The Incidence of Catheter Tract Hemorrhage and Catheter Placement Accuracy in the CLEAR III Trial.
Incidence of catheter tract hemorrhage (CTH) after initial ventriculostomy placement ranges from 10 to 34%. We investigated CTH incidence in the Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III trial. Prospective observational analysis of 1000 computer tomography (CT) scans from all 500 patients enrolled in the trial. All catheters were evaluated on first CT post-placement and on last CT prior to randomization for placement location and CTH size, location, and severity. Clinical variables were assessed for association with CTH with multivariable logistic regression. Of 563 catheters, CTH was detected in 14 and 21% of patients on first and last CT (median 3.7 and 43.4 h after catheter placement, respectively). All, but one were asymptomatic. Majority of CTH (86%) occurred within 24 h after placement, were located within 1 cm of the skull, and had at least one diameter > 5 mm. Most catheters (71%) terminated in the third or lateral ventricle ipsilateral to insertion site. Factors significantly associated with CTH were pre-admission use of antiplatelet drugs, accuracy of catheter placement, non-operating room catheter placement, Asian race, and intraventricular hemorrhage expansion. CTH incidence on initial catheter placement and during stabilization was relatively low, despite emergent placement in a high-risk population. Catheter placement accuracy was similar or better than convenience samples from the published literature. Decreasing risk of CTH may be achieved with attention to catheter placement accuracy and placement in the operating room. Antiplatelet agent use was an independent risk factor for CTH.


Histological and immunohistochemical features in fatal acute fulminant hepatitis E.
Hepatitis E is being increasingly recognized as an emerging infection in developed countries. Data on histological findings and nature of inflammatory cell infiltrate in liver in this disease are quite sparse. This study was planned to study the histological features and the type of inflammatory infiltrate in liver biopsies of patients with acute fulminant hepatitis E. We retrieved postmortem liver biopsies of 11 Indian patients with fulminant hepatitis E, and compared these with biopsies from seven patients with fulminant hepatitis B. Biopsies from acute fulminant hepatitis E showed varying degrees of hepatocyte necrosis, mixed portal and lobular inflammation, accompanied by bile ductular proliferation, lymphocytic cholangitis, Kupffer cell prominence, cholestasis, apoptotic bodies, pseudo-rosette formation, steatosis, and presence of plasma cells in portal tracts. Interface hepatitis was more frequent in acute hepatitis B than in acute hepatitis E (100% vs 20%; P<0.05). These findings differ from those reported in cases with autochthonous hepatitis E in Europe. On immunohistochemistry, lymphocyte infiltrate consisted predominantly of CD3 + T cells in both hepatitis E and hepatitis B; these cells contained a predominant cytotoxic (CD8 + ) cell subpopulation in 81.8% of cases with hepatitis E and in 50% of cases with hepatitis B. Our findings suggest that histological changes in HEV infection may vary with geographical location because of prevalent HEV genotypes, and that CD8 + lymphocytes play a role in HEV-induced liver injury.


Allyl isothiocyanate ameliorates lipid accumulation and inflammation in nonalcoholic fatty liver disease via the Sirt1/AMPK and NF-κB signaling pathways.
Allyl isothiocyanate (AITC), a classic anti-inflammatory and antitumorigenic agent, was recently identified as a potential treatment for obesity and insulin resistance. However, little is known about its direct impact on the liver. To investigate the effect and underlying mechanism of AITC in nonalcoholic fatty liver disease (commonly referred to as NAFLD). To establish a mouse and cellular model of NAFLD, C57BL/6 mice were fed a high fat diet (HFD) for 8 wk, and AML-12 cells were treated with 200 μM palmitate acid for 24 h. For AITC treatment, mice were administered AITC (100 mg/kg/d) orally and AML-12 cells were treated with AITC (20 μmol/L). AITC significantly ameliorated HFD-induced weight gain, hepatic lipid accumulation and inflammation in vivo. Furthermore, serum alanine aminotransferase and aspartate aminotransferase levels were markedly reduced in AITC-treated mice. Mechanistically, AITC significantly downregulated the protein levels of sterol regulatory element-binding protein 1 (SREBP1) and its lipogenesis target genes and upregulated the levels of proteins involved in fatty acid β-oxidation, as well as the upstream mediators Sirtuin 1 (Sirt1) and AMP-activated protein kinase α (AMPKα), in the livers of HFD-fed mice. AITC also attenuated the nuclear factor kappa B (NF-κB) signaling pathway. Consistently, AITC relieved palmitate acid-induced lipid accumulation and inflammation in AML-12 cells in vitro through the Sirt1/AMPK and NF-κB signaling pathways. Importantly, further studies showed that the curative effect of AITC on lipid accumulation was abolished by siRNA-mediated knockdown of either Sirt1 or AMPKα in AML-12 cells. AITC significantly ameliorates hepatic steatosis and inflammation by activating the Sirt1/AMPK pathway and inhibiting the NF-κB pathway. Therefore, AITC is a potential therapeutic agent for NAFLD.


Non-genomic mechanisms of progesterone action in the brain.
Progesterone is a gonadal steroid hormone whose physiological effects extend well beyond the strict confines of reproductive function. In fact, progesterone can have important effects on a variety of tissues, including the bone, the heart and the brain. Mechanistically, progesterone has been thought to exert its effects through the progesterone receptor (PR), a member of the nuclear steroid hormone superfamily, and as such, acts through specific progesterone response elements (PRE) within the promoter region of target genes to regulate transcription of such genes. This has been often described as the "genomic" mechanism of progesterone action. However, just as progesterone has a diverse range of tissue targets, the mechanisms through which progesterone elicits its effects are equally diverse. For example, progesterone can activate alternative receptors, such as membrane-associated PRs (distinct from the classical PR), to elicit the activation of several signaling pathways that in turn, can influence cell function. Here, we review various non-nuclear (i.e., non-genomic) signaling mechanisms that progesterone can recruit to elicit its effects, focusing our discussion primarily on those signaling mechanisms by which progesterone influences cell viability in the brain.


Trajectories of Recovery Among Formerly Homeless Adults With Serious Mental Illness.
Recovery from mental illness is possible, but individuals with co-occurring disorders and homelessness face challenges. Although a nonlinear recovery course is assumed, few studies have analyzed recovery over time. This mixed-methods study examined recovery trajectories over 18 months after enrollment in supportive housing programs of 38 participants with DSM axis I diagnoses. Qualitative interview data were quantified through consensual ratings to generate a recovery score for four waves of data collection based on eight recovery domains culled from the literature. Case study analyses were conducted of participants whose scores varied by one standard deviation or more between baseline and 18 months to identify which domains were important. Most of the 38 participants (N=23) had no significant change in recovery; seven had a negative trajectory, and eight had a positive trajectory. Case studies of these 15 participants indicated domains that contributed to change: significant-other relationships (N=9), engagement in meaningful activities (N=9), mental health (N=7), family relationships (N=6), general medical health (N=5), housing satisfaction (N=5), employment (N=2), and substance use (N=1). Except for mental health and substance use (which contributed only to negative trajectories), the influence of domains was both positive and negative. Domains were intertwined; for example, variation in relationships was linked to changes in meaningful activities. This study showed little change in recovery over time for most participants and a decline in mental health for a small minority. Findings underscore the importance of social relationships and meaningful activities among individuals with serious mental illness, who experience complex challenges.


Prevention of hypertension and diabetes in an urban setting in South Africa: participatory action research with community health workers.
The project aimed to identify factors that contribute to hypertension and diabetes and to design and implement appropriate local interventions to prevent these noncommunicable diseases and promote healthy lifestyles. This was a community-based participatory action research project in which researchers and community health workers (CHWs) were the main participants. The triple A approach to planning interventions was used, that is, the process of assessing the situation, analyzing the findings, and taking action based on this analysis. Both qualitative and quantitative methods were employed. Twenty-two CHWs working in site C, Khayelitsha, a deprived urban area of Cape Town, South Africa, participated in the study. Findings from the situational assessment indicated a lack of knowledge among CHWs and the community about hypertension and diabetes and the risk factors for these non-communicable diseases. Economic constraints and cultural beliefs and practices influenced the community's food choices and participation in physical activity. On the basis of these findings, a training program was proposed that would provide CHWs with the skills to prevent hypertension and diabetes in their community. A program was developed and piloted by the project team. A health club that focuses on promoting healthy lifestyles is currently being piloted. This paper illustrates the unique involvement of CHWs in a successful participatory action research project on the prevention of hypertension and diabetes and promotion of health in a deprived urban setting. The project emphasizes the importance of involving local people in community-based initiatives to promote health and identifies that the primary role of health services is to develop appropriate skills in the local community, monitor activities, and facilitate a link with primary health services.


Co-regulation of metabolic genes is better explained by flux coupling than by network distance.
To what extent can modes of gene regulation be explained by systems-level properties of metabolic networks? Prior studies on co-regulation of metabolic genes have mainly focused on graph-theoretical features of metabolic networks and demonstrated a decreasing level of co-expression with increasing network distance, a naïve, but widely used, topological index. Others have suggested that static graph representations can poorly capture dynamic functional associations, e.g., in the form of dependence of metabolic fluxes across genes in the network. Here, we systematically tested the relative importance of metabolic flux coupling and network position on gene co-regulation, using a genome-scale metabolic model of Escherichia coli. After validating the computational method with empirical data on flux correlations, we confirm that genes coupled by their enzymatic fluxes not only show similar expression patterns, but also share transcriptional regulators and frequently reside in the same operon. In contrast, we demonstrate that network distance per se has relatively minor influence on gene co-regulation. Moreover, the type of flux coupling can explain refined properties of the regulatory network that are ignored by simple graph-theoretical indices. Our results underline the importance of studying functional states of cellular networks to define physiologically relevant associations between genes and should stimulate future developments of novel functional genomic tools.


Molecularly Imprinted Filtering Adsorbents for Odor Sensing.
Versatile odor sensors that can discriminate among huge numbers of environmental odorants are desired in many fields, including robotics, environmental monitoring, and food production. However, odor sensors comparable to an animal's nose have not yet been developed. An animal's olfactory system recognizes odor clusters with specific molecular properties and uses this combinatorial information in odor discrimination. This suggests that measurement and clustering of odor molecular properties (e.g., polarity, size) using an artificial sensor is a promising approach to odor sensing. Here, adsorbents composed of composite materials with molecular recognition properties were developed for odor sensing. The selectivity of the sensor depends on the adsorbent materials, so specific polymeric materials with particular solubility parameters were chosen to adsorb odorants with various properties. The adsorption properties of the adsorbents could be modified by mixing adsorbent materials. Moreover, a novel molecularly imprinted filtering adsorbent (MIFA), composed of an adsorbent substrate covered with a molecularly imprinted polymer (MIP) layer, was developed to improve the odor molecular recognition ability. The combination of the adsorbent and MIP layer provided a higher specificity toward target molecules. The MIFA thus provides a useful technique for the design and control of adsorbents with adsorption properties specific to particular odor molecules.


Lipid oxidation and improving the oxidative stability.
Lipids are a major component of food and important structural and functional constituents of cells in biological systems. However, this diverse group of substances is prone to oxidation through various pathways. Their oxidative stability depends on a number of intrinsic and extrinsic factors, including the unsaturation of their fatty acids, composition of minor components, environment conditions, delivery techniques and use of antioxidants, among others. Lipid oxidation has detrimental effects on both food quality and human health, and efforts must be made to minimize oxidation and improve oxidative stability of lipid products. Antioxidant strategy has been successfully employed in the food industry for quality preservation of the food products and in the medicinal industry for risk reduction of numerous oxidative stress-mediated diseases. This tutorial review will provide important knowledge about lipid oxidation, including the mechanism and factors involved in oxidation, as well as strategies for improving oxidative stability of lipids.


Efficient method for launching in-gap solitons in fiber Bragg gratings using a two-segment apodization profile.
We theoretically demonstrate what is a new method for efficient launching of in-gap solitons in fiber Bragg gratings. The method is based on generating a soliton outside the grating bandgap. Then, the soliton is adiabatically coupled into the bandgap by using its particlelike behavior. We compare our method to a previously published launching scheme that is based on generating the soliton directly within the grating bandgap. When using low-intensity incident pulses, the transmission efficiency of our method is three times higher than that of the previously published scheme.


An artificial regulatory circuit for stable expression of DNA-binding proteins in a T7 expression system.
We had earlier overproduced the transcription activator protein C of bacteriophage Mu in a phage-T7 expression system. Although we achieved a high level of overproduction, the expression was not consistent. This could be due to the leaky expression of T7 RNA polymerase in the uninduced state. Introduction of pLysS, a plasmid encoding T7 lysozyme, a natural inhibitor of T7 RNA polymerase, resulted in consistent, but extremely low production of the C protein. To overcome this problem, we have devised an artificial regulatory circuit to obtain stabilised, consistent overproduction of C protein. The C-binding site was cloned downstream from the transcription start point of T7 lys. Upon induction, the C protein produced binds to its site with a very high affinity, possibly acting as a transcriptional roadblock for lys. This would overcome the inhibitory effect of T7 lysozyme on T7 RNA polymerase.


Alterations in high-density lipoprotein subfractions during postprandial lipidaemia induced by fat with and without ethanol.
1. Serum lipid and apolipoprotein levels, distribution and composition of high-density lipoprotein (HDL) subfractions and lecithin:cholesterol acryltransferase activity were analysed in nine normolipidaemic subjects, in whom a hypertriglyceridaemic state was induced by the acute administration of ethanol (40 g) plus fat (70 g) or of fat only. 2. Triglyceride (TG) levels increased by 180% 4-6 h after fat plus ethanol intake, the hypertriglyceridaemic response being inversely correlated with the basal HDL2 mass (r = -0.82). Serum apolipoprotein (apo) B levels rose by 8%, HDL-cholesterol decreased by 10% and HDL-TG increased by 57% at 6-8 h. 3. When ethanol was omitted, serum cholesterol and TG rose by 6% and 70%, respectively; both apo AI and apo B levels went up by 8%, whereas HDL-cholesterol rose progressively (15%) at 12 h. 4. The flotation rates of both HDL2 and HDL3 increased, reaching a maximum 6-8 h after ethanol plus fat intake. These changes were due to an increase in TG and phospholipid contents, whereas cholesteryl esters and proteins decreased. 5. The alterations in HDL are attributable to the increase in TG-rich lipoproteins, to the stimulated cholesterol esterification (+15%) and to an enhanced transfer of newly formed cholesteryl esters to apo-B-containing lipoproteins in exchange for TG. 6. Changes in HDL properties were evident only when ethanol was given concomitantly with fat. 7. These findings suggest that in the postprandial phase lipoprotein changes may occur, which facilitate an improved removal of cholesterol from tissues.


Electrode material studies and cell voltage characteristics of the in situ water electrolysis performed in a pH-neutral electrolyte in bioelectrochemical systems.
Hydrogen-oxidizing bacteria (HOB) have been shown to be promising micro-organisms for the reduction of carbon dioxide to a wide range of value-added products in bioelectrochemical systems with in situ water electrolysis of the cultivation medium, also known as a hybrid biological-inorganic systems (HBI). However, scaling up of this process requires overcoming the inherent constraints of the low energy efficiency partly associated with the pH-neutral electrolyte with low conductivity. Most of the research in the field is concentrated on the bacterial cultivation, whereas the analysis and evaluation of the electrode material performance have received little attention in the literature so far. Therefore, in the present work, in situ electrolysis of a pH-neutral medium for HOB cultivation was performed with different combinations of electrode materials. Besides conventional electrode types, electrodes with coatings made of earth-abundant cobalt and a nickel-iron alloy, known for their catalytic activity for the kinetically sluggish oxygen evolution reaction (OER), were prepared and tested as potential substitutes for catalysts made of precious metals. The cultivation of HOB with in situ water electrolysis has been successfully tested in a small scale electrobioreactor in order to support the experimental results. A simplified water electrolysis model was developed and applied to evaluate the current-voltage characteristics of an bioelectrochemical system prototype. Application of the developed model allows quantitative evaluation and comparison of reversible, ohmic, and activation overvoltages of different electrode sets. The modeling results were found to agree well with the experimental data. The developed model and the data gathered can be applied to further investigation, simulation, and optimization of HBI systems.


Microwave quantum logic gates for trapped ions.
Control over physical systems at the quantum level is important in fields as diverse as metrology, information processing, simulation and chemistry. For trapped atomic ions, the quantized motional and internal degrees of freedom can be coherently manipulated with laser light. Similar control is difficult to achieve with radio-frequency or microwave radiation: the essential coupling between internal degrees of freedom and motion requires significant field changes over the extent of the atoms' motion, but such changes are negligible at these frequencies for freely propagating fields. An exception is in the near field of microwave currents in structures smaller than the free-space wavelength, where stronger gradients can be generated. Here we first manipulate coherently (on timescales of 20 nanoseconds) the internal quantum states of ions held in a microfabricated trap. The controlling magnetic fields are generated by microwave currents in electrodes that are integrated into the trap structure. We also generate entanglement between the internal degrees of freedom of two atoms with a gate operation suitable for general quantum computation; the entangled state has a fidelity of 0.76(3), where the uncertainty denotes standard error of the mean. Our approach, which involves integrating the quantum control mechanism into the trapping device in a scalable manner, could be applied to quantum information processing, simulation and spectroscopy.


Acquisition of resistance to androgen deprivation therapy in salivary duct carcinoma: A case report.
Salivary duct carcinoma is a relatively rare salivary cancer, and most cases are androgen receptor -positive. Salivary duct carcinoma growth is suggested to be androgen dependent, which can reportedly be controlled by androgen deprivation therapy. However, the effectiveness and underlying molecular mechanisms of androgen deprivation therapy for salivary duct carcinoma remain unknown. We report a salivary duct carcinoma case (65-year-old man) arising from the parotid gland with metastasis to the neck lymph nodes and lungs. Androgen deprivation therapy was performed according to the same protocol for prostate cancer treatment. Expression levels of androgen receptor and FOXA1 (forkhead box A1) were immunohistochemically analyzed before and after androgen deprivation therapy. Although the tumor volume was partially diminished during the first 3 months, acquired resistance to androgen deprivation therapy occurred. FOXA1 was not detected in parotid gland after androgen deprivation therapy, whereas androgen receptor expression was positive. FOXA1 expression might be related to acquired androgen deprivation therapy resistance in salivary duct carcinoma.


Predicted Loop Regions Promote Aggregation: A Study of Amyloidogenic Domains in the Functional Amyloid FapC.
Protein fibrillation is traditionally associated with misfolding, loss of functional phenotype, and gain of toxicity in neurodegenerative diseases. However, many organisms exploit fibrils in the form of functional amyloids (FA), as seen in bacteria, such as E. coli, Salmonella, Bacillus, and Pseudomonas. Here, we provide structural information and mechanistic data for fibrillation of the smallest amyloidogenic truncation unit along with the full-length version (FL) of the major amyloid protein FapC from Pseudomonas, predicted to consist of three β-hairpin-forming imperfect repeats separated by disordered regions. Using a series of truncation mutants, we establish that the putative loops (linkers) increase the rate of aggregation. The minimal aggregation unit consisting of a single repeat with flanking disordered regions (R3C) aggregates in a pathway dominated by secondary nucleation, in contrast to the primary nucleation favored by full-length (FL) FapC. SAXS on FapC FL, R3C, and remaining truncation constructs resolves two major coexisting species in the fibrillation process, namely pre-fibrillar loosely aggregated monomers, and cylindrical, elliptical cross-section fibrils. Solid-state NMR spectra identified rigid parts of the FapC fibril. We assigned Cα-Cβ chemical shifts, indicative of a predominant β-sheet topology with some α-helix or loop chemical shifts. Our work emphasizes the complex nature of FapC fibrillation. In addition, we are able to deduce the importance of non-repeat regions (i.e., predicted loops), which enhance the amyloid protein aggregation and their influence on the polymorphism of the fibril architecture.


In medio stat virtus: unanticipated consequences of telomere dysequilibrium.
The integrity of chromosome ends, or telomeres, depends on myriad processes that must balance the need to compact and protect the telomeric, G-rich DNA from detection as a double-stranded DNA break, and yet still permit access to enzymes that process, replicate and maintain a sufficient reserve of telomeric DNA. When unable to maintain this equilibrium, erosion of telomeres leads to perturbations at or near the telomeres themselves, including loss of binding by the telomere protective complex, shelterin, and alterations in transcription and post-translational modifications of histones. Although the catastrophic consequences of full telomere de-protection are well described, recent evidence points to other, less obvious perturbations that arise when telomere length equilibrium is altered. For example, critically short telomeres also perturb DNA methylation and histone post-translational modifications at distal sites throughout the genome. In murine stem cells for example, this dysregulated chromatin leads to inappropriate suppression of pluripotency regulator factors such as Nanog This review summarizes these recent findings, with an emphasis on how these genome-wide, telomere-induced perturbations can have profound consequences on cell function and fate.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.


Evaluation of anti-inflammatory activity and fast UHPLC-DAD-IT-TOF profiling of polyphenolic compounds extracted from green lettuce (Lactuca sativa L.; var. Maravilla de Verano).
Fresh cut vegetables represent a widely consumed food worldwide. Among these, lettuce (Lactuca sativa L.) is one of the most popular on the market. The growing interest for this "healthy" food is related to the content of bioactive compounds, especially polyphenols, that show many beneficial effects. In this study, we report the anti-inflammatory and antioxidant potential of polyphenols extracted from lettuce (var. Maravilla de Verano), in J774A.1 macrophages stimulated with Escherichia coli lipopolysaccharide (LPS). Lettuce extract significantly decreased reactive oxygen species, nitric oxide release, inducible nitric oxide synthase and cycloxygenase-2 expression. A detailed quali/quantitative profiling of the polyphenolic content was carried out, obtaining fast separation (10 min), good retention time and peak area repeatability, (RSD% 0.80 and 8.68, respectively) as well as linearity (R(2)⩾ 0.999) and mass accuracy (⩽ 5 ppm). Our results show the importance in the diet of this cheap and popular food for his healthy properties.


Association of a common genetic variant within ANKK1 with six-month cognitive performance after traumatic brain injury.
Genetic association analyses suggest that certain common single nucleotide polymorphisms (SNPs) may adversely impact recovery from traumatic brain injury (TBI). Delineating their causal relationship may aid in development of novel interventions and in identifying patients likely to respond to targeted therapies. We examined the influence of the (C/T) SNP rs1800497 of ANKK1 on post-TBI outcome using data from two prospective multicenter studies: the Citicoline Brain Injury Treatment (COBRIT) trial and Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot). We included patients with ANKK1 genotyping results and cognitive outcomes at six months post-TBI (n = 492: COBRIT n = 272, TRACK-TBI Pilot n = 220). Using the California Verbal Learning Test Second Edition (CVLT-II) Trial 1-5 Standard Score, we found a dose-dependent effect for the T allele, with T/T homozygotes scoring lowest on the CVLT-II Trial 1-5 Standard Score (T/T 45.1, C/T 51.1, C/C 52.1, ANOVA, p = 0.008). Post hoc testing with multiple comparison-correction indicated that T/T patients performed significantly worse than C/T and C/C patients. Similar effects were observed in a test of non-verbal processing (Wechsler Adult Intelligence Scale, Processing Speed Index). Our findings extend those of previous studies reporting a negative relationship of the ANKK1 T allele with cognitive performance after TBI. In this study, we demonstrate the value of pooling shared clinical, biomarker, and outcome variables from two large datasets applying the NIH TBI Common Data Elements. The results have implications for future multicenter investigations to further elucidate the role of ANKK1 in post-TBI outcome.


Small molecule-protein interactions in branch migration thermodynamics: modelling and application in the homogeneous detection of proteins and small molecules.
We have disclosed the unique inhibition effect of small molecule-protein interactions toward the DNA branch migration process and constructed a complete thermodynamic model for it. The disclosed effect was further coupled with the steric hindrance effect to establish a homogeneous assay for proteins and small molecules with ultra-high inhibition factors and sensitivity.


Novel p47(phox)-related organizers regulate localized NADPH oxidase 1 (Nox1) activity.
The mechanisms that determine localized formation of reactive oxygen species (ROS) through NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase (Nox) family members in nonphagocytic cells are unknown. We show that the c-Src substrate proteins Tks4 (tyrosine kinase substrate with four SH3 domains) and Tks5 are functional members of a p47(phox)-related organizer superfamily. Tks proteins selectively support Nox1 and Nox3 (and not Nox2 and Nox4) activity in reconstituted cellular systems and interact with the NoxA1 activator protein through an Src homology 3 domain-mediated interaction. Endogenous Tks4 is required for Rac guanosine triphosphatase- and Nox1-dependent ROS production by DLD1 colon cancer cells. Our results are consistent with the Tks-mediated recruitment of Nox1 to invadopodia that form in DLD1 cells in a Tks- and Nox-dependent fashion. We propose that Tks organizers represent previously unrecognized members of an organizer superfamily that link Nox to localized ROS formation.


Sudden cardiac death in low-resource settings: lessons from a resuscitated cardiac arrest.
We report on the case of an adult black African who was resuscitated from several cardiac arrests but suffered behavioural impairment, and discuss diagnostic pitfalls. The aetiology of coronary free lesion myocardial infarction with depressed left ventricular function was diagnosed when the patient travelled abroad. The low prevalence of recognised sudden cardiac arrest (SCA), as well as the lack of diagnostic and appropriate resuscitation facilities in parts of sub-Saharan Africa lead to the mismanagement of victims. Increased awareness of SCA and its causes is urgently needed.


Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters.
Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients.


Slowly adapting mechanoreceptors in the borders of the human fingernail encode fingertip forces.
There are clusters of slowly adapting (SA) mechanoreceptors in the skin folds bordering the nail. These "SA-IInail" afferents, which constitute nearly one fifth of the tactile afferents innervating the fingertip, possess the general discharge characteristics of slowly adapting type II (SA-II) tactile afferents located elsewhere in the glabrous skin of the human hand. Little is known about the signals in the SA-IInail afferents when the fingertips interact with objects. Here we show that SA-IInail afferents reliably respond to fingertip forces comparable to those arising in everyday manipulations. Using a flat stimulus surface, we applied forces to the finger pad while recording impulse activity in 17 SA-IInail afferents. Ramp-and-hold forces (amplitude 4 N, rate 10 N/s) were applied normal to the skin, and at 10, 20, or 30 degrees from the normal in eight radial directions with reference to the primary site of contact (25 force directions in total). All afferents responded to the force stimuli, and the responsiveness of all but one afferents was broadly tuned to a preferred direction of force. The preferred directions among afferents were distributed all around the angular space, suggesting that the population of SA-IInail afferents could encode force direction. We conclude that signals in the population of SA-IInail afferents terminating in the nail walls contain vectorial information about fingertip forces. The particular tactile features of contacted surfaces would less influence force-related signals in SA-IInail afferents than force-related signals present in afferents terminating in the volar skin areas that directly contact objects.


Novel haloarchaeal viruses from Lake Retba infecting Haloferax and Halorubrum species.
The diversity of archaeal viruses is severely undersampled compared with that of viruses infecting bacteria and eukaryotes, limiting our understanding on their evolution and environmental impacts. Here, we describe the isolation and characterization of four new viruses infecting halophilic archaea from the saline Lake Retba, located close to Dakar on the coast of Senegal. Three of the viruses, HRPV10, HRPV11 and HRPV12, have enveloped pleomorphic virions and should belong to the family Pleolipoviridae, whereas the forth virus, HFTV1, has an icosahedral capsid and a long non-contractile tail, typical of bacterial and archaeal members of the order Caudovirales. Comparative genomic and phylogenomic analyses place HRPV10, HRPV11 and HRPV12 into the genus Betapleolipovirus, whereas HFTV1 appears to be most closely related to the unclassified Halorubrum virus HRTV-4. Differently from HRTV-4, HFTV1 encodes host-derived minichromosome maintenance helicase and PCNA homologues, which are likely to orchestrate its genome replication. HFTV1, the first archaeal virus isolated on a Haloferax strain, could also infect Halorubrum sp., albeit with an eightfold lower efficiency, whereas pleolipoviruses nearly exclusively infected autochthonous Halorubrum strains. Mapping of the metagenomic sequences from this environment to the genomes of isolated haloarchaeal viruses showed that these known viruses are underrepresented in the available viromes.


Antibiotic resistance mechanisms inform discovery: identification and characterization of a novel amycolatopsis strain producing ristocetin.
Discovering new antibiotics is a major scientific challenge, made increasingly urgent by the continued development of resistance in bacterial pathogens. A fundamental understanding of the mechanisms of bacterial antibiotic resistance will be vital for the future discovery or design of new, more effective antibiotics. We have exploited our intimate knowledge of the molecular mechanism of glycopeptide antibiotic resistance in the harmless bacterium Streptomyces coelicolor to develop a new two-step cell wall bioactivity screen, which efficiently identified a new actinomycete strain containing a previously uncharacterized glycopeptide biosynthetic gene cluster. The screen first identifies natural product extracts capable of triggering a generalized cell wall stress response and then specifically selects for glycopeptide antibacterials by assaying for the induction of glycopeptide resistance genes. In this study, we established a diverse natural product extract library from actinomycete strains isolated from locations with widely varying climates and ecologies, and we screened them using the novel two-step bioassay system. The bioassay ultimately identified a single strain harboring the previously unidentified biosynthetic gene cluster for the glycopeptide ristocetin, providing a proof of principle for the effectiveness of the screen. This is the first report of the ristocetin biosynthetic gene cluster, which is predicted to include some interesting and previously uncharacterized enzymes. By focusing on screening libraries of microbial extracts, this strategy provides the certainty that identified producer strains are competent for growth and biosynthesis of the detected glycopeptide under laboratory conditions.


Recurrent myocardial infarctions secondary to luetic coronary arteritis in hypertrophic cardiomyopathy. A case report.
A 43-year-old coloured man had no risk factors for atheromatous coronary artery disease but suffered two acute myocardial infarctions (MIs) in rapid succession. Serological reactions for previous syphilitic (luetic) infection were positive. Hypertrophic cardiomyopathy (HCM) without obstruction was verified, although right ventricular endomyocardial biopsy specimens did not demonstrate histological features of this disease. Extensive MI was verified on left ventricular cine angiography. Selective coronary arteriography showed that the coronary arterial tree was diffusely aneurysmal in the absence of any obstruction. We postulate that syphilitic coronary arteritis, in the absence of the more pathognomonic coronary ostial stenotic lesions, was present and may have predisposed to coronary thrombus formation and repeated acute MI. Recurrent coronary vasospasm, associated with the HCM, cannot be excluded with certainty.


Individual differences in regulatory focus predict neural response to reward.
Although goal pursuit is related to both functioning of the brain's reward circuits and psychological factors, the literatures surrounding these concepts have often been separate. Here, we use the psychological construct of regulatory focus to investigate individual differences in neural response to reward. Regulatory focus theory proposes two motivational orientations for personal goal pursuit: (1) promotion, associated with sensitivity to potential gain, and (2) prevention, associated with sensitivity to potential loss. The monetary incentive delay task was used to manipulate reward circuit function, along with instructional framing corresponding to promotion and prevention in a within-subject design. We observed that the more promotion oriented an individual was, the lower their ventral striatum response to gain cues. Follow-up analyses revealed that greater promotion orientation was associated with decreased ventral striatum response even to no-value cues, suggesting that promotion orientation may be associated with relatively hypoactive reward system function. The findings are also likely to represent an interaction between the cognitive and motivational characteristics of the promotion system with the task demands. Prevention orientation did not correlate with ventral striatum response to gain cues, supporting the discriminant validity of regulatory focus theory. The results highlight a dynamic association between individual differences in self-regulation and reward system function.


Understanding How Much TV is Too Much: A Nonlinear Analysis of the Association Between Television Viewing Time and Adverse Health Outcomes.
To inform potential guideline development, we investigated nonlinear associations between television viewing time (TV time) and adverse health outcomes. From 2006 to 2010, 490,966 UK Biobank participants, aged 37 to 73 years, were recruited. They were followed from 2006 to 2018. Nonlinear associations between self-reported TV time (hours per day) and outcomes explored using penalized cubic splines in Cox proportional hazards adjusted for demographics and lifestyle. Population-attributable and potential impact fractions were calculated to contextualize population-level health outcomes associated with different TV time levels. Nonlinear isotemporal substitution analyses were used to investigate substituting TV time with alternative activities. Primary outcomes were mortality: all-cause, cardiovascular disease (CVD) and cancer; incidence: CVD and cancer; secondary outcomes were incident myocardial infarction, stroke, and heart failure and colon, lung, breast, and prostate cancer. Those with noncommunicable disease (109,867 [22.4%]), CVD (32,243 [6.6%]), and cancer (37,81 [7.7%]) at baseline were excluded from all-cause mortality, CVD, and cancer analyses, respectively. After 7.0 years (mortality) and 6.2 years (disease incidence) mean follow-up, there were 10,306 (2.7%) deaths, 24,388 (5.3%) CVD events, and 39,121 (8.7%) cancer events. Associations between TV time and all-cause and CVD mortality were curvilinear (Pnon-linear ≤.003), with lowest risk observed <2 hours per day. Theoretically, 8.64% (95% confidence interval [CI], 6.60-10.73) of CVD mortality is attributable to TV time. Limiting TV time to 2 hours per day might have prevented, or at least delayed, 7.97% (95% CI, 5.54-10.70) of CVD deaths. Substituting TV time with sleeping, walking, or moderate or vigorous physical activity was associated with reduced risk for all outcomes when baseline levels of substitute activities were low. TV time is associated with numerous adverse health outcomes. Future guidelines could suggest limiting TV time to less than 2 hours per day to reduce most of the associated adverse health events.


Inheritance of larval resistance to permethrin in Aedes aegypti and association with sex ratio distortion and life history variation.
The genetic mechanisms that confer larval permethrin resistance were investigated in two strains of Aedes aegypti, vectors of yellow fever and dengue hemorrhagic fever. Larval resistance to permethrin in an Ae. aegypti field-collected resistant Couva (R) strain was associated with the sex-determining locus by analysis of backcrosses to the susceptible Rockefeller (S) strain. The median lethal concentrations (LC50s) of these strains were 23.1 (95% confidence interval = 22.0-24.3) and 2.2 (2.0-2.3) parts/billion of permethrin, respectively. The estimated resistance ratio (RR) for the R strain was 10.8 (10.3-11.4) compared with the S strain. Resistance was inherited as partly recessive (dominance [D] = -0.31) with an estimated RR of 2.3 (2.1-2.4) in the F1 hybrids when the R parent was male. There were also significantly male-biased sex ratios for this cross. In contrast, inheritance was slightly dominant (D = 0.19) with an estimated RR of 4.1 (3.8-4.4) when the R parent was female, and no significant sex ratio bias of progeny was observed. Analysis revealed a strong paternal-strain effect in bioassay mortality, sex ratio, egg hatch, and fecundity. A maternal-strain effect was also evident for bioassay mortality. Similarly, a strong maternal by paternal strain interaction was also evident for sex ratio. Progeny of single-family backcrosses of F1 hybrids to R were statistically homogeneous for sex ratio, duration of oviposition, fecundity, and hatch rate. A significant increase in male bias was found for only one backcross to R, after treatment with permethrin. In contrast, complex patterns of inheritance of life histories were observed among backcrosses to S. Backcrosses to S had greater mean fecundities, shorter mean times to the start of oviposition, and shorter mean oviposition periods than did backcrosses to R. Hatch rates were statistically homogeneous among backcrosses, but all strikingly reduced relative to the parental generation. Times of start and duration of oviposition were highly negatively correlated with fecundity (first gonotropic cycle only) and rate of egg hatch. Females with lower fecundities had lower hatch rates, and there was a threshold of approximately 80 eggs per female, below which no eggs hatched. Generally all backcrosses had higher LC50s than expected from single-locus inheritance. Association between sex bias and inheritance of resistance was apparent, but no single genetic linkage model based on current understanding of sex chromosome genetics was consistent with these observations. These results may have epidemiologic importance considering that permethrin-soaked bed nets are being used in many countries to control the biting activity of disease vectors.


High-order nonlinear Schrödinger equation and weak-light superluminal solitons in active Raman gain media with two control fields.
We propose a scheme to generate superluminal optical solitons in a four-level atomic system with two control fields via an active Raman gain. We derive a modified nonlinear Schrödinger equation with high-order corrections contributed from linear and differential absorption, nonlinear dispersion, and delay response of nonlinear refractive index of the system. We predict various optical solitons in different regimes of system parameters, and show that these optical solitons have superluminal propagating velocity and very low generation power.


A six-gene model for differentiating benign from malignant thyroid tumors on the basis of gene expression.
Thyroid nodules are common; fine-needle aspirations commonly are read as indeterminate, necessitating surgery to exclude carcinoma. We developed a 6-gene array-based predictor model to diagnose benign versus malignant thyroid lesions. In this study, we verified whether quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using this model reliably can differentiate benign from malignant thyroid nodules. Molecular profiles of benign (follicular adenomas, hyperplastic nodules) and malignant tumors (papillary thyroid carcinomas, follicular variants of papillary thyroid carcinomas) were analyzed using qRT-PCR from our 6-gene model (kit, Hs.296031, Hs.24183, LSM7, SYNGR2, C21orf4). The gold standard was standard pathologic criteria. A diagnosis-predictor model was built by using the training samples and was then used to predict the class of 10 additional samples analyzed as unknowns. Our predictor model using 47 training samples correctly predicted 9/10 unknowns. One sample diagnosed as benign by standard histologic criteria was diagnosed as malignant by our model (sensitivity 75%; specificity, 100%; positive predictive value, 100%; negative predictive value, 85.7%). Molecular diagnosis with our 6-gene model can differentiate between benign and malignant thyroid tumors with high sensitivity and specificity. In combination, these genetic markers may be a reliable test to preoperatively diagnose the malignant potential of thyroid nodules.


Ultrasound Evaluation of the Peroneal Tendons in an Asymptomatic Elite Military Population: A Prospective Cohort Study.
The purpose of this study was to identify the location of the peroneal tendons in relationship to the fibular groove in an asymptomatic population of elite U.S. Military Service members. The peroneal tendons of 41 active duty U.S. Army Rangers were examined. Subjects were placed in a lateral recumbent position with the ankle in a resting neutral position to visualize the tendon in a retromalleolar short-axis view. Maximum active ankle eversion followed by gravity inversion was facilitated while the ultrasound probe was maintained in its original position. Distance from the fibrous lateral ridge of the retromalleolar groove to the anterior aspect of the peroneal brevis was measured in the short axis in neutral, eversion, and inversion. The mean sagittal distance and standard deviation was 0.48 ± 0.9 mm. No subjects demonstrated greater than 1 mm difference between positions, and no dislocations were identified. Side-to-side difference and dominant vs nondominant differences were not statistically significant. The study demonstrates that the distance between the peroneal brevis and the lateral fibular ridge is consistent throughout extremes of motion. These results further the understanding of peroneal tendon function under dynamic examination. Our findings also establish side-to-side consistency prompting a bilateral examination to help identify abnormal pathology.


Dz13, a DNAzyme targeting c-jun, induces off-target cytotoxicity in endothelial cells with features of nonapoptotic programmed cell death.
We have previously shown that Dz13, a catalytic DNA molecule (DNAzyme) designed against c-jun, is cytotoxic to nonquiescent cells by a mechanism independent of c-jun mRNA cleavage. In this report, we evaluated programmed cell death (PCD) pathways in order to gain further insight into the mechanism of action of Dz13. Using human dermal microvascular endothelial cells (HMEC-1), we found that Dz13-mediated cell death is characterized by mitochondrial depolarization, caspase-8 activation, lysosomal increase, and autophagosome formation. Classical DNA laddering and translocation of mitochondrial proteins were not observed. An array of inhibitors, including those targeting caspases, failed to abrogate cytotoxicity and mitochondrial depolarization. Cytotoxicity did not proceed from endoplasmic reticulum (ER) stress. The possible involvement of PARP-1 in Dz13-mediated cytotoxicity was indicated by its differential release as gauged by protein extraction data and its apparent binding to Dz13, as evidenced by protein pull-down experiments. This study on Dz13-mediated cytotoxicity presents a detailed investigation into the interplay of cell death effectors involved in apoptosis, autophagy, and necrosis, and demonstrates a novel form of oligonucleotide-mediated cytotoxicity with features of PCD.


Height and weight at menarche and a hypothesis of critical body weights and adolescent events.
Height and weight at menarche were found for each subject in three longitudinal growth studies. Early and late maturing girls have menarche at the same mean weight, but late maturers are taller at menarche. Two other major events of adolescence, initiation of the weight growth spurt and maximum rate of weight gain, also occur at an invariant mean weight. The hypothesis is proposed that a critical body weight may trigger each of these adolescent events. Such an interaction would explain the secular trend to an earlier menarche.


Limited sufficiency of antigen presentation by dendritic cells in models of central nervous system autoimmunity.
Experimental autoimmune encephalomyelitis (EAE), a model for the human disease multiple sclerosis (MS), is dependent upon the activation and effector functions of autoreactive CD4 T cells. Multiple interactions between CD4 T cells and major histocompatibility class II (MHCII)+ antigen presenting cells (APCs) must occur in both the periphery and central nervous system (CNS) to elicit autoimmunity. The identity of the MHCII+ APCs involved throughout this process remains in question. We investigated which APC in the periphery and CNS mediates disease using transgenic mice with MHCII expression restricted to dendritic cells (DCs). MHCII expression restricted to DCs results in normal susceptibility to peptide-mediated EAE. Indeed, radiation-sensitive bone marrow-derived DCs were sufficient for all APC functions during peptide-induced disease. However, DCs alone were inefficient at promoting disease after immunization with the myelin protein myelin oligodendrocyte glycoprotein (MOG), even in the presence of MHCII-deficient B cells. Consistent with a defect in disease induction following protein immunization, antigen presentation by DCs alone was incapable of mediating spontaneous optic neuritis. These results indicate that DCs are capable of perpetuating CNS-targeted autoimmunity when antigens are readily available, but other APCs are required to efficiently initiate pathogenic cognate CD4 T cell responses.


Selectively reduced regional cortical volumes in post-traumatic stress disorder.
Different subterritories of anterior cingulate cortex (ACC) and adjacent ventromedial frontal cortex have been shown to serve distinct functions. This scheme has influenced contemporary pathophysiologic models of psychiatric disorders. Prevailing neurocircuitry models of post-traumatic stress disorder (PTSD) implicate dysfunction within pregenual ACC and subcallosal cortex (SC), as well as amygdala and hippocampus. In the current study, cortical parcellation of magnetic resonance imaging data was performed to test for volumetric differences in pregenual ACC and SC, between women with PTSD and trauma-exposed women without PTSD. The PTSD group exhibited selectively decreased pregenual ACC and SC volumes. These results are consistent with contemporary schemes regarding functional and structural dissection of frontal cortex, and suggest specific regional cortical pathology in PTSD.


Effects of strong government measures against tobacco in Hong Kong.
The government of Hong Kong grasped the political nettle of control of tobacco in the early 1980s, since when a comprehensive policy of legislation, education, and publicity, together with large increases in taxation on tobacco products, has been introduced. This has led to almost all of the population of Hong Kong having knowledge of the harmful effects of tobacco and of antismoking measures taken by the government. From 1982 to 1984 the number of people who smoked daily fell appreciably from 888 300 to 744 500, a reduction of 16%, while the number of teenage smokers was halved (from 22 600 to 11 200). Government commitment is crucial in programmes against tobacco in developing countries; without it antismoking efforts are unlikely to be successful.


Outstanding questions in the study of archaic hominin admixture.
The complete sequencing of archaic and modern human genomes has revolutionized the study of human history and evolution. The application of paleogenomics has answered questions that were beyond the scope of archaeology alone-definitively proving admixture between archaic and modern humans. Despite the remarkable progress made in the study of archaic-modern human admixture, many outstanding questions remain. Here, we review some of these questions, which include how frequent archaic-modern human admixture was in history, to what degree drift and selection are responsible for the loss and retention of introgressed sequences in modern human genomes, and how surviving archaic sequences affect human phenotypes.


Emergency Department-Initiated Palliative Care in Advanced Cancer: A Randomized Clinical Trial.
The delivery of palliative care is not standard of care within most emergency departments (EDs). To compare quality of life, depression, health care utilization, and survival in ED patients with advanced cancer randomized to ED-initiated palliative care consultation vs care as usual. A single-blind, randomized clinical trial of ED-initiated palliative care consultation for patients with advanced cancer vs usual care took place from June 2011 to April 2014 at an urban, academic ED at a quaternary care referral center. Adult patients with advanced cancer who were able to pass a cognitive screen, had never been seen by palliative care, spoke English or Spanish, and presented to the ED met eligibility criteria; 136 of 298 eligible patients were approached and enrolled in the ED and randomized via balanced block randomization. Intervention participants received a comprehensive palliative care consultation by the inpatient team, including an assessment of symptoms, spiritual and/or social needs, and goals of care. The primary outcome was quality of life as measured by the change in Functional Assessment of Cancer Therapy-General Measure (FACT-G) score at 12 weeks. Secondary outcomes included major depressive disorder as measured by the Patient Health Questionnaire-9, health care utilization at 180 days, and survival at 1 year. A total of 136 participants were enrolled, and 69 allocated to palliative care (mean [SD], 55.1 [13.1] years) and 67 were randomized to usual care (mean [SD], 57.8 [14.7] years). Quality of life, as measured by a change in FACT-G score from enrollment to 12 weeks, was significantly higher in patients randomized to the intervention group, who demonstrated a mean (SD) increase of 5.91 (16.65) points compared with 1.08 (16.00) in controls (P = .03 using the nonparametric Wilcoxon test). Median estimates of survival were longer in the intervention group than the control group: 289 (95% CI, 128-453) days vs 132 (95% CI, 80-302) days, although this did not reach statistical significance (P = .20). There were no statistically significant differences in depression, admission to the intensive care unit, and discharge to hospice. Emergency department-initiated palliative care consultation in advanced cancer improves quality of life in patients with advanced cancer and does not seem to shorten survival; the impact on health care utilization and depression is less clear and warrants further study. clinicaltrials.gov Identifier: NCT01358110.


Fibroblast Growth Factor 21 Stimulates Pancreatic Islet Autophagy via Inhibition of AMPK-mTOR Signaling.
Islet autophagy plays a role in glucose/lipid metabolism in type 2 diabetes mellitus. Meanwhile, fibroblast growth factor 21 (FGF21) has been found to regulate insulin sensitivity and glucose homeostasis. Whether FGF21 induces islet autophagy, remains to be elucidated. This study aimed to explore the physiological roles and signaling pathways involved in FGF21-stimulated islet autophagy under glucolipotoxic conditions. C57/BL6J mice were fed a standard diet or high-fat diet (HFD) for 12 weeks, and islets were isolated from normal and FGF21 knockout (KO) mice. Isolated islets and INS-1E cells were exposed to normal and high-concentration glucose and palmitic acid with/without FGF21 or AMPK inhibitor compound C. Real-time PCR, Western blot and immunohistochemistry/transmission electron microscopy were performed for the expression of targeted genes/proteins. HFD-treated mice showed increases in fasting plasma glucose, body weight and impaired glucose tolerance; islet protein expression of FGF21 was induced after HFD treatment. Protein expression levels of FGF21 and LC3-II (autophagy marker) were induced in mouse islets treated with high concentrations of palmitic acid and glucose, while phosphorylation of AMPK was reduced, compared with controls. In addition, induction of LC3-II protein expression was reduced in islets isolated from FGF21 KO mice. Furthermore, exogenous administration of FGF21 diminished phosphorylation of AMPK and stimulated protein expression of LC3-II. Consistently, compound C significantly induced increased expression of LC3-II protein. Our data indicate that glucolipotoxicity-induced FGF21 activation mediates islet autophagy via AMPK inhibition, and further consolidate the evidence for the FGF21/analog being a pharmacotherapeutic target for obesity and its related T2DM.


Advanced training enhances readiness to return to sport after anterior cruciate ligament reconstruction.
Patients with anterior cruciate ligament reconstruction (ACLR) are often psychologically and physically under-prepared for sports participation. This study compared readiness to return to sport based on completion of advanced training after ACLR. Patients with ACLR who self-selected participation in a 6-week group-format advanced training program (TRAINING) were compared to age- and sex-matched patients who did not participate (NoTRAINING). Each group had 23 participants (14 females). Advanced training consisted of plyometric, strengthening, and agility exercises. Baseline and follow-up testing included psychological measures (Anterior Cruciate Ligament Return to Sport after Injury [ACL-RSI]; Tampa Scale for Kinesiophobia [TSK-11]; Knee Activity Self-Efficacy [KASE]; and fear intensity for the primary fear-evoking task or situation) and a hop test battery. Return to sport criteria were ACL-RSI score ≥70 points and limb symmetry index ≥90% on all hop tests. At follow-up, KASE score was higher in TRAINING than NoTRAINING (92.7 vs. 89.1 points; respectively), but ACL-RSI, TSK-11 and fear intensity scores were not significantly different between groups. Return to sport criteria passing rate was not significantly different between groups at baseline (TRAINING: 13%, NoTRAINING: 30%) or follow-up (TRAINING: 52%, NoTRAINING: 43%); however, the distribution of criteria met at follow-up differed with more patients in TRAINING than NoTRAINING meeting hop test criteria (30% vs. 4%, respectively) and more patients in NoTRAINING than TRAINING failing to meet any criteria (25% vs. 0%, respectively). Advanced training after ACLR facilitated readiness for sport participation by improving confidence and hop performance, but may not have a preferential effect on fear.


Comparison of sperm adenosine triphosphate content, motility and fertility of immobilized and conventionally cryopreserved Norwegian Red bull semen.
Estrus detection and timing of AI remains a challenge in cattle breeding. Prolonging spermatozoa lifespan after AI, making sperm cells available over an extended period, could make timing of AI relative to ovulation less crucial and improve fertility. Immobilization of sperm cells by the patented SpermVital technology in an alginate gel will provide a gradual release of spermatozoa after AI. The first aim of this study was to examine fertility, measured as non-return rate after 56 days (NR56), of SpermVital (SV) processed semen with reduced sperm cell number per dose compared to earlier studies, and compare with conventionally processed semen in Biladyl, a proprietary version of the egg yolk Tris semen extender. The second aim was to examine in vitro sperm quality post-thaw and after thermal stress. The third aim was to examine potential correlations between in vitro sperm parameters and NR56. Ejaculates from 16 Norwegian Red young bulls were split in three, processed and cryopreserved as Biladyl semen (B15; 15 million spermatozoa/dose) or by SpermVital technology (SV25; 25 million spermatozoa/dose or SV15; 15 million spermatozoa/dose). 1400 semen doses were produced per bull and distributed throughout Norway for a blinded field trial. Fertility was recorded as NR56 after first AI (N = 7155). Two ejaculates from each bull were randomly selected for in vitro experiments. B15 and SV15 semen samples were analyzed for motility by computer-assisted sperm analysis, viability and acrosome integrity by flow cytometry and ATP content by bioluminescence assay, post-thaw and after thermal stress. The AI trial detected no differences in NR56; least square means being 75.5% (B15), 75.6% (SV25) and 74.8% (SV15) (p > 0.05). There were no differences in total motility and progressive motility post-thaw, however, after three hours incubation at 38 °C, SV sperm motility and progressivity were higher for SV15 than for B15 spermatozoa (p < 0.05). The percentage of acrosome intact live sperm cells was higher for SV15 than B15 spermatozoa at all timepoints analyzed (0 h, 3 h, 24 h, p < 0.05). B15 semen showed a higher ATP level than SV15 at 0 h (p < 0.05), while SV15 sperm cells had higher ATP levels after 3 and 24 h (p < 0.05). No association was detected between in vitro sperm parameters and NR56. In conclusion, SV15, SV25 and B15 semen yielded equal fertility after AI. However, there were differences in sperm quality, as SV15 spermatozoa displayed higher motility, viability and ATP levels after thermal stress than B15 spermatozoa (p < 0.05).


Induction of persistent double strand breaks following multiphoton irradiation of cycling and G1-arrested mammalian cells-replication-induced double strand breaks.
DNA double strand breaks (DSBs) are amongst the most deleterious lesions induced within the cell following exposure to ionizing radiation. Mammalian cells repair these breaks predominantly via the nonhomologous end joining pathway which is active throughout the cell cycle and is error prone. The alternative pathway for repair of DSBs is homologous recombination (HR) which is error free and active during S- and G2/M-phases of the cell cycle. We have utilized near-infrared laser radiation to induce DNA damage in individual mammalian cells through multiphoton excitation processes to investigate the dynamics of single cell DNA damage processing. We have used immunofluorescent imaging of gamma-H2AX (a marker for DSBs) in mammalian cells and investigated the colocalization of this protein with ATM, p53 binding protein 1 and RAD51, an integral protein of the HR DNA repair pathway. We have observed persistent DSBs at later times postlaser irradiation which are indicative of DSBs arising at replication, presumably from UV photoproducts or clustered damage containing single strand breaks. Cell cycle studies have shown that in G1 cells, a significant fraction of multiphoton laser-induced prompt DSBs persists for > 4 h in addition to those induced at replication.


Correlation Between Hepatocyte Growth Factor (HGF) and Gamma-Aminobutyric Acid (GABA) Plasma Levels in Autistic Children.
There is much support for the role of Gamma-Aminobutyric acid (GABA) in the etiology of autism. Recent research has shown that hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility. This study was designed to determine and correlate plasma levels of HGF, GABA, as well as symptom severity, in autistic children and neurotypical controls. Plasma from 48 autistic children and 29 neurotypical controls was assessed for HGF and GABA concentration using ELISAs. Symptom severity was assessed in these autistic individuals and compared to HGF and GABA concentrations. We previously reported that autistic children had significantly decreased levels of HGF. In this study, the same autistic children had significantly increased plasma levels of GABA (P = 0.002) and decreased HGF levels correlated with these increased GABA levels (r = 0.3; P = 0.05). High GABA levels correlated with increasing hyperactivity (r = 0.6; P = 0.0007) and impulsivity severity (r = 0.5; P = 0.007), tip toeing severity (r = 0.35; P = 0.03), light sensitivity (r = 0.4; P = 0.02), and tactile sensitivity (r = 0.4; P = 0.01). HGF levels did not correlate significantly with any symptom severity. These results suggest an association between HGF and GABA levels and suggest that plasma GABA levels are related to symptom severity in autistic children.


Beveled needle technique is not associated with low "take" rates in Israeli smallpox revaccination campaign.
In its first large-scale smallpox vaccination campaign in the 20(th) century, Israel has experienced an exceptionally high rate of failure to achieve clinical take following vaccination. It was hypothesized that this failure rates might be attributed to the unique vaccination technique adopted in Israel, of using beveled needles rather than bifurcated needles. We retrospectively identified two cohorts vaccinated in the defined dates during the Israeli revaccination campaign, in which beveled needles and bifurcated needles were used alternately, and studied the impact of different covariates on clinical vaccination outcome measures. Of 116 subjects that were vaccinated within the defined dates, 46 were vaccinated using bifurcated needles, and 70 by beveled needles. 'Take' rates in subjects vaccinated up to 20 years earlier was 77.5%, compared with 97.2% among those vaccinated in the more distant past (p = 0.001). In multivariate analyses, vaccination 'take' was independently associated with a shorter time from previous vaccination (p = 0.013), but not with gender, birth country, vaccinator or the vaccination technique used. The low take rates observed in the Israeli smallpox revaccination campaign could not be attributed to the unique local vaccination technique, and was most likely induced by a higher rate of residual immunity among vaccinees, compared with the US, as well as by the lower vaccine concentrations used in Israel. In countries and circumstances when bifurcated needles are not sufficiently available, the beveled needle technique may be considered an appropriate alternative.


Pronounced Impairment of Activities of Daily Living in Posterior Cortical Atrophy.
The impact of several dementia syndromes on activities of daily living (ADLs) has been well documented, but no study has yet investigated functional ability in posterior cortical atrophy (PCA). The primarily visual nature of deficits in this condition is likely to have a pronounced impact on ADLs. The aim of this study was to profile functional change in PCA and identify predictors of change. Twenty-nine PCA patients and 25 patients with typical Alzheimer's disease (AD) and their caregivers were included in this cross-sectional study. ADLs were assessed using the Disability Assessment for Dementia (DAD), administered to caregivers, assessing basic ADLs (e.g., eating, dressing) and instrumental ADLs (e.g., managing finances, meal preparation). The predictive utility of cognitive domains (Addenbrooke's Cognitive Examination), behavioural impairment (Cambridge Behavioural Inventory-Revised) and demographic variables on ADL ability was also examined. PCA patients showed significantly reduced total ADL scores compared to AD patients (medium effect size, d = -0.7; p < 0.05), with significantly more impairment on basic ADLs (large effect size, d = -0.8; p < 0.05) but similar impairment on instrumental ADLs (medium effect size, d = -0.5; p > 0.05). A model combining patient mood, disinhibition, apathy, symptom duration, and memory and attention/orientation scores explained the variance of scores in functional decline (61.2%), but the key factor predicting ADL scores was attention/orientation (p = 0.048). This study shows the profound impact of PCA on ADLs and factors underpinning patients' disability. Attention/orientation deficits were found to correlate and contribute to variance in ADL scores. Future work to develop tailored interventions to manage ADL impairment in PCA should take these findings into account.


Biomechanical comparison of four prosthetic ligament repair techniques for tarsal medial collateral ligament injury in dogs.
To compare joint stability and ultimate strength among 4 prosthetic ligament constructs for repair of tarsal medial collateral ligament (MCL) injury in dogs. 13 canine cadavers (26 hind limbs). Each limb was stripped of all soft tissues except those associated with the tarsal joint and assigned to 1 of 4 prosthetic ligament constructs. The AN construct consisted of 3 bone anchors connected with monofilament nylon suture. The AU construct consisted of low-profile suture anchors connected with multifilament ultrahigh-molecular-weight polyethylene (UHMWPE) suture. The TN and TU constructs involved the creation of 3 bone tunnels and use of nylon or UHMWPE suture, respectively. Each limb underwent biomechanical testing before and after MCL transection and before and after cyclic range-of-motion testing following completion of the assigned construct. Tarsal joint stability (extent of laxity) was assessed with the joint in each of 3 positions (75°, 135°, and 165°). After completion of biomechanical testing, each limb was tested to failure to determine the ultimate strength of the construct. Relative to intact tarsal joints, joint laxity was significantly increased following completion of all 4 constructs. Construct type was not associated with the magnitude of change in joint laxity. Ultimate strength was greatest for the UHMWPE-suture constructs. Results indicated that all 4 constructs effectively stabilized MCL-deficient tarsal joints. Implants used for the TU, TN, and AU constructs had a lower profile than those used for the AN construct, which may be clinically advantageous. In vivo studies are warranted.


[Headache secondary to carbon monoxide poisoning].
Chronic intoxication due to carbon monoxide (CO) is a condition in which the frequency is underestimated since the clinical features are nonspecific. It is important since serious neurological sequelae may result: an extrapyramidal syndrome, dementia or a vegetative state. The diagnosis is established when there are venous blood levels of carboxyhemoglobin greater than 10%. Early treatment with hyperbaric O2 rapidly improves the symptoms and avoids the development of neurological sequelae. We report the case of a 30 year old woman who was admitted to hospital for investigation into two episodes of loss of consciousness with vomiting and subsequent somnolence not accompanied by other neurological sequelae. For the previous eight months she had had daily pulsatile biparietal headaches, sometimes accompanied by a fainting feeling, nausea and vomiting. During her admission she remained asymptomatic and all neurophysiological, cardiological and neuroimaging studies were normal. The day after medical discharge she returned with the same clinical condition. A woman who lived with her and accompanied her also complained of similar symptoms. Venous gasometry showed raised levels of carboxyhemoglobin in both the patient (30.4%) and her companion (31.2%). Treatment with hyperbaric 100% O2 reverted the symptoms within a few hours. Later studies showed that the domestic gas burner was faulty. Occult CO intoxication causes headache which often requires differential diagnosis from psychiatric disorders and episodes of migraine. In patients with refractory nonspecific headache, irregular course and systemic symptoms, usually in winter, CO intoxication should be considered to be a possible cause. Diagnosis is based on finding venous blood levels of carboxyhemoglobin of over 10%. Early treatment avoids lesion of the globus pallidus and irreversible extrapyramidal sequelae.


Duration of post-operative hypocortisolism predicts sustained remission after pituitary surgery for Cushing's disease.
Transsphenoidal surgery (TSS) is the primary treatment modality for Cushing's disease (CD). However, the predictors of post-operative remission and recurrence remain debatable. Thus, we studied the post-operative remission and long-term recurrence rates, as well as their respective predictive factors. A retrospective analysis of case records of 230 CD patients who underwent primary microscopic TSS at our tertiary care referral centre between 1987 and 2015 was undertaken. Demographic features, pre- and post-operative hormonal values, MRI findings, histopathological features and follow-up data were recorded. Remission and recurrence rates as well as their respective predictive factors were studied. Overall, the post-operative remission rate was 65.6% (early remission 46%; delayed remission 19.6%), while the recurrence rate was 41% at mean follow-up of 74 ± 61.1 months (12-270 months). Significantly higher early remission rates were observed in patients with microadenoma vs macroadenoma (51.7% vs 30.6%, P = 0.005) and those with unequivocal vs equivocal MRI for microadenoma (55.8% vs 38.5%, P = 0.007). Patients with invasive macroadenoma had poorer (4.5% vs 45%, P = 0.001) remission rates. Recurrence rates were higher in patients with delayed remission than those with early remission (61.5% vs 30.8%, P = 0.001). Duration of post-operative hypocortisolemia ≥13 months predicted sustained remission with 100% specificity and 46.4% sensitivity. Recurrence could be detected significantly earlier (27.7 vs 69.2 months, P < 0.001) in patients with available serial follow-up biochemistry as compared to those with infrequent follow-up after remission. In our study, remission and recurrence rates were similar to that of reported literature, but proportion of delayed remission was relatively higher. Negative/equivocal MRI findings and presence of macroadenoma, especially those with cavernous sinus invasion were predictors of poor remission rates. In addition to early remission, longer duration of post-operative hypocortisolism is an important predictor of sustained remission. Regular biochemical surveillance may help in identifying recurrence early.


Evaluation of topical epidural analgesia delivered in gelfoam for postoperative hemilaminectomy pain control.
To evaluate efficacy of a topical epidural analgesia used alone, or in combination with hydromorphone, against a standard pain protocol for the 48 hours immediately after hemilaminectomy. Randomized, blinded, controlled, clinical trial. Dogs (n = 30) with thoracolumbar intervertebral disc disease treated with hemilaminectomy. Dogs were randomly divided into 3 groups: group 1 received intermittent hydromorphone postoperatively, group 2 received a topical epidural of preservative-free morphine and dexmedetomidine administered via gel foam, group 3 received both forms of analgesia. All dogs were monitored and assessed for pain for 48 hours immediately postoperatively. Data were analyzed using MANOVA and Wilcoxon Rank Sum Tests. There was a significant temporal difference in treatment groups 1 and 3 when using a 0-10 pain scale (MANOVA, P = .02). There was also a significant difference at the 48th hour postoperatively between groups 1 and 3 (Wilcoxon Rank Sum Test). Topical epidural of preservative-free morphine and dexmedetomidine administered via gelfoam is not sufficient analgesia alone post hemilaminectomy but in conjunction with other opioid administration may lead to superior pain relief.


Direct transcriptional regulation of the progesterone receptor by retinoic acid diminishes progestin responsiveness in the breast cancer cell line T-47D.
Retinoic acid (RA) treatment of T-47D human breast cancer cells results in a rapid decrease in the concentration of progesterone receptor (PR) mRNA which causes a slow loss of cellular PR protein (Clarke, C. L., Roman, S. D., Graham, J., Koga, M., Sutherland, R. L. (1990) J. Biol. Chem. 265, 12694-12700). The mechanisms involved are unknown and this study was undertaken to determine whether the decline in PR mRNA was due to transcriptional inhibition and to evaluate the functional consequences of the RA-mediated decrease in PR. The transcription rate of the PR gene was decreased by RA, and the effect was maximal 2-3 h after treatment. Cycloheximide cotreatment was unable to relieve the inhibitory effect of RA and PR transcription suggesting that the effect was not dependent on ongoing protein synthesis. There was no effect of RA on PR mRNA half-life at the times examined (0-6 h of RA treatment). To determine the functional consequence of PR down-regulation the progestin-responsive plasmid pMSG-CAT was expressed transiently in T-47D cells which were then exposed to RA for 24 h. RA-pretreated cells were then treated with the synthetic progestin ORG 2058 and the extent of progestin stimulation of chloramphenicol acetyltransferase (CAT) activity measured. ORG 2058 treatment resulted in an induction of CAT activity which was maximal at a progestin concentration of 1 nM. Interestingly, the ability of ORG 2058 to induce CAT activity was decreased in RA-pretreated cells. The diminished progestin responsiveness of RA-pretreated cells was confirmed in separate experiments which showed that the progestin inducibility of TGF-alpha mRNA was also decreased in cells treated with ORG 2058 following pretreatment with RA for 24 h. These data demonstrate that RA decreases PR mRNA concentrations by direct transcriptional inhibition, leading to decreased cellular PR concentrations. The decreased levels of PR result in impaired responsiveness to progestins and this suggests that RA derived from dietary vitamin A may have a role in modulating cellular sensitivity to progestins.


Morphological changes in the cochlear nucleus of congenitally deaf white cats.
Investigations in animal models and humans have indicated that congenital deafness produces degenerative changes in the central auditory pathway. The cochlear nucleus is the first central structure that receives cochlear input, and may be considered the origin of ascending auditory pathways. In this context, we studied congenitally deaf white cats, who express early onset cochlear receptor loss, in order to assess the nature of structural changes in cells of the cochlear nucleus. It is conceivable that pathologic alterations in higher auditory structures are transneuronally distributed through this nucleus. The cochlear nuclei of nonwhite cats with normal hearing were compared to those of deaf white cats exhibiting hearing loss in excess of 70 dB SPL. The cochlear nuclei of the deaf white cats were smaller in volume by roughly 50%, with the ventral and dorsal divisions being equally affected. Cell body silhouette area was determined for spherical bushy cells of the anteroventral cochlear nucleus (AVCN), pyramidal cells of the dorsal cochlear nucleus (DCN), sensory neurons from the principal trigeminal nucleus, and motoneurons of the facial nucleus. We found no statistical difference in neuronal cell body size between nonauditory neurons of these two groups of cats, whereas auditory neurons of deaf white cats were 30.8-39.4% smaller than those of normal cats. These data imply that neuronal changes in congenitally deaf cats are specific to the auditory pathway. Although cochlear nucleus volume loss was uniform for both divisions, there was a differential effect on cell density: AVCN cell density increased by 40%, whereas DCN cell density was relatively unaffected (10% increase). Astrocyte density was also greater in the AVCN (52%) compared to that in the DCN (5%). These observations reveal a differential impact on cells in the cochlear nucleus to congenital deafness, suggesting selective processing impairment at this level. If similar patterns of degeneration occur in humans, such pathologies may underlie reduced processing of input from cochlear implants in congenitally deaf adults.


Influence of dietary iron overload on cell proliferation and intestinal tumorigenesis in mice.
Iron-enriched diets caused an increase of tumor rate in two models of dimethylhydrazine(DMH)-induced colon tumorigenesis in mice. The effect was independent of the time the iron-diet was fed, i.e. during DMH-treatment or following the DMH-treatment period. The increase of tumor rate depended on the iron concentration in the diet (0.5-3.5%). The concentration-dependent iron accumulation in the colonic mucosa of mice was paralleled by increments of malonaldehyde contents indicating lipid peroxidation, another factor known to be involved in tumor development. It is suggested that iron exerts cocarcinogenic activity in the DMH-model by stimulating cell proliferation and inducing oxidative stress in the colonic mucosa. This effect of iron is independent of the time of tumor-initiation by DMH, as it is also observed in the period of tumor-promotion/progression after DMH-treatment.


Anterior subtemporal approach for posterolateral brainstem cavernomas: report of ten cases.
The neuronavigation-assisted anterior subtemporal approach is proposed in this article as an alternative to surgery of posterolateral brainstem cavernomas. Brainstem cavernomas represent a neurosurgical challenge because of the high morbidity and mortality rate related to their surgical removal. Several nerve nuclei, ascending and descending fibers make this region at high risk of serious postoperative deficits. Between 1998 and 2010, 24 patients underwent surgical removal of brainstem cavernomas in our institution. Ten of these patients presented a cavernous malformation in the posterolateral region of the brainstem and underwent surgical removal by means of a neuronavigation-assisted anterior subtemporal approach. Lesion removal was complete for all patients. There were no cases of surgery-related death. Neurological status improved or remained unchanged after surgery in all cases. All patients presented good outcomes at 12 to 154 months' follow-up (mean 70 months; GOS = 5 in 8/10 patients, 4 in 2/10 patients; mRS = 0-1 in all patients). Only one patient presented transient confusion, aphasia and seizures related to temporal lobe swelling, which resolved completely within a few days. One patient developed cranial nerve III palsy and left hemiparesis with gradual recovery. This approach represents a valid alternative to the "more classical" approaches for the surgery of posterolateral cavernomas of the pontomesenchephalic junction reaching the tentorial incisura, reducing the risk of damaging the vein of Labbé, temporal lobe swelling, cerebellar swelling, ophtalmoparesis, fourth ventricle cranial nerve nuclei lesions. Skeletonization of sigmoidal sinus provides with good outcomes, low morbidity and mortality.


Childhood socio-economic circumstances and dementia: prospective register-based cohort study of adulthood socio-economic and cardiovascular health mediators.
This study analysed the association between childhood socio-economic circumstances and the risk of dementia, and investigated the mediating role of potentially modifiable risk factors including adulthood socio-economic position and cardiovascular health. We used a 10% sample of the 1950 Finnish population census linked with subsequent population and health registers (n = 95 381). Information of socio-economic characteristics, family structure and housing conditions at the age of 0-15 years was obtained from the 1950 census. We identified cohort members who developed dementia in 2000-2018 using national hospital, medication and death registers. Discrete time survival analysis using logistic regression and mediation analysis applying the Karlson-Holm-Breen (KHB) method were employed. An excess risk of dementia was observed for household crowding [odds ratio (OR) = 1.10; 95% CI 1.02-1.18 for 3 to <4 persons per heated room; OR = 1.19; 95% CI 1.11-1.27 for ≥4 persons], single-father family (OR = 1.27; 95% CI 1.07-1.51) and eastern and northern region of residence (OR = 1.19; 95% CI 1.10-1.28). The effects of single-father family and region of residence were mostly direct with adulthood characteristics mediating 14% and 29% of the total effect, respectively. The largest indirect effect was observed for household crowding mediated through adulthood socio-economic position (47-65%). The study shows that childhood socio-economic circumstances are associated with dementia, and that the underlying mechanisms only partly relate to adulthood socio-economic position and cardiovascular health. Socio-economic and health interventions targeted at families with children may carry long-term benefits by contributing to a lower dementia risk in later life.


Vacuolar H+-ATPase inhibitors overcome Bcl-xL-mediated chemoresistance through restoration of a caspase-independent apoptotic pathway.
The anti-apoptotic oncoproteins Bcl-2 and Bcl-xL play crucial roles in tumorigenesis and chemoresistance, and are thus therapeutic cancer targets. We searched for small molecules that disturbed the anti-apoptotic function of Bcl-2 or Bcl-xL, and found vacuolar H(+)-ATPase (V-ATPase) inhibitors, such as bafilomycin A1 (BMA), that showed such activity. Bcl-xL-overexpressing Ms-1 cells displayed resistance to anticancer drugs, but underwent apoptosis following treatment with a combination of V-ATPase inhibitors at doses similar to those that caused inhibitory activities of V-ATPase. We investigated the apoptosis mechanism induced by cotreatment of Bcl-xL-overexpressing Ms-1 cells with BMA as a V-ATPase inhibitor and taxol (TXL) as an anticancer drug. With BMA, TXL triggered mitochondrial membrane potential loss and cytochrome c release, whereas downstream caspase activation was not observed. In contrast, pronounced nuclear translocation of mitochondrial apoptosis-inducing factor and endonuclease G, known as effectors of caspase-independent apoptosis, was observed with BMA and TXL cotreatment. Moreover, depletion of apoptosis-inducing factor and endonuclease G using each siRNA significantly rescued cells from BMA- and TXL-induced apoptosis. Hence, the apoptosis-inducing factor- and endonuclease G-dependent pathway was critical for apoptosis induction by BMA and TXL cotreatment. Our data suggest that V-ATPase inhibitors could not only suppress anti-apoptotic Bcl-2 nor Bcl-xL but could also facilitate the caspase-independent apoptotic pathway. V-ATPase inhibition will be a promising therapeutic approach for Bcl-2- or Bcl-xL-overexpressing malignancies.


Enhancement and Passive Acoustic Mapping of Cavitation from Fluorescently Tagged Magnetic Resonance-Visible Magnetic Microbubbles In Vivo.
Previous work has indicated the potential of magnetically functionalized microbubbles to localize and enhance cavitation activity under focused ultrasound exposure in vitro. The aim of this study was to investigate magnetic targeting of microbubbles for promotion of cavitation in vivo. Fluorescently labelled magnetic microbubbles were administered intravenously in a murine xenograft model. Cavitation was induced using a 0.5-MHz focused ultrasound transducer at peak negative focal pressures of 1.2-2.0 MPa and monitored in real-time using B-mode imaging and passive acoustic mapping. Magnetic targeting was found to increase the amplitude of the cavitation signal by approximately 50% compared with untargeted bubbles. Post-exposure magnetic resonance imaging indicated deposition of magnetic nanoparticles in tumours. Magnetic targeting was similarly associated with increased fluorescence intensity in the tumours after the experiments. These results suggest that magnetic targeting could potentially be used to improve delivery of cavitation-mediated therapy and that passive acoustic mapping could be used for real-time monitoring of this process.


Individual and culture-level components of survey response styles: A multi-level analysis using cultural models of selfhood.
Variations in acquiescence and extremity pose substantial threats to the validity of cross-cultural research that relies on survey methods. Individual and cultural correlates of response styles when using 2 contrasting types of response mode were investigated, drawing on data from 55 cultural groups across 33 nations. Using 7 dimensions of self-other relatedness that have often been confounded within the broader distinction between independence and interdependence, our analysis yields more specific understandings of both individual- and culture-level variations in response style. When using a Likert-scale response format, acquiescence is strongest among individuals seeing themselves as similar to others, and where cultural models of selfhood favour harmony, similarity with others and receptiveness to influence. However, when using Schwartz's (2007) portrait-comparison response procedure, acquiescence is strongest among individuals seeing themselves as self-reliant but also connected to others, and where cultural models of selfhood favour self-reliance and self-consistency. Extreme responding varies less between the two types of response modes, and is most prevalent among individuals seeing themselves as self-reliant, and in cultures favouring self-reliance. As both types of response mode elicit distinctive styles of response, it remains important to estimate and control for style effects to ensure valid comparisons.


Hyperphosphatemic familial tumoral calcinosis: response to acetazolamide and postulated mechanisms.
Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized by enhanced renal phosphate absorption, hyperphosphatemia, and tumor-like extraosseous calcifications due to inactivating mutations in FGF23 or associated proteins. Surgical excision is needed when low phosphate diet and phosphate binders are ineffective. Sporadic reports have supported acetazolamide use. We report on a 7-year-old African American boy who presented with severe HFTC requiring numerous surgical excisions. Tumors continued to appear and others reoccurred despite phosphate restriction and sevelamer carbonate. At the age of 9.5 years, acetazolamide (40 mg/kg/day) was added and resulted in mild metabolic acidosis (bicarbonate 25.3 mEq/L vs. 21.4 mEq/L, P < 0.001; serum pH 7.38 vs. 7.31, P = 0.013, pre- and post-acetazolamide, respectively) but no change in tubular reabsorption of phosphate (TRP) (96.9% vs. 95.9%, P = 0.34) or serum phosphate (6.6 mg/dl vs. 6.9 mg/dl, P = 0.52 pre- and post-acetazolamide, respectively). Following the initiation of acetazolamide therapy, the patient experienced significant improvement in disease course as indicated by resolution of localized bone pain, cessation of tumor formation, and no tumor recurrence. Despite mild metabolic acidosis, our patient had improved linear growth and did not develop any other side effects related to therapy. Intact FGF23 remained abnormally low throughout disease course, while C-terminal FGF23 increased with acetazolamide. We conclude that acetazolamide can control severe HFTC by inducing mild metabolic acidosis despite no change in serum phosphate or TRP. This effect may be exerted though improved calcium-phosphate complex solubility and increased FGF23 locally.


Addressing the appropriateness of elective colon resection for diverticulitis: a report from the SCOAP CERTAIN collaborative.
To assess the reported indications for elective colon resection for diverticulitis and concordance with professional guidelines. Despite modern professional guidelines recommending delay in elective colon resection beyond 2 episodes of uncomplicated diverticulitis, the incidence of elective colectomy has increased dramatically in the last 2 decades. Whether surgeons have changed their threshold for recommending a surgical intervention is unknown. In 2010, Washington State's Surgical Care and Outcomes Assessment Program initiated a benchmarking and education initiative related to the indications for colon resection. Prospective cohort study evaluating indications from chronic complications (fistula, stricture, bleeding) or the number of previously treated diverticulitis episodes for patients undergoing elective colectomy at 1 of 49 participating hospitals (2010-2013). Among 2724 patients (58.7 ± 13 years; 46% men), 29.4% had a chronic complication indication (15.6% fistula, 7.4% stricture, 3.0% bleeding, 5.8% other). For the 70.5% with an episode-based indication, 39.4% had 2 or fewer episodes, 56.5% had 3 to 10 episodes, and 4.1% had more than 10 episodes. Thirty-one percent of patients failed to meet indications for either a chronic complication or 3 or more episodes. Over the 4 years, the proportion of patients with an indication of 3 or more episodes increased from 36.6% to 52.7% (P < 0.001) whereas the proportion of those who failed to meet either clinical or episode-based indications decreased from 38.4% to 26.4% (P < 0.001). The annual rate of emergency resections did not increase significantly, varying from 5.6 to 5.9 per year (P = 0.81). Adherence to a guideline based on 3 or more episodes for elective colectomy increased concurrently with a benchmarking and peer-to-peer messaging initiative. Improving adherence to professional guidelines related to appropriate care is critical and can be facilitated by quality improvement collaboratives.


Paclitaxel-loaded N-octyl-O-sulfate chitosan micelles for superior cancer therapeutic efficacy and overcoming drug resistance.
The nanoparticle-based drug delivery system holds great attraction to overcome or circumvent multidrug resistance (MDR) in cancer to date. In this work, a synthesized amphiphilic graft copolymer, N-octyl-O-sulfate chitosan (NOSC), and its paclitaxel (PTX)-encapsulated micelles (PTX-M) have been systematically investigated on the MDR reversal effect in vitro and in vivo as well as the mechanism of P-glycoprotein (P-gp) inhibition. NOSC in a wide concentration range even above the critical micelle concentration showed an effective effect on inhibiting P-gp-mediated PTX efflux, which was remarkably different from the surfactants and the Pluronic copolymers. Multiple mechanisms were involved in this effect of NOSC, such as stimulating P-gp ATPase, competitively impeding the binding of PTX with P-gp and reducing the fluidity of the cell membrane. PTX-M presented the highest cellular uptake and the lowest efflux rate of PTX, thereby yielding the optimal cytotoxicity on both the human hepatocellular liver carcinoma (HepG2) cells and the multidrug resistance HepG2 (HepG2-P) cells, which resulted from a combination of the inhibiting P-gp effect of NOSC and the bypassing P-gp action of the intact PTX-M. Additionally, PTX-M had superior blood persistence, tumor accumulation, and therapeutic efficacy after intravenous injection into the tumor-bearing mice. Furthermore, it was demonstrated that most of PTX-M as an intact form was delivered at the tumor site, which ensures the synergetic effect of NOSC micelles on drug delivery and P-gp inhibition. The aforementioned results suggested that NOSC micelles presented promising potential as an anticancer drug carrier for enhanced MDR cancer therapy.


[Prehospital triage in trauma patients; ambulance care and deployment of a mobile medical team].
- The prehospital trauma triage system consisting of regional ambulance services and overarching availability of mobile medical teams, the level criteria for trauma centres and in-hospital care for trauma patients are well-organised in the Netherlands.- However, the quality of prehospital triage in the Netherlands is inadequate at the moment, with an average under-triage rate of more than 30%. There is, thus, much room for improvement in the quality of prehospital triage.- Research in this area is now taking off, partly because of the arrival of a new quality indicator from the Netherlands National Health Care Institute, which states that at least 90% of multiple-trauma patients should be primarily taken to a level 1 trauma centre.