliers. This scheme further incorporates a "peek" step via Jacobi under-relaxation for optimal performance. Simulation evidence suggests that our proposed scheme can achieve energy convergence akin to that of point-charge models within a limited number of iterations, thus promising significant improvements in efficiency and accuracy.


Critical care management and intensive care unit outcomes following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
To study the early postoperative intensive care unit (ICU) management and complications in the first 2 wk of patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Our study is a retrospective, observational study performed at Icahn School of Medicine at Mount Sinai, quaternary care hospital in New York City. All adult patients who underwent CRS and HIPEC between January 1, 2007 and December 31, 2012 and admitted to ICU postoperatively were studied. Fifty-one patients came to the ICU postoperatively out of 170 who underwent CRS and HIPEC therapy during the study period. Data analysis was performed using descriptive statistics. Of the 170 patients who underwent CRS and HIPEC therapy, 51 (30%) came to the ICU postoperatively. Mean ICU length of stay was 4 d (range 1-60 d) and mean APACHE II score was 15 (range 7-23). Thirty-one/fifty-one (62%) patients developed postoperative complications. Aggressive intraoperative and postoperative fluid resuscitation is required in most patients. Hypovolemia was seen in all patients and median amount of fluids required in the first 48 h was 6 L (range 1-14 L). Thirteen patients (25%) developed postoperative hypotension with seven requiring vasopressor support. The major cause of sepsis was intraabdominal, with 8 (15%) developing anastomotic leaks and 5 (10%) developing intraabdominal abscess. The median survival was 14 mo with 30 d mortality of 4% (2/51) and 90 d mortality of 16% (8/51). One year survival was 56.4% (28/51). Preoperative medical co morbidities, extent of surgical debulking, intraoperative blood losses, amount of intra op blood products required and total operative time are the factors to be considered while deciding ICU vs non ICU admission. Overall, ICU outcomes of this study population are excellent. Triage of these patients should consider preoperative and intraoperative factors. Intensivists should be vigilant to aggressive postop fluid resuscitation, pain control and early detection and management of surgical complications.


Colorectal cancer in ulcerative colitis patients: survival curves and surveillance.
Survival curves can provide useful information for designing cancer surveillance programs. To outline how to derive the density and hazard functions from the survival curve and to use this information to make recommendations regarding cancer surveillance in patients with ulcerative colitis. The hazard of cancer or dysplasia remains low during the first decade of ulcerative colitis but rises exponentially thereafter. After 40 years, approximately 20% of patients with ulcerative colitis acquire cancer or dysplasia per year. A reasonable recommendation for cancer surveillance based on information from survival curves would be a colonoscopy with biopsy approximately 10 years after the onset of ulcerative colitis, and repeated every 3 years for the next decade, every 2 years for the subsequent decade, and every year thereafter. Prophylactic proctocolectomy is an option after 40 years of disease due to the extremely high cancer risk, but data supporting this option are sparse.


From Human Megakaryocytes to Platelets: Effects of Aspirin on High-Mobility Group Box 1/Receptor for Advanced Glycation End Products Axis.
Platelets (PLTs) are the major source of high-mobility group box 1 (HMGB1), a protein that is involved in sterile inflammation of blood vessels and thrombosis. Megakaryocytes (MKs) synthesize HMGB1 and transfer both protein and mRNA into PLTs and PLT-derived microvesicles (MV). Free HMGB1 found in supernatants of in vitro differentiated MKs and in a megakaryoblastic cell line (DAMI cells). Aspirin "in vivo" and "in vitro" not only reduces HMGB1 and receptor for advanced glycation end products expression on MKs and PLTs but also drives the movement of HMGB1 from MKs into PLTs and PLT-derived MV. These findings suggest that consumption of low doses of aspirin reduces the risk of atherosclerosis complications as well as reducing PLT aggregation by the inhibition of COX-1.


[Ru(TAP)3]2+-photosensitized DNA cleavage studied by atomic force microscopy and gel electrophoresis: a comparative study.
Topological modifications of plasmid DNA adsorbed on a variety of surfaces were investigated by using atomic force microscopy (AFM). On mica modified with 3-aminopropyltriethoxysilane (APS) or poly-L-lysine, the interaction between the plasmid DNA and the surface "freezes" the plasmid DNA conformation deposited from solution, and the AFM images resemble the projection of the three-dimensional conformation of the plasmid DNA in solution. Modified mica with low concentrations of Mg(2+) leads to a decrease in the interaction strength between plasmid DNA and the substrate, and the AFM images reflect the relaxed or equilibrium conformation of the adsorbed plasmid DNA. Under these optimized deposition conditions, topological modifications of plasmid DNA were produced under irradiation in the presence of [Ru(TAP)(3)](2+) (TAP = 1,4,5,8-tetraazaphenanthrene), which is a non-intercalating complex, and were followed as a function of illumination time. The observed structural changes correlate well with the conversion of the supercoiled covalently closed circular form (ccc form) into the open circular form (oc form), induced by a single-strand photocleavage. The AFM results obtained after fine-tuning of the plasmid DNA-substrate interaction compare well with those observed from gel electrophoresis, indicating that under the appropriate deposition conditions, AFM is a reliable technique to investigate irradiation-induced topological changes in plasmid DNA.


Three-shift system increases job-related stress in Japanese workers.
We assessed the relationship between shift work and job stress. The target subjects were 4,962 male workers (3,078 day workers and 1,884 shift workers) aged 18 to 60 yr who work in a Japanese steel company. We used the "Brief Job Stress Questionnaire", which was developed by a research group organized by the Japanese Ministry of Labour. We evaluated the effect of shift work on job stress using logistic regression analysis including age, lifestyle factors, work conditions, marital status, and living arrangements in the model. Job schedule type was significantly associated with job control, with an odds ratio of 2.22 for shift workers compared to day workers. The logistic regression analysis revealed that the odd ratios for having one or more stressor items in an unfavorable condition were significantly higher for shift workers compared to day workers. Increase in the amount of overtime and decrease in the number of holidays led to a significant deterioration in job stress. Our study reveals that the 3-shift system of employment increases work-related stress, and that job control is low among shift workers. To reduce job stress in this occupational population, a reduction in the amount of overtime and an increase in the number of holidays seem to be useful interventions.


New Diagnostic Strategies for Detection of Helicobacter pylori Infection in Pediatric Patients.
Helicobacter pylori (H pylori) is a common chronic bacterial infection that is an important cause of peptic ulcer disease and gastroduodenal disease in children. H pylori is also associated with extragastric manifestations, including growth reduction, iron-deficiency anemia, and idiopathic thrombocytopenic purpura. Current guidelines recommend endoscopy with biopsy for the definitive demonstration of H pylori infection. In contrast to serology, the fecal antigen test and the urea breath test provide reliable, sensitive, and specific results for detecting active H pylori infection in children before and after treatment. The first-line treatment option for pediatric patients is triple therapy with a proton pump inhibitor and 2 antibiotics, which include amoxicillin and clarithromycin or metronidazole. Decreasing eradication rates and the emergence of antibiotic-resistant strains of H pylori have led to the use of other treatments, such as sequential therapy or triple therapy with newer antibiotics, particularly in geographic areas with high rates of antibiotic resistance. Patients should be tested after treatment to confirm eradication, as the absence of symptoms does not necessarily mean that H pylori is no longer present. This clinical roundtable monograph provides an overview of H pylori infection, as well as expert insight into the diagnosis and management of H pylori infection in children.


Projections of future wildfires impacts on air pollutants and air toxics in a changing climate over the western United States.
Wildfires emit smoke particles and gaseous pollutants that greatly aggravate air quality and cause adverse health impacts in the western US (WUS). This study evaluates how wildfire impacts on air pollutants and air toxics evolve from the present climate to the future climate under a high anthropogenic emission scenario at regional and city scales. Through employing multiple climate and chemical transport models, small changes in domain-averaged air pollutant concentrations by wildfires are simulated over WUS. However, such changes significantly increase future city-scale pollutant concentrations by up to 53 ppb for benzene, 158 ppb for formaldehyde, 655 μg/m3 for fine particulate matter (PM2.5), and 102 ppb for ozone, whereas that for the present climate are 104 ppb for benzene, 332 ppb for formaldehyde, 1,378 μg/m3 for PM2.5, and 140 ppb for ozone. Despite wildfires induce smaller changes in the future, the wildfire contribution ratios can increase by more than tenfold compared to the present climate, indicating wildfires become a more critical contributor to future air pollution in WUS. In addition, additional 6 exceedance days/year for formaldehyde and additional 3 exceedance days/year for ozone suggest increasing health impacts by wildfires in the future.


Two-stage hybrid repair of Kommerell diverticulum with supra-aortic debranching.
The surgical treatment of Kommerell diverticula is associated with high mortality and morbidity rates. In the mid-2000s, hybrid aortic arch repair was developed, and the procedure has since been used to repair Kommerell diverticula. In the present study, we focused on the postoperative outcomes of two-stage hybrid repair of Kommerell diverticula that required supra-aortic debranching (type I hybrid arch repair). From August 2010 to July 2013, a total of four patients (aged 73.5 ± 9.5 years) underwent two-stage hybrid repair (type I hybrid arch repair) for Kommerell diverticula, and their cases were retrospectively studied. All four patients had right aortic arches and aberrant left subclavian arteries. The repair procedure consisted of two stages: (1) debranching of the supra-aortic vessels via a median sternotomy; (2) exclusion of the Kommerell diverticulum by performing thoracic endovascular repair via a femoral approach and coil embolization of the orifice of the aberrant subclavian artery. There were no in-hospital deaths. One patient developed an acute kidney injury and required hemodialysis on postoperative day 2, although his renal function recovered within 48 hours. No strokes, paraplegia, or early aortic events were observed in our series. The mean follow-up period was 19.5 months (range, 5-47 months). All patients remained free from aortic events and endoleaks during the follow-up period. The early and mid-term outcomes of hybrid repair for Kommerell diverticula that require supra-aortic debranching, which are less invasive and do not involve hypothermic circulatory arrest, are acceptable. However, this procedure requires the insertion of an endograft into the ascending aorta, and careful and long-term follow-up is required to confirm its efficacy.


A Protective Role of Low Polygenic Risk Score in Healthy Individuals Carrying Attention-Deficit/Hyperactivity Disorder-Associated Copy Number Variations.
Previous studies have implicated both rare copy number variations (CNVs) and common variants in liability for attention-deficit/hyperactivity disorder (ADHD). However, how common and rare genetic variants jointly contribute to individual liability requires further investigation in larger cohorts. This study comprises 9385 participants of European descent and 7810 participants of African American ancestry who were recruited from the greater Philadelphia area by the Children's Hospital of Philadelphia. The polygenic risk score (PRS) of each participant was estimated by linkage disequilibrium pruning and p-value thresholding (P + T) methods using PRSice-2. We investigated whether the risk of ADHD follows a polygenic liability threshold model wherein 1) the risk of ADHD requires less contribution from common variants in the presence of a rare CNV, and 2) control carriers of ADHD-associated CNVs have lower common risk allele burden than noncarriers. CNVs previously reported in ADHD cases were significantly associated with ADHD risk in both the European American cohort and the African American cohort. Healthy control participants carrying those same risk CNVs had lower PRSs than those without risk CNVs in the European American cohort. This result was replicated in the African American cohort. However, PRSs were not significantly different in case participants carrying risk CNVs versus those without risk CNVs. These findings provide evidence in support of interactive effects of PRS and ADHD-associated CNVs on disease risk and add novel insights into the genetic basis of ADHD by highlighting a protective role of low PRS in ADHD.


Molecular Conformation in Charge Tunneling across Large-Area Junctions.
Self-assembled monolayers are predicated on thermodynamic equilibrium; hence, their properties project accessible relaxation pathways. Herein, we demonstrate that charge tunneling correlates with conformational degrees of freedom(s). Results from open chain and cyclic head groups show that, as expected, distribution in tunneling data correlates with the orientation of the head group, akin to the odd-even effect and more importantly the degree of conformational freedom, but fluctuates with applied bias. Trends in nature of distributions in current density illuminate the need for higher statistical moments in understanding these rather dynamic systems. We employ skewness, kurtosis, and estimation plots to show that the conformational degree of freedom in the head group significantly amplifies the odd-even effect and may lead to enhanced or perturbed tunneling based on whether the head group is on an odd- or even-parity spacer.


Endpoints and patient stratification in clinical trials for alcoholic hepatitis.
In some areas of medicine the clinical development pathway through phase II and III clinical trials has been well mapped out and refined through extensive experience. In contrast, a number of key questions remain unanswered in the development of novel therapeutics for alcoholic hepatitis. The use of mortality as an endpoint in phase II clinical trials will potentially restrict the appeal of this therapeutic area for pharmaceutical companies, as the number of patients required for adequately powered clinical trials becomes impractical. Herein, we discuss alternative endpoints and conclude that dynamic assessment of liver function is the most pragmatic option in early stage studies. Stratification based on disease severity should be applied to avoid uneven distribution of patients with substantially differing mortality risks. Consensus on early phase trial design would help to facilitate new therapeutic development in this area of high unmet medical need.


Monolithic nano-porous polymer in microfluidic channels for lab-chip liquid chromatography.
In this paper, a nano-porous polymer has been integrated into the microfluidics device as on-chip monolithic liquid chromatography column for separation of chemical and biological samples. Monolithic nano-porous polymer (MNP) was formed and firmly grafted on the surface of the microfluidic channel. Neurotransmitters, 5-hydroxyindole-3-acetic acid (5-HIAA) and 5-hydroxytryptamine (serotonin, 5-HT), were successfully separated with the developed on-chip MNP column.


Structure and Properties of Poly-α-olefins Containing Quaternary Carbon Centers.
In this paper, poly-α-olefins (PAO) containing quaternary carbon centers were prepared by two-step oligomerization using a metallocene catalyst followed by a Ziegler-Natta catalyst. First, the 1-decene dimer was oligomerized with [t-BuN(Me)2C(η5-C5H4)]ZrCl2, and the effects of the oligomerization temperature, Al/Zr molar ratio, and catalyst loading on the oligomerization were investigated. In the second step, the obtained 1-decene dimers were copolymerized with 1-decene with TiCl4/Et2AlCl, and the effects of the catalysts, monomer/dimer ratio, and α-olefin species on the copolymerization were investigated. The composition and structure of the dimers and copolymerization products were characterized by gas chromatography (GC) and 1H NMR and 13C NMR spectroscopy. The results of GC and 13C NMR analyses indicated that the metallocene catalyzed the formation of the 1-decene oligomerization product, resulting in the branched olefin dimer being the major product, and the existence of quaternary carbons in the 1-decene/1-decene dimer copolymerization product could also be found. The polymerization mechanism for the formation of the quaternary carbon centers is proposed. The 1-decene/1-decene dimer copolymerization product containing quaternary carbon centers has a kinematic viscosity of 10.8 mm2/s at 100 °C, a viscosity index of 165, and a pour point of -52 °C; thus, the product with quaternary carbon centers has a better viscosity-temperature performance and low-temperature fluidity than those of the 1-decene oligomerization product and typical PAO products, but the kinematic viscosity is similar.


Indolent palatal swelling: Catch 22.
We present an interesting but intriguing case of an indolent palatal swelling. The lesion was asymptomatic causing little discomfort to the patient and thus was an incidental clinical finding. Provisional diagnosis was a benign, minor salivary gland tumor. Clinical differential diagnoses included benign lymphoepithelial lesion or mucus extravasation phenomenon. Nevertheless, we also considered malignancies such as mucoepidermoid carcinoma, lymphoma, and neoplasm of the maxillary sinus. However, the histopathology revealed a rare clinicopathologic entity prompting immediate treatment of the lesion.


Targeting histone deacetylase suppresses tumor growth through eliciting METTL14-modified m6 A RNA methylation in ocular melanoma.
Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6-methyladenine (m6 A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in-depth understanding of the crosstalk between histone acetylation and m6 A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m6 A modifications in the regulation of tumorigenesis of ocular melanoma. Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m6 A RNA modification level. Multi-omics assays, including RNA-sequencing, cleavage under targets and tagmentation, single-cell sequencing, methylated RNA immunoprecipitation-sequencing (meRIP-seq), and m6 A individual nucleotide resolution cross-linking and immunoprecipitation-sequencing (miCLIP-seq), were performed to reveal the mechanisms of HDACis on methyltransferase-like 14 (METTL14) and FAT tumor suppressor homolog 4 (FAT4) in ocular melanoma. Quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA-binding protein immunoprecipitation-qPCR, meRIP-seq, miCLIP-seq, and RNA stability assay were adopted to investigate the mechanism by which m6 A levels of FAT4 were affected. First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m6 A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo-histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14, thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4, a tumor suppressor, in a m6 A-YTH N6-methyladenosine RNA-binding protein 1-dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14-mediated m6 A modification in tumorigenesis. These results demonstrate that HDACis exert anti-cancer effects by orchestrating m6 A modification, which unveiling a "histone-RNA crosstalk" of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.


Extraction of the Landau-Migdal Parameter from the Gamow-Teller Giant Resonance in ^{132}Sn.
The key parameter to discuss the possibility of the pion condensation in nuclear matter, i.e., the so-called Landau-Migdal parameter g^{'}, was extracted by measuring the double-differential cross sections for the (p,n) reaction at 216 MeV/u on a neutron-rich doubly magic unstable nucleus, ^{132}Sn with the quality comparable to data taken with stable nuclei. The extracted strengths for Gamow-Teller (GT) transitions from ^{132}Sn leading to ^{132}Sb exhibit the GT giant resonance (GTR) at the excitation energy of 16.3±0.4(stat)±0.4(syst) MeV with the width of Γ=4.7±0.8 MeV. The integrated GT strength up to E_{x}=25 MeV is S_{GT}^{-}=53±5(stat)_{-10}^{+11}(syst), corresponding to 56% of Ikeda's sum rule of 3(N-Z)=96. The present result accurately constrains the Landau-Migdal parameter as g^{'}=0.68±0.07, thanks to the high sensitivity of the GTR energy to g^{'}. In combination with previous studies on the GTR for ^{90}Zr and ^{208}Pb, the result of this work shows the constancy of this parameter in the nuclear chart region with (N-Z)/A=0.11 to 0.24 and A=90 to 208.


Influence of Bio-Based Plasticizers on the Properties of NBR Materials.
A high number of technical elastomer products contain plasticizers for tailoring material properties. Some additives used as plasticizers pose a health risk or have inadequate material properties. Therefore, research is going on in this field to find sustainable alternatives for conventional plasticizers. In this paper, two modified bio-based plasticizers (epoxidized esters of glycerol formal from soybean and canola oil) are of main interest. The study aimed to determine the influence of these sustainable plasticizers on the properties of acrylonitrile-butadiene rubber (NBR). For comparison, the influence of conventional plasticizers, e.g., treated distillate aromatic extract (TDAE) and Mesamoll® were additionally investigated. Two types of NBR with different ratios of monomers formed the polymeric basis of the prepared elastomers. The variation of the monomer ratio results in different polarities, and therefore, compatibility between the NBR and plasticizers should be influenced. The mechanical characteristics were investigated. In parallel, dynamic mechanical analysis (DMA) and thermogravimetric analysis (TGA) were performed and filler macro-dispersion was determined. Bio-based plasticizers were shown to have better mechanical and thermal properties compared to conventional plasticizers. Further, thermo-oxidative aging was realized for 500 h, and afterwards, mechanical characterizations were done. It was observed that bio-based plasticizers have almost the same aging properties compared to conventional plasticizers.


A New Solution Concept for the Ultimatum Game leading to the Golden Ratio.
The Ultimatum Game is a paradigmatic two-player game. A proposer can offer a certain fraction of some valuable good. A responder can accept the offer or reject it, implying that the two players receive nothing. The only subgame-perfect Nash equilibrium is to only offer an infinitesimal amount and to accept this. However, this equilibrium is not in agreement with experimental observations, which show varying accepted offers around 40%. While some authors suggest that the fairest split of 50% vs. 50% would be explainable on theoretical grounds or by computer simulation, a few authors (including myself) have recently suggested that the Golden Ratio, about 0.618 vs. about 0.382, would be the solution, in striking agreement with observations. Here we propose a solution concept, based on an optimality approach and epistemic arguments, leading to that suggested solution. The optimality principle is explained both in an axiomatic way and by bargaining arguments, and the relation to Fibonacci numbers is outlined. Our presentation complements the Economic Harmony theory proposed by R. Suleiman and is based on infinite continued fractions. The results are likely to be important for the theory of fair salaries, justice theory and the predictive value of game theory.


Immunomodulatory properties of dental tissue-derived mesenchymal stem cells.
In addition to their well-established self-renewal and multipotent differentiation properties, mesenchymal stem cells (MSCs) also possess potent immunomodulatory functions both in vitro and in vivo, which render them a potential novel immunotherapeutic tool for a variety of autoimmune and inflammation-related diseases. The major mechanisms may involve (1) the secretion of an array of soluble factors such as prostaglandin E2 (PGE2 ), indoleamine 2, 3-dioxygenase (IDO), transforming growth factor-β (TGF-β), and human leukocyte antigen G5 (HLA-G5); (2) interactions between MSCs and immune cells such as T cells, B cells, macrophages, and dendritic cells. Recently, increasing evidence has supported that MSCs derived from dental tissues are promising alternative sources of multipotent MSCs. We here provide a thorough and extensive review about new findings in the immunomodulatory functions of MSCs derived from several dental tissues, including dental pulp, periodontal ligament, gingiva, exfoliated deciduous teeth, apical papilla, and dental follicle, respectively. The immunomodulatory properties of dental MSCs place them as a more accessible cell source than bone marrow-derived MSCs for cell-based therapy of immune and inflammation-related diseases.


Exon concatenation to increase the efficiency of mutation screening by DGGE.
For genes that have a substantial number of exons and long intronic sequences, mutation screening by denaturing gradient gel electrophoresis (DGGE) requires the amplification of each exon from genomic DNA by PCR. This results in a high number of fragments to be analyzed by DGGE so that the analysis of large sample sets becomes labor intensive and time consuming. To address this problem, we have developed a new strategy for mutation analysis, lexon-DGGE, which combines the joining of different exons by PCR (also known as lexons) with a highly sensitive technique such as DGGE to screen for mutations. The lexon technique is based on the concatenation of several exons, adjacent or not, from genomic DNA into a single DNA fragment so that this approach could simultaneously be used to check the mutational status of several small genes. To show the feasibility of the approach, we have used the lexon-DGGE technique to analyze all coding exons, intron-exon junctions, noncoding exon 1, and part of the noncoding region of exon 11 of the TP53 gene. The validity and performance of the technique were confirmed by using negative and positive controls for each of the DNAfragments analyzed.


Cross-fostering study of methyl mercury retention, demethylation and excretion in the neonatal hamster.
The cross-fostering technique was used in order to compare methyl mercury (MeHg) metabolism in hamsters following prenatal (in utero) and neonatal (lactational) exposure. Pregnant Syrian golden hamsters were administered radiolabeled MeHg on day 12 of gestation. The offspring was nursed by foster mothers unexposed to MeHg, while the pups from the unexposed animals were nursed by the MeHg-administered animals. Under these conditions, each pup in the litter received a dose of MeHg in utero corresponding to 0.9% of the maternal dose. The average amount of mercury found in the pups exposed via milk corresponded to 4.5% of the total body burden of the foster dam at the onset of lactation. This was about half the amount received by the pups exposed in utero. The total body burden of mercury, and the amount of mercury in the liver, brain and kidney of the pups exposed in utero began to decrease at seven days of age. The rate of decrease differed among the tissues and was lowest in the kidney. The amount of mercury in pups exposed via milk reached a peak level when the pups were 10-15 days old. The total body burden of mercury showed a slow decrease while the liver, brain and kidney levels decreased rapidly. In both groups of animals, up to 80% of the total body burden of mercury was found in the pelt. These data show that milk may be a significant exposure route for mercury and that neonatal hamsters are unable to demethylate MeHg and excrete mercury in urine and faeces.


BODIPY-Functionalized Natural Polymer Coatings for Multimodal Therapy of Drug-Resistant Bacterial Infection.
The fact that multidrug resistance (MDR) could induce medical device-related infections, along with the invalidation of traditional antibiotics has become an intractable global medical issue. Therefore, there is a pressing need for innovative strategies of antibacterial functionalization of medical devices. For this purpose, a multimodal antibacterial coating that combines photothermal and photodynamic therapies (PTT/PDT) is developed here based on novel heavy atom-free photosensitizer compound, BDP-6 (a kind of boron-dipyrromethene). The photothermal conversion efficiency of BDP-6 is of 55.9%, which could improve biocompatibility during PTT/PDT process by reducing the exciting light power density. Furthermore, BDP-6, together with oxidized hyaluronic acid, is crosslinked with a natural polymer, gelatin, to fabricate a uniform coating (denoted as polyurethane (PU)-GHB) on the surface of polyurethane. PU-GHB has excellent synergistic in vitro PTT/PDT antibacterial performance against both susceptible bacteria and MDR bacteria. The antibacterial mechanisms are revealed as that hyperthermia could reduce the bacterial activity and enhance the permeability of inner membrane to reactive oxygen species by disturbing cell membrane. Meanwhile, in an infected abdominal wall hernia model, the notable anti-infection performance, good in vivo compatibility, and photoacoustic imaging property of PU-GHB are verified. A promising strategy of developing multifunctional antibacterial coatings on implanted medical devices is provided here.


Synthesis and characterization of novel plasmonic Ag/AgX-CNTs (X = Cl, Br, I) nanocomposite photocatalysts and synergetic degradation of organic pollutant under visible light.
A series of novel well-defined Ag/AgX (X = Cl, Br, I) loaded carbon nanotubes (CNTs) composite photocatalysts (Ag/AgX-CNTs) were fabricated for the first time via a facile ultrasonic assistant deposition-precipitation method at the room temperature (25 ± 1 °C). X-ray diffraction, X-ray photoelectron spectroscopy, nitrogen adsorption-desorption analysis, scanning electron microscopy, and ultraviolet-visible light absorption spectra analysis were used to characterize the structure, morphology, and optical properties of the as-prepared photocatalysts. Results confirmed the existence of the direct interfacial contact between Ag/AgX nanoparticles and CNTs, and Ag/AgX-CNTs nanocomposites exhibit superior absorbance in the visible light (VL) region owing to the surface plasmon resonance (SPR) of Ag nanoparticles. The fabricated composite photocatalysts were employed to remove 2,4,6-tribromophenol (TBP) in aqueous phase. A remarkably enhanced VL photocatalytic degradation efficiency of Ag/AgX-CNTs nanocomposites was observed when compared to that of pure AgX or CNTs. The photocatalytic activity enhancement of Ag/AgX-CNTs was due to the effective electron transfer from photoexcited AgX and plasmon-excited Ag(0) nanoparticles to CNTs. This can effectively decrease the recombination of electron-hole pairs, lead to a prolonged lifetime of the photoholes that promotes the degradation efficiency.


[Chapter 3. Concretely enhancing the role of elderly through capacitating health care].
This paper questions the signification of reinforcing the active role of elderly between societal injunction to feel responsible of the costs to the collectivity and the freedom to choose one's way of life and having the means to realize it. It describes two experiences in two Brussels communes of a model of co-construction with the elderly of a project to live in one's own home, to reinforce the active roles of persons. We want to illustrate the difficulty of such an approach in Belgium, separating the organization and the financing of medical and social care, that does not foster the accompanying and the active role of elderly. The conflict of interest between the different actors is not allowing the proper multidisciplinary approach to empower and allow the maintenance of elderly capability of choice and well being.


CCR7/p-ERK1/2/VEGF signaling promotes retinal neovascularization in a mouse model of oxygen-induced retinopathy.
To investigate the role of CCR7/p-ERK1/2/VEGF signaling in the mouse model of oxygen-induced retinopathy (OIR). Neonatal C57BL/6J mice were evenly randomized into four groups: normoxia, OIR, OIR control (treated with scramble siRNA), and OIR treated (treated with CCR7 siRNA). Normoxia group was not specially handled. Postnatal day 7 (P7) mice in the OIR group were exposed to 75%±5% oxygen for 5d (P7-P12) and then maintained under normoxic conditions for 5d (P12-P17). Mice in the OIR control and OIR treated groups were given injections of scramble or CCR7 siRNA plasmid on P12 before returning to normoxic conditions for 5d (P12-P17). Retina samples were collected from all mice on P17, stained with adenosine diphosphatase (ADPase), and retinal neovascularization (RNV) was assessed. Retinas were also stained with hematoxylin and eosin (H&E) for RNV quantitation. The distribution and expression of CCR7, p-ERK1/2 and vascular endothelial growth factor (VEGF) were assessed via immunohistochemistry, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). High oxygen promoted retinal neovascularization (P<0.05) and increased the number of endothelial nuclei in new vessels extending from the retina to the vitreous body; CCR7 promoted this process (P<0.05). CCR7 and VEGF mRNA were expressed at higher levels in the OIR and OIR control groups than in the normoxia and OIR treated groups. CCR7, p-ERK1/2, and VEGF protein were expressed in the retinas of mice in the OIR and OIR control groups. Intravitreal injection of CCR7 siRNA significantly reduced CCR7, p-ERK1/2, and VEGF expression in the OIR mouse model (all P<0.05). CCR7 significantly enhanced the neovascularization and non-perfusion areas in the OIR group (P<0.05). CCR7 siRNA significantly reduced levels of p-ERK1/2 and VEGF as compared to OIR controls (P<0.05). These results suggest that CCR7/p-ERK 1/2/VEGF signaling plays an important role in OIR. CCR7 may be a potential target for the prevention and treatment of retinopathy of prematurity.


Characterization and expression profile of CaNAC2 pepper gene.
The plant-specific NAC (NAM, ATAF, and CUC) transcription factors have diverse role in development and stress regulation. A new transcript encoding NAC protein, homologous to nam-like protein 4 from Petunia was identified from an ABA-regulated subtractive cDNA library of Capsicum annuum seedling. Here, this homolog (named CaNAC2) from C. annuum was characterized and investigated its role in abiotic stress tolerance. Our results indicated that a plant-specific and conserved NAC domain was located in the N-terminus domain of CaNAC2 which was predicted to encode a polypeptide of 410 amino acids. Phylogenetic analysis showed that CaNAC2 belonged to the NAC2 subgroup of the orthologous group 4d. The protein CaNAC2 was subcellularly localized in the nucleus and it had transcriptional activity in yeast cell. CaNAC2 was expressed mainly in seed and root. The transcription expression of CaNAC2 was strongly induced by cold, salt and ABA treatment and inhibited by osmotic stress and SA treatment. Silence of CaNAC2 in virus-induced gene silenced pepper seedlings resulted in the increased susceptibility to cold stress and delayed the salt-induced leaf chlorophyll degradation. These results indicated that this novel CaNAC2 gene might be involved in pepper response to abiotic stress tolerance.


[The future of medical investigation in Mexico].
The current situation of clinical research in Mexico is analyzed. The main findings are as follows: 10% of total number of researchers in Mexico are engaged in medical research; there is a highly centralized distribution in the Mexico City metropolitan area; there exists unequal academic development among disciplines, and there is an overwhelming number of researchers in public educational and health institutions. A substantial increase in medical publications during the last 15 years with reasonable citation impact was also found. Several urgent matters to attend were identified, such as financing problems, effect of health services descentralization completed in 1997, and the need to selectively support certain research areas such as accidents, mental health, addictions, geriatrics and chronic diseases.


Congenital posterolateral defect in the right side of the diaphragm.
The infant born with a posterolateral defect in the right side of the diaphragm may appear normal at birth. His abdominal viscera may be normally located; the right side of the diaphragm may seem to be intact. Later, part of the liver may herniate. As it does, it displaces the lower part of the right lung, and hepatic flexure follows into a high posterior position in the right upper quadrant of the abdomen. Rarely, obstruction of portal and hepatic venous flow at the hernial ring may cause liquid to accumulate in the right side of the chest. At any time the liver may resume its interrupted passage. Increase in herniation will quickly make the patient sicker.


Adult survival selection in relation to multilocus heterozygosity and body size in a tropical bird species, the Zenaida dove, Zenaida aurita.
Both phenotypic and genetic quality can influence the survival of individuals through time, although their relative influences are rarely addressed simultaneously. Here we used capture-mark-recapture modelling to assess the influence of both multilocus heterozygosity (MLH) and body size on apparent adult survival in a tropical bird species, the Zenaida dove, Zenaida aurita, using a sample of 391 individuals genotyped at 11 microsatellites, while controlling for the effects of sex. No effect of body size on either adult survival or capture rate was found. In the best model, survival was a logit linear function of MLH, whereas detection probability was a sex-dependent logit linear function of the logarithm of field effort, increasing with time and affected by a random individual effect. Using a Bayesian approach, we found that MLH explained 1.14% of the total deviance, as expected from theory and previous studies of heterozygosity-fitness correlations, with no evidence for local effects. However, results from capture-mark-recapture modelling indicated that expected longevity varied from 4.8 years in the least heterozygous individuals (MLH = 0.37) to 10.6 years in the most heterozygous ones (MLH = 1), thus suggesting that MLH had potentially a substantial effect on survival. We discuss our results in relation to current hypotheses about the origin of heterozygosity-fitness correlations.


Lamotrigine Drug Interactions in Combination Therapy and the Influence of Therapeutic Drug Monitoring on Clinical Outcomes of Adult Patients.
The aim was to study the impact of therapeutic drug monitoring (TDM) on patients on lamotrigine (LTG) therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001-2014, 3118 predose samples were taken from 1137 patients >15 years of age as part of their routine TDM. Drug interactions were evaluated using calculation of LTG clearance (CL). Valproic acid (VPA) decreased LTG CL by 66% in bitherapy, and by 35% and 31% in triple therapy with carbamazepine (CBZ) and phenytoin (PHT), respectively. CBZ and PHT increased LTG CL by 52% and 96% in respective bitherapies but by 88% in triple therapy. Clonazepam, levetiracetam, and topiramate had no effect. The LTG therapeutic range (TR) was exceeded in 1% of cases in monotherapy, and in 4%-5% of cases in combination therapy. Only 54% of results were within the TR during 2001-2005, whereas 60%-62% were within the TR during 2006-2014. Adverse drug reactions (ADRs) were reported in 88 cases and occurred more frequently during TR during 2001-2005. Higher number of supratherapeutic levels in combination therapy led to a 3-fold higher incidence of ADR and poorer seizure control, as seizures occurred more often monthly (2.5%) or a few per year (41%) and fewer patients were seizure free (18%). Seizures occurred more often daily and monthly during the first period and in patients with 3 or 4 drugs in combination. A significantly higher number of supratherapeutic levels were found in combinations with VPA, despite lower doses of LTG. Hepatic enzyme inducers, such as CBZ and PHT only partially compensated for the inhibitory effect of VPA. Decrease of both the frequency of seizures and the incidence of ADRs after TDM implementation suggests that TDM may have given clinicians the opportunity to achieve more optimal patient treatment.


LIGO and the opening of a unique observational window on the universe.
A unique window on the universe opened on September 14, 2015, with direct detection of gravitational waves by the Advanced Laser Interferometer Gravitational-Wave Observatory (LIGO) detectors. This event culminated a half-century effort around the globe to develop terrestrial detectors of adequate sensitivity to achieve this goal. It also happened appropriately only a few months before the centennial of Einstein's final paper introducing the general theory of relativity. This detection provided the surprising discovery of a coalescing pair of "heavy" black holes (more massive than [Formula: see text] M[Formula: see text]) leading to the formation of a spinning [Formula: see text]62 solar mass black hole. One more binary black-hole detection and a significant candidate event demonstrated that a population of such merging binaries is formed in nature with a broad mass spectrum. This unique observational sample has already provided concrete measurements on the coalescence rates and has allowed us to test the theory of general relativity in the strong-field regime. As this nascent field of gravitational-wave astrophysics is emerging we are looking forward to the detection of binary mergers involving neutron stars and their electromagnetic counterparts, as well as continuous-wave sources, supernovae, a stochastic confusion background of compact-object mergers, known sources detected in unexpected ways, and completely unknown sources.


The liquid<−>amorphous transition and the high pressure phase diagram of carbon.
The phase diagram of carbon is mapped to high pressure using a computationally-tractable potential model. The use of a relatively simple (Tersoff-II) potential model allows a large range of phase space to be explored. The coexistence (melting) curve for the diamond crystal/liquid dyad is mapped directly by modelling the solid/liquid interfaces. The melting curve is found to be re-entrant and belongs to a conformal class of diamond/liquid coexistence curves. On supercooling the liquid a phase transition to a tetrahedral amorphous form (ta-C) is observed. The liquid <−> amorphous coexistence curve is mapped onto the pT plane and is found to also be re-entrant. The entropy changes for both melting and the amorphous −> liquid transitions are obtained from the respective coexistence curves and the associated changes in molar volume. The structural change on amorphization is analysed at different points on the coexistence curve including for transitions that are both isochoric and isocoordinate (no change in nearest-neighbour coordination number). The conformal nature of the melting curve is highlighted with respect to the known behaviour of Si. The relationship of the observed liquid/amorphous coexistence curve to the Si low- and high-density amorphous (LDA/HDA) transition is discussed.


Suppression of nociceptive responses by spinal mu opioid agonists: effects of stimulus intensity and agonist efficacy.
To determine the influence of stimulation intensity on dose-response curves of three analgesics in halothane-anesthetized rats, continued immersion of the tail in 52.5 degrees C or 60 degrees C water for 15 s results first in a nociceptive reflex tail movement (tail flick = 2.8 +/- 0.4 s and 1.4 +/- 0.2 s, respectively), and a progressive increase in arterial blood pressure (delta BP = 21 +/- 1 and 24 +/- 1 mm Hg) and heart rate (delta HR = 27 +/- 2 and 32 +/- 2 beats/min). Intrathecally administered mu opioids, morphine (MOR), sufentanil (SUF), and [D-Ala2-N-Phe4,Gly-ol]-enkephalin (DAG), produced a dose-dependent inhibition of the tail flick and BP response with the relative activity being SUF = DAG > MOR. Although the magnitude of the response evoked by increasing stimulus intensity from 52.5 degrees C to 60 degrees C was increased only mildly (suggesting that both represented essentially supramaximal stimuli), this increase in stimulus intensity resulted in a significant rightward shift in the dose-response curves (decrease in apparent potency) of the three agonists, with the magnitude of the shift being MOR > SUF = DAG. Thus, the dose ratio (ED50 at 60 degrees C/ED50 at 52.5 degrees C) for these three analgesics given intrathecally on the tail flick and BP response was, respectively, 3.7 +/- 0.9 and 6500 +/- 465 for MOR; 0.5 +/- 0.9 and 2.4 +/- 0.9 for SUF; and 0.5 +/- 1.2 and 7.0 +/- 0.9 for DAG. Unlike SUF and DAG, with the 60 degrees C stimulus, the highest dose of MOR failed to abolish the BP and heart rate response. Previous work with an irreversible antagonist to define receptor occupancy requirements showed that the relative efficacy was SUF = DAG >> MOR. The present studies thus confirm the pharmacodynamically based prediction that for a given change in stimulus intensity, anesthetics with a high efficacy (DAG and SUF) show less shift in their dose response curves with a given increase in stimulus intensity than an agonist with low efficacy (MOR).