Attentional and evaluative biases for smoking cues in nicotine dependence: component processes of biases in visual orienting.
The present study investigated attentional and evaluative biases for smoking-related cues in cigarette smokers and non-smokers. Using a visual probe task, we manipulated the presentation conditions of the stimuli to examine: (1). whether smokers have a bias to allocate attention towards smoking-related pictures that appear below the threshold of conscious awareness; and (2). whether attentional biases for smoking-related pictures that appear above the threshold of awareness operate both in initial orienting and in the maintenance of attention. We also obtained explicit and implicit measures of the valence of the smoking-related pictures from pleasantness ratings and from behavioural responses on a stimulus-response compatibility (SRC) task. Results showed that smokers, but not non-smokers, had an attentional bias for smoking-related pictures which had been presented at two exposure durations (200 and 2000 ms). The bias was not found in a brief (17 ms) masked exposure condition, so there was no evidence that it operated preconsciously. Smokers also showed greater preferences for smoking-related than control cues, compared with non-smokers, on both the explicit and implicit indices of stimulus valence. Results are discussed with reference to incentive and cognitive models of addiction.


Don't sleep on it: Less sleep reduces risk for depressive symptoms in cognitively vulnerable undergraduates.
The current research tested a new theory of depression that integrates work on sleep and cognition. In general, good sleep is essential for physical and mental health. However, we theorize that sleep can actually increase risk for depressive symptoms in cognitively vulnerable individuals. This is because the negative cognitions generated by these individuals are strengthened and consolidated each night during sleep. Three studies were conducted to test this theory. Studies 1 (n = 134) and 2 (n = 47) used prospective designs and showed that undergraduates with high, but not low, levels of cognitive vulnerability were most likely to exhibit increases in depressive symptoms when sleeping well as operationalized by self-reported quality and objectively measured duration (via actigraphy). Study 3 (n = 40) used an experimental design and provides the first causal evidence that it may be possible to prevent future depressive symptoms in cognitively at-risk undergraduates by restricting their sleep during times of high perceived stress. (PsycINFO Database Record


Changing the urban design of cities for health: The superblock model.
Car-dependent city planning has resulted in high levels of environmental pollution, sedentary lifestyles and increased vulnerability to the effects of climate change. The Barcelona Superblock model is an innovative urban and transport planning strategy that aims to reclaim public space for people, reduce motorized transport, promote sustainable mobility and active lifestyles, provide urban greening and mitigate effects of climate change. We estimated the health impacts of implementing this urban model across Barcelona. We carried out a quantitative health impact assessment (HIA) study for Barcelona residents ≥20 years (N = 1,301,827) on the projected Superblock area level (N = 503), following the comparative risk assessment methodology. We 1) estimated expected changes in (a) transport-related physical activity (PA), (b) air pollution (NO2), (c) road traffic noise, (d) green space, and (e) reduction of the urban heat island (UHI) effect through heat reductions; 2) scaled available risk estimates; and 3) calculated attributable health impact fractions. Estimated endpoints were preventable premature mortality, changes in life expectancy and economic impacts. We estimated that 667 premature deaths (95% CI: 235-1,098) could be prevented annually through implementing the 503 Superblocks. The greatest number of preventable deaths could be attributed to reductions in NO2 (291, 95% PI: 0-838), followed by noise (163, 95% CI: 83-246), heat (117, 95% CI: 101-137), and green space development (60, 95% CI: 0-119). Increased PA for an estimated 65,000 persons shifting car/motorcycle trips to public and active transport resulted in 36 preventable deaths (95% CI: 26-50). The Superblocks were estimated to result in an average increase in life expectancy for the Barcelona adult population of almost 200 days (95% CI: 99-297), and result in an annual economic impact of 1.7 billion EUR (95% CI: 0.6-2.8). The Barcelona Superblocks were estimated to help reduce harmful environmental exposures (i.e. air pollution, noise, and heat) while simultaneously increase PA levels and access to green space, and thereby provide substantial health benefits. For an equitable distribution of health benefits, the Superblocks should be implemented consistently across the entire city. Similar health benefits are expected for other cities that face similar challenges of environmental pollution, climate change vulnerability and low PA levels, by adopting the Barcelona Superblock model.


Proteolytic self-cleavage of hepatitis B virus core protein may generate serum e antigen.
A model is proposed to explain the presence of the e antigen (HBeAg) of hepatitis B virus (HBV) in the serum of individuals infected with this virus. The e antigen, which has only recently been characterized, is a fragment of the virus core, or nucleocapsid, protein. Serum HBeAg is a valuable clinical marker for active HBV infection because its appearance correlates both with virus replication in the liver and with the presence of circulating virions. In this study a protease-like amino acid sequence was identified at the amino terminus of the core protein sequence. Experimental evidence indicates that HBeAg may be produced by proteolytic self-cleavage of the core protein.


Substrate utilization and high energy phosphate levels of hearts from hyperdynamic septic rats.
Experiments were conducted to test the hypothesis that the previously demonstrated depression in ventricular function of rats with hyperdynamic sepsis was a result of depressed high energy phosphate levels or altered myocardial substrate utilization. Rats were inoculated with a pooled fecal homogenate, and 48 hr later their hearts were removed and studied using the Langendorff preparation. The coronaries were perfused with a hydrostatic pressure of 90 mmHg, and hearts were paced at 310-320 beats/min. Substrate oxidation was determined by supplying 14C-labeled glucose, lactate, or palmitate in physiologic concentrations, ie, 5.5, 1, and 0.6 mM, respectively. Hearts were frozen either in situ or after 40-50 min of perfusion for the determination of tissue metabolite levels. Myocardial content of high energy phosphates, total adenine nucleotides, and creatine were similar in septic animals and time-matched controls both in situ and after perfusion. Oxidation of exogenous substrates accounted for the total myocardial O2 consumption in both groups of perfused hearts. Palmitate oxidation was responsible for approximately 50% of the total O2 consumption of the heart, with glucose accounting for approximately 20% and lactate for the remainder. The percentage contribution of the three substrates to oxidative metabolism was similar in hearts from septic and time-matched controls; therefore, myocardial substrate preference was not altered by sustained sepsis. These studies also indicate that ischemia and the concomitant fall in high energy phosphates do not contribute to the myocardial dysfunction of hyperdynamic sepsis.


Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer.
There is growing evidence that chronic stress and other behavioral conditions are associated with cancer pathogenesis and progression, but the mechanisms involved in this association are poorly understood. We examined the effects of two mediators of stress, norepinephrine and epinephrine, on the activation of signal transducer and activator of transcription-3 (STAT3), a transcription factor that contributes to many promalignant pathways. Exposure of ovarian cancer cell lines to increasing concentrations of norepinephrine or epinephrine showed that both independently increased levels of phosphorylated STAT3 in a dose-dependent fashion. Immunolocalization and ELISA of nuclear extracts confirmed increased nuclear STAT3 in response to norepinephrine. Activation of STAT3 was inhibited by blockade of the beta1- and beta2-adrenergic receptors with propranolol, and by blocking protein kinase A with KT5720, but not with the alpha receptor blockers prazosin (alpha1) and/or yohimbine (alpha2). Catecholamine-mediated STAT3 activation was not inhibited by pretreatment with an anti-interleukin 6 (IL-6) antibody or with small interfering RNA (siRNA)-mediated decrease in IL-6 or gp130. Regarding the effects of STAT3 activation, exposure to norepinephrine resulted in an increase in invasion and matrix metalloproteinase (MMP-2 and MMP-9) production. These effects were completely blocked by STAT3-targeting siRNA. In mice, treatment with liposome-incorporated siRNA directed against STAT3 significantly reduced isoproterenol-stimulated tumor growth. These studies show IL-6-independent activation of STAT3 by norepinephrine and epinephrine, proceeding through the beta1/beta2-adrenergic receptors and protein kinase A, resulting in increased matrix metalloproteinase production, invasion, and in vivo tumor growth, which can be ameliorated by the down-regulation of STAT3.


Impaired beta-adrenergic hyperpolarization in arteries from prehypertensive spontaneously hypertensive rats.
Stimulation of beta-adrenoceptors leads to vascular smooth muscle hyperpolarization, presumably through the beta-adrenoceptors/Gs protein/adenylate cyclase/ATP-sensitive K(+)-channels (KATP) signaling cascade, which may play an important role in the sympathetic control of membrane potential. beta-Adrenoceptor-mediated hyperpolarization has been shown to be impaired in the established stage of experimental hypertension. The present study tested the hypothesis that beta-adrenergic hyperpolarization may be defective before the development of hypertension in some forms of genetic hypertension. We evaluated beta-adrenoceptor-mediated hyperpolarization using microelectrodes in mesenteric resistance arteries from 5-week-old, prehypertensive, spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). Isoproterenol-induced hyperpolarization was significantly smaller in SHR than in WKY (10(-7) mol/L: -4.6+/-0.6 versus -7.8+/-0.8 mV, P<0.01; 10(-6) mol/L -7.8+/-0.5 versus -9.8+/-0.6 mV, P<0.05; n=9). Furthermore, hyperpolarization to cholera toxin, a direct activator of Gs protein, was also impaired in SHR. On the other hand, hyperpolarization to forskolin, an adenylate cyclase activator, and to levcromakalim, a KATP opener, was comparable between groups. These findings suggest that beta-adrenoceptor-mediated hyperpolarization is defective in SHR before the development of hypertension, presumably because of an abnormality at the Gs protein site. Considering the importance of membrane potential in the control of vascular tone, altered beta-adrenergic control of membrane potential might play a role in the development of hypertension in SHR.


Metabolomic profile of response to supplementation with β-carotene in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
Two chemoprevention trials found that supplementation with β-carotene increased the risk of lung cancer and overall mortality. The biologic basis of these findings remains poorly understood. The objective was to compare the on-study change in metabolomic profiles of men randomly assigned to receive or not receive β-carotene supplements in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial; participants were Finnish male smokers assigned to 1 of 4 intervention groups: 1) α-tocopherol, 2) β-carotene, 3) both, or 4) placebo. Fifty participants with both baseline and follow-up fasting serum samples were randomly selected from each of these groups. Metabolomic profiling was conducted by mass spectrometry. The association between change in each metabolite over time and trial assignment (β-carotene or no β-carotene) was estimated by linear regression. We measured 489 metabolites, and 17 changed significantly (P < 0.05) in response to β-carotene supplementation. More of these 17 metabolites were of xenobiotic origin than would be expected by chance (9 of 60, or 15%; P = 0.00004). We also found a suggestive association with 1,5-anhydroglucitol-a marker of glycemic control (β = -0.379, P = 0.0071). Male smokers supplemented with β-carotene developed metabolomic profiles consistent with the induction of cytochrome P450 enzymes, the primary metabolizers of xenobiotics in humans. These findings may shed light on the increased mortality associated with β-carotene supplementation in the ATBC Study and suggest the need to explore potential interactions between medication use and dietary supplements, particularly among smokers. This trial was registered at clinicaltrials.gov as NCT00342992.


Nucleolin-Targeted DNA Nanotube for Precise Cancer Therapy through Förster Resonance Energy Transfer-Indicated Telomerase Responsiveness.
Precise drug delivery holds great promise in cancer treatment but still faces challenges in controllable drug release in tumor cells specifically. Herein, a nucleolin-targeted and telomerase-responsive DNA nanotube for drug release was developed. First, a DNA nanosheet with four capture strands on its surface was prepared, which could bind and load ricin A chain (RTA). The RTA-loaded nanosheet was further converted into a DNA nanotube with a high Förster resonance energy transfer (FRET) efficiency in the presence of a Cy3-modified DNA fastener by hybridizing with the Cy5-modified DNA and another DNA-containing telomerase primer sequence along the long sides. Moreover, the aptamer of nucleolin was assembled on the DNA nanotube by combining with the hybrid chain at the terminal. The aptamer-functionalized and RTA-loaded DNA nanotube displayed enhanced tumor permeability and precise drug release in response to the telomerase in tumor cells, following the change of the FRET signal and RTA-induced cell death. Moreover, the DNA nanotube was applied successfully in vivo, and there was an obvious inhibition of tumor growth on xenograft-bearing mice following systemic administration, indicating that the constructed DNA nanotube represents a promising platform for precise RTA delivery in target cancer therapy.


Characterization of silver particles in the stratum corneum of healthy subjects and atopic dermatitis patients dermally exposed to a silver-containing garment.
Silver is increasingly being used in garments to exploit its antibacterial properties. Information on the presence of silver nanoparticles (AgNPs) in garments and their in vivo penetration across healthy and impaired skin from use is limited. We investigated the presence of AgNPs in a silver containing garment and in the stratum corneum (SC) of healthy subjects (CTRLs) and individuals with atopic dermatitis (AD). Seven CTRLs and seven AD patients wore a silver sleeve (13% Ag w/w) 8 h/day for five days on a forearm and a placebo sleeve on the other forearm. After five days, the layers of the SC were collected by adhesive tapes. The silver particles in the garment and SC were characterized by scanning electron microscopy with energy dispersive X-ray analysis (SEM-EDX) and atomic force microscopy (AFM). AFM and SEM revealed the presence of sub-micrometre particles having a broad range of sizes (30-500 nm) on the surface of the garment that were identified as silver. On the SC tapes collected from different depths, aggregates with a wide range of sizes (150 nm-2 μm) and morphologies were found. Most aggregates contained primarily silver, although some also contained chlorine and sulfur. There was no clear difference in the number or size of the aggregates observed in SC between healthy and AD subjects. After use, AgNPs and their aggregates were present in the SC at different depths of both healthy subjects and AD patients. Their micrometre size suggests that aggregation likely occurred in the SC.


Role of hexaminolevulinate-guided fluorescence cystoscopy in bladder cancer: critical analysis of the latest data and European guidance.
Hexaminolevulinate (HAL) is an optical imaging agent used with fluorescence cystoscopy (FC) for the detection of non-muscle-invasive bladder cancer (NMIBC). Guidelines from the European Association of Urology (EAU) and a recent, more detailed European expert consensus statement agree that HAL-FC has a role in improving detection of NMIBC and provide recommendations on situations for its use. Since the publication of the EAU guidelines and the European consensus statement, new evidence on the efficacy of HAL-FC in reducing recurrence of NMIBC, compared with white light cystoscopy (WLC), have been published. To consider whether these new trials have an impact on the expert guidelines and on clinical practice (e.g. supporting existing recommendations or providing evidence for a change or expansion of practice), a group of bladder cancer experts from Denmark, Finland, Norway and Sweden met to address the following questions: What is the relevance of the new data on HAL-FC for clinical practice in managing NMIBC? What impact do the new data have on European guidelines? How could HAL-FC be used in clinical practice? and What further information on HAL-FC is required to optimize the management of NMIBC? This article reports the outcomes of the discussion at the Nordic expert panel meeting, concluding that, in line with European guidance, HAL-FC has an important role in the initial detection of NMIBC and for follow-up of patients to assess tumour recurrence after WLC. It provides practical advice, with an algorithm on the use of this diagnostic procedure for urologists managing NMIBC.


Architecture for a Mobile Robotic Camera Positioning System for Photogrammetric Data Acquisition in Hydroelectric Tunnels.
The structural condition of hydroelectric tunnels is important to the overall performance, safety, and longevity of generating stations. Significant effort is required to inspect, monitor, and maintain these tunnels. Photogrammetry is an effective method of collecting highly accurate visual and spatial data. However, it also presents the complex challenge of positioning a camera at thousands of difficult-to-reach locations throughout the large and varying-diameter tunnels. A semi-automated robotic camera positioning system was developed to enhance the collection of images within hydroelectric tunnels for photogrammetric inspections. A continuous spiral image network was developed to optimize the collection speed within the bounds of photography and capture-in-motion constraints. The positioning system and image network optimization reduce the time and effort required while providing the ability to adapt to different and varying tunnel diameters. To demonstrate, over 28,000 images were captured at a ground sampling distance of 0.4 mm in the 822 m long concrete-lined section of the Grand Falls Generating Station intake tunnel.


Modification of saccadic gain by reinforcement.
Control of saccadic gain is often viewed as a simple compensatory process in which gain is adjusted over many trials by the postsaccadic retinal error, thereby maintaining saccadic accuracy. Here, we propose that gain might also be changed by a reinforcement process not requiring a visual error. To test this hypothesis, we used experimental paradigms in which retinal error was removed by extinguishing the target at the start of each saccade and either an auditory tone or the vision of the target on the fovea was provided as reinforcement after those saccades that met an amplitude criterion. These reinforcement procedures caused a progressive change in saccade amplitude in nearly all subjects, although the rate of adaptation differed greatly among subjects. When we reversed the contingencies and reinforced those saccades landing closer to the original target location, saccade gain changed back toward normal gain in most subjects. When subjects had saccades adapted first by reinforcement and a week later by conventional intrasaccadic step adaptation, both paradigms yielded similar degrees of gain changes and similar transfer to new amplitudes and to new starting positions of the target step as well as comparable rates of recovery. We interpret these changes in saccadic gain in the absence of postsaccadic retinal error as showing that saccade adaptation is not controlled by a single error signal. More generally, our findings suggest that normal saccade adaptation might involve general learning mechanisms rather than only specialized mechanisms for motor calibration.


Locally Informed Simulation to Predict Hospital Capacity Needs During the COVID-19 Pandemic.
The coronavirus disease 2019 (COVID-19) pandemic challenges hospital leaders to make time-sensitive, critical decisions about clinical operations and resource allocations. To estimate the timing of surges in clinical demand and the best- and worst-case scenarios of local COVID-19-induced strain on hospital capacity, and thus inform clinical operations and staffing demands and identify when hospital capacity would be saturated. Monte Carlo simulation instantiation of a susceptible, infected, removed (SIR) model with a 1-day cycle. 3 hospitals in an academic health system. All people living in the greater Philadelphia region. The COVID-19 Hospital Impact Model (CHIME) (http://penn-chime.phl.io) SIR model was used to estimate the time from 23 March 2020 until hospital capacity would probably be exceeded, and the intensity of the surge, including for intensive care unit (ICU) beds and ventilators. Using patients with COVID-19 alone, CHIME estimated that it would be 31 to 53 days before demand exceeds existing hospital capacity. In best- and worst-case scenarios of surges in the number of patients with COVID-19, the needed total capacity for hospital beds would reach 3131 to 12 650 across the 3 hospitals, including 338 to 1608 ICU beds and 118 to 599 ventilators. Model parameters were taken directly or derived from published data across heterogeneous populations and practice environments and from the health system's historical data. CHIME does not incorporate more transition states to model infection severity, social networks to model transmission dynamics, or geographic information to account for spatial patterns of human interaction. Publicly available and designed for hospital operations leaders, this modeling tool can inform preparations for capacity strain during the early days of a pandemic. University of Pennsylvania Health System and the Palliative and Advanced Illness Research Center.


Determination of carbamates in edible vegetable oils by ultra-high performance liquid chromatography-tandem mass spectrometry using a new clean-up based on zirconia for QuEChERS methodology.
In this study a fast, selective and sensitive multiresidue method based on QuEChERS methodology has been evaluated and validated for the determination of carbamate pesticides, in edible vegetable oils by UHPLC-MS/MS. A new clean-up sorbent, Supel(TM) QuE Z-Sep(+), has been successfully applied in vegetable oil extracts. Z-Sep(+) was compared with other sorbents (i.e. mixture of C18 and PSA) previously used for dispersive solid phase extraction of these matrices, reducing more effectively matrix effects without a significant decrease of analyte recoveries. Matrix effect was studied in different matrices (extra-virgin olive, sunflower, maize, linseed and sesame oil) being ≤│30│% for most of the studied pesticides. Under optimum conditions, recoveries ranged from 74% to 101%, with relative standard deviations lower than 10%. Limits of quantification ranged from 0.09 to 2.0 µg kg(-1), allowing their determination at the low concentration levels demanding by current legislation.


Translation and validation of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) version 4 quality of life instrument into Arabic language.
Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) has been translated from English into several languages. Currently, there is no validated translation of FACT-BMT in Arabic. Here, we are reporting the first Arabic translation and validation of the FACT-BMT. The study was approved by the Institutional Research Advisory Council. The Arabic translation followed the standard Functional Assessment of Chronic Illness Therapy (FACIT.org) translation methodology (with permission). Arabic FACT-BMT (50- items) was statistically validated. Cronbach's alpha for internal consistency, Spearman's rank correlation coefficients method for Inter-scale correlations and Principal Component Analysis for factorial construct validity was used. One hundred and eight consecutive relapsed /refractory lymphoma patients who underwent high dose chemotherapy and autologous stem cell transplant were enrolled. There were 68 males (63%) and 40 females (37%) with a median age of 29 years (range 14-62). After Arabic questionnaire pre-testing (Cronbach's alpha 0.744), the study included 108 patients. Cronbach's alpha for the entire FACT-BMT indicated an excellent internal consistency (0.90); range (0.67 to 0.91). Cronbach's alpha for sub-groups of social (0.78), emotional (0.67) and functional wellbeing was (0.88). Cronbach's alpha for bone marrow transplant (0.81), FACT-General (0.89), and FACT- Trial Outcome Index (TOI); (0.91) also revealed excellent internal consistency. Patients had high scores in all domains of quality of life, indicating that most patients were leading a normal life. This translation of FACT-BMT in Arabic was reviewed and approved for submission by the FACIT.org. Our data reports the first translated, validated and approved Arabic version of FACT-BMT. This will help large numbers of Arabic speaking patients undergoing stem cell/bone marrow transplantation, across the globe.


Topological Analysis of Transthyretin Disassembly Mechanism: Surface-Induced Dissociation Reveals Hidden Reaction Pathways.
The proposed mechanism of fibril formation of transthyretin (TTR) involves self-assembly of partially unfolded monomers. However, the mechanism(s) of disassembly to monomer and potential intermediates involved in this process are not fully understood. In this study, native mass spectrometry and surface-induced dissociation (SID) are used to investigate the TTR disassembly mechanism(s) and the effects of temperature and ionic strength on the kinetics of TTR complex formation. Results from the SID of hybrid tetramers formed during subunit exchange provide strong evidence for a two-step mechanism whereby the tetramer dissociates to dimers that then dissociate to monomers. Also, the SID results uncovered a hidden pathway in which a specific topology of the hybrid tetramer is directly produced by assembly of dimers in the early steps of TTR disassembly. Implementation of SID to dissect protein topology during subunit exchange provides unique opportunities to gain unparalleled insight into disassembly pathways.


Nitidine Chloride-Induced CYP1 Enzyme Inhibition and Alteration of Estradiol Metabolism.
The cytochrome P450 (P450) 1 family is an important phase I enzyme involved in carcinogen activation. Nitidine chloride (NC) is a pharmacologically active alkaloid with polyaromatic hydrocarbon found in the roots of Zanthoxylum nitidum (Roxb.) DC, a traditional medicinal herb widely used in China. We examined the inhibitory effects of NC on CYP1A1, 1B1, and 1A2. NC significantly inhibited CYP1A1- and 1B1-catalyzed ethoxyresorufin O-deethylation activity (IC50 = 0.28 ± 0.06 and 0.32 ± 0.02 μM, respectively) in a concentration-dependent manner, but only showed slight inhibition of CYP1A2 activity (IC50 > 50 μM). Kinetic analysis revealed that NC competitively inhibited CYP1B1 with a K i value of 0.47 ± 0.05 μM, whereas NC caused a mixed type of inhibition on CYP1A1 with K i and K I values of 0.14 ± 0.04 and 0.19 ± 0.09 μM, respectively. The observed enzyme inhibition neither required NADPH nor revealed time dependency. Molecular docking manifested the generation of strong hydrogen-bonding interactions of Ser116 in CYP1A1 and Ser127 in CYP1B1 with methoxy moiety of NC. Additionally, NC-induced alteration of estradiol (E2) metabolism was also investigated in the present study. Hydroxyestradiols, including 2-hydroxyestradiol [(2-OHE2) nontoxic] and 4-hydroxyestradiol [(4-OHE2) genotoxic] generated in recombinant enzyme incubation systems and cultured MCF-7 cells were analyzed, and NC was found to preferentially inhibit the nontoxic 2-hydroxylation activity of E2 mediated by CYP1A1. In conclusion, NC was a mixed type inhibitor of CYP1A1 and a competitive inhibitor of CYP1B1. The remarkable inhibition on E2 2-hydroxylation might increase the risk of 4-OHE2-induced genotoxicity. SIGNIFICANCE STATEMENT: CYP1 enzymes catalyze oxidative metabolism of a variety of compounds and are known to play a crucial role in the development of cancer. CYP1A1 and CYP1A2 are responsible for hydroxylation of estradiol (E2) at the C-2 position, resulting in the formation of 2-OHE2, which is proposed to be a detoxification pathway. However, CYP1B1-mediated hydroxylation of E2 at the C-4 position has been suggested to be a tumor initiator. The present study found that nitidine chloride is a mixed type inhibitor of CYP1A1 and a competitive inhibitor of CYP1B1. NC preferentially inhibited the nontoxic E2 2-hydroxylation pathway mediated by CYP1A1, which might increase the risk of 4-OHE2-induced genotoxicity and cause severe drug-drug interactions.


Human papillomavirus vaccination and risk of autoimmune diseases: A large cohort study of over 2million young girls in France.
Whether human papillomavirus (HPV) vaccination could induce or trigger autoimmune diseases (AID) has been questioned, and potentially contributes to low immunization coverage in France. This study evaluated the association between HPV vaccination and the risk of AID using routinely collected data sources. All girls aged 13-16years between 2008 and 2012, covered by the general health insurance scheme and without history of HPV vaccination or AID, were included and followed using French nationwide databases. Fourteen neurological, rheumatological, haematological, gastrointestinal or endocrine AID, were identified from ICD-10 codes allocated to hospital stays and long-term illnesses or by marker drugs. Their incidence was compared between girls exposed and non-exposed to HPV vaccination, using a Cox model adjusted for inclusion year, geographic area, socio-economic indicators, healthcare use level and other immunizations. Among 2,252,716 girls, 37% received HPV vaccine and 4,096 AID occurred during a mean follow-up time of 33months. The incidence of AID was not increased after exposure to HPV vaccination, except for Guillain-Barré syndrome (GBS) (incidence rate of 1.4 among exposed [20 cases] versus 0.4 per 100,000 PY among unexposed [23 cases]; adjusted HR: 3.78 [1.79-7.98]). This association persisted across numerous sensitivity analyses and was particularly marked in the first months following vaccination. Under the hypothesis of a causal relationship, this would result in 1-2 GBS cases attributable to HPV vaccine per 100,000 girls vaccinated. Our study provides reassuring results regarding the risk of AID after HPV vaccination, but an apparently increased risk of GBS was detected. Further studies are warranted to confirm this finding.


Two-dimensional electrophoresis protein profiling and identification in rat bronchoalveolar lavage fluid following allergen and endotoxin challenge.
The protein content of bronchoalveolar lavage fluid (BALF) from actively sensitised Brown Norway (BN) rats challenged with allergen (ovalbumin, OA) and from naïve Brown Norway rats challenged with endotoxin (lipopolysaccharide, LPS) was analyzed and compared to healthy controls treated with vehicle only. BALF proteins were analyzed by one-dimensional (1-D) and two-dimensional (2-D) gel electrophoresis and identified by peptide mass fingerprinting matrix assisted laser desorption/ionization-mass spectrometry (MALDI-MS) or nanoliquid chromatography-tandem MS (nanoLC-MS/MS) after in-gel trypsin digestion of selected 2-D gel spots. Our study shows that the BALF protein profile is significantly different in animals after allergen (OA) or endotoxin (LPS) challenge as compared to controls, concerning the content of proteins derived from plasma or produced locally in the lung. In both challenges the following proteins presented patterns which differed qualitatively compared to control: T-kininogen I and II, alpha-1-antitrypsin, calgranulin A, fetuin A and B, and haptoglobin. Other proteins were diminished in both challenges, such as Clara cell 10 kDa secretory protein (CC10) and pulmonary surfactant associated protein B (SP-B); c-reactive protein increased in the OA-challenge and decreased in the LPS-challenge, and pulmonary surfactant associated protein A (SP-A) was decreased in the OA-challenge and was not significantly changed in the LPS-challenge. The identified proteins could be important not only for the diagnosis but have also interesting implications for medical treatment of lung inflammatory conditions. Furthermore, even if based on a limited number of animals, our results are of interest for the identification of lung protein markers and a better understanding of the mechanisms involved in the pathogenesis of lung diseases.


Least-mean-squares phase unwrapping by use of an incomplete set of residue branch cuts.
A new technique for the least-mean-squares (LMS) phase-unwrapping method is developed that incorporates the concept of branch cuts between phase singularities (residues), which are usually associated with the path-following gradient integration technique. These branch cuts are introduced by decomposition of the least-mean-squares unwrapped phase into two separate components. The first results from the transverse part of the wrapped phase gradient, which is induced by residues of the original phase, and the second component is due to a potential component, independent of the residues. This decomposition allows the reconstruction of phase patterns with a high level of accuracy and consistency with the initial (wrapped) phase, even when only partial knowledge of the placement of branch cuts between residues is available. We show how the residue-induced phase, ignored by conventional LMS phase estimators, is reconstructed for a given boundary-value problem. The method is illustrated with interferometric quality-control measurements of optical fiber-connector terminations and also with synthetic aperture radar interferometry. These experiments demonstrate the high accuracy of the method in practical situations in which only a limited number of branch cuts are available.


A single-system account of semantic and lexical deficits in five semantic dementia patients.
In semantic dementia (SD), there is a correlation between performance on semantic tasks such as picture naming and lexical tasks such as reading aloud. However, there have been a few case reports of patients with spared reading despite profound semantic impairment. These reports have sparked an ongoing debate about how the brain processes conceptual versus lexical knowledge. One possibility is that there are two functionally distinct systems in the brain-one for semantic and one for lexical processing. Alternatively, there may be a single system involved in both. We present a computational investigation of the role of individual differences in explaining the relationship between naming and reading performance in five SD patients, among whom there are cases of both association and dissociation of deficits. We used a connectionist model where information from different modalities feeds into a single integrative layer. Our simulations successfully produced the overall relationship between reading and naming seen in SD and provided multiple fits for both association and dissociation data, suggesting that a single, cross-modal, integrative system is sufficient for both semantic and lexical tasks and that individual differences among patients are essential in accounting for variability in performance.


Can conditional cash transfers improve maternal health care? Evidence from El Salvador's Comunidades Solidarias Rurales program.
There is growing evidence on positive human capital impacts of large, poverty-focused cash transfer programs. However, evidence is inconclusive on whether cash transfer programs affect maternal health outcomes, and if so, through which pathways. We use a regression discontinuity design with an implicit threshold to evaluate the impact of Comunidades Solidarias Rurales in El Salvador on four maternal health service utilization outcomes: (a) prenatal care; (b) skilled attendance at birth; (c) birth in health facilities; and (d) postnatal care. We find robust impacts on outcomes at the time of birth but not on prenatal and postnatal care. In addition to income effects, supply-side health service improvements and gains in women's agency may have played a role in realizing these gains. With growing inequalities in maternal health outcomes globally, results contribute to an understanding of how financial incentives can address health systems and financial barriers that prevent poor women from seeking and receiving care at critical periods for both maternal and infant health.


Implementing and Optimizing Inpatient Access to Dermatology Consultations via Telemedicine: An Experiential Study.
Background/Introduction: In-house dermatology consultation services for hospitalized patients are not universally available in acute care hospitals. We encountered an unanticipated access gap for in-person dermatology consultations in our tertiary care hospital that routinely cares for complex high acuity patients with multiple comorbidities. To bridge this gap in specialist expertise in a timely manner, we expeditiously designed and implemented a telemedicine-supported inpatient dermatology consultation service. Methods: We conducted a retrospective review of 155 teledermatology consultations conducted between November 2017 and March 2019 as well as periodic prospective multidisciplinary process improvement meetings to optimize service-associated process maps and workflows. Results: Teledermatology consultations changed the working diagnosis of the primary team in 52.3% of cases and most commonly recommended medical management (61.9% of cases). In total 100% of patients accepted telemedicine support and rated their experience as positive. The first three periodic process improvement meetings led to significant improvements in teledermatology-related process maps and workflows. Discussion: Diagnostic concordance rates between the primary team and the teledermatologist were similar to those reported in the literature for in-person dermatology consultations. Important process improvements include establishing central responsibility of preparing and overseeing the consultation process, mandating the presence of a primary team representative during consultation and patient chart review by the teledermatologist before teleconsultation. Conclusion: Inpatient teledermatology consultation services can be instituted timely and continuously improved to reliably and effectively bridge access gaps, improve diagnostic accuracy and differentiate therapeutic approaches while maintaining patient satisfaction.


Specificity determinants for tyrosine protein kinase. A study with recombinant hirudin mutants.
Hirudin, the powerful anticoagulant agent of leech (Hirudo medicinalis) saliva, was readily phosphorylated by two spleen tyrosine protein kinases (TPK-IIB and TPK-III) at Tyr63 with Km values of 238 microM and 74 microM, respectively. The synthetic tridecapeptide DGDFEEIPEEYLQ, corresponding to the hirudin 53-65 C-terminal fragment, was phosphorylated even more efficiently than hirudin itself. Four hirudin mutants, in which one or more of the glutamic acids at positions 57, 58, 61 and 62 have been replaced by glutamines, were poorer substrates than hirudin. The mutant in which all four glutamates were substituted, [Gln57,58,61,62]hirudin, was virtually not phosphorylated by either TPK-IIB and TPK-III. Substitution of Glu57 and Glu58 was less deleterious than substitution of the two glutamic acids adjacent to Tyr63: [Gln61,62]hirudin exhibited a 20-fold lower phosphorylation efficiency with TPK-IIB. With TPK-III, however, the Km value of [Gln61,62]hirudin was slightly lower, while the Vmax decreased sixfold. The substitution of Glu62 alone was also more detrimental with TPK-IIB than with TPK-III. The behaviour of a third spleen TPK, named lyn TPK-I and belonging to the src family, was markedly different in that it did not phosphorylate hirudin but exhibited significant activity towards [Gln57,58,61,62]hirudin. Taken together, these data confirm and extend with a protein substrate the results obtained with short model peptides which indicated the stringent substrate requirements of TPK-IIB (and of TPK-III to a lesser extent) for N-terminal acidic residues. In contrast, such residues are deleterious with lyn TPK-I. These observations also support the concept that tyrosine protein kinases recognize specificity determinants situated in the vicinity of the target residue rather than requiring higher-order structural features.


Significance of skull osteoporosis to the development of peritumoral brain edema after LINAC-based radiation treatment in patients with intracranial meningioma.
Disruption of the tumor-brain barrier in meningioma plays a critical role in the development of peritumoral brain edema (PTBE). We hypothesized that osteoporotic conditions may be associated with PTBE occurrence after radiation in patients with intracranial meningioma. We measured Hounsfield units (HU) of the frontal skull on simulation brain CT in patients who underwent linear accelerator (LINAC)-based radiation treatment for intracranial meningioma. Receiver operating characteristic curve analysis was performed to determine the optimal cut-off values for several predictive factors. The cumulative hazard for PTBE was estimated and classified according to these factors. Hazard ratios were then estimated to identify independent predictive factors associated with the development of PTBE after radiation in intracranial meningioma patients. A total of 83 intracranial meningiomas in 76 patients who received LINAC-based radiation treatment in our hospital over an approximate 5-year period were included for the study. We found mean frontal skull HU ≤630.625 and gross tumor volume >7.194 cc to be independent predictors of PTBE after radiation treatment in patients with meningioma (hazard ratio, 8.41; P = 0.019; hazard ratio, 5.92; P = 0.032, respectively). In addition, patients who were ≥65 years showed a marginally significant association with PTBE. Our study suggests that possible osteoporotic conditions, large tumor volume, and older age may be associated with PTBE occurrence after LINAC-based radiation treatment for intracranial meningioma. In the future we anticipate that these findings may enhance the understanding of the underlying mechanisms of PTBE after radiation in meningioma patients.


Usage of compromised lung volume in monitoring steroid therapy on severe COVID-19.
Quantitative computed tomography (QCT) analysis may serve as a tool for assessing the severity of coronavirus disease 2019 (COVID-19) and for monitoring its progress. The present study aimed to assess the association between steroid therapy and quantitative CT parameters in a longitudinal cohort with COVID-19. Between February 7 and February 17, 2020, 72 patients with severe COVID-19 were retrospectively enrolled. All 300 chest CT scans from these patients were collected and classified into five stages according to the interval between hospital admission and follow-up CT scans: Stage 1 (at admission); Stage 2 (3-7 days); Stage 3 (8-14 days); Stage 4 (15-21 days); and Stage 5 (22-31 days). QCT was performed using a threshold-based quantitative analysis to segment the lung according to different Hounsfield unit (HU) intervals. The primary outcomes were changes in percentage of compromised lung volume (%CL, - 500 to 100 HU) at different stages. Multivariate Generalized Estimating Equations were performed after adjusting for potential confounders. Of 72 patients, 31 patients (43.1%) received steroid therapy. Steroid therapy was associated with a decrease in %CL (- 3.27% [95% CI, - 5.86 to - 0.68, P = 0.01]) after adjusting for duration and baseline %CL. Associations between steroid therapy and changes in %CL varied between different stages or baseline %CL (all interactions, P < 0.01). Steroid therapy was associated with decrease in %CL after stage 3 (all P < 0.05), but not at stage 2. Similarly, steroid therapy was associated with a more significant decrease in %CL in the high CL group (P < 0.05), but not in the low CL group. Steroid administration was independently associated with a decrease in %CL, with interaction by duration or disease severity in a longitudinal cohort. The quantitative CT parameters, particularly compromised lung volume, may provide a useful tool to monitor COVID-19 progression during the treatment process. Trial registration Clinicaltrials.gov, NCT04953247. Registered July 7, 2021, https://clinicaltrials.gov/ct2/show/NCT04953247.


Regulation of nicotinic receptor expression by the ubiquitin-proteasome system.
Control of ligand-gated ion channel (LGIC) expression is essential for the formation, maintenance and plasticity of synapses. Treatment of mouse myotubes with proteasome inhibitors increased the number of surface nicotinic acetylcholine receptors (AChRs), indicating LGIC expression is regulated by the ubiquitin-proteasome system (UPS). Elevated surface expression resulted from increased AChR delivery to the plasma membrane and not from decreased turnover from the surface. The rise in AChR trafficking was the direct result of increased assembly of subunits in the endoplasmic reticulum (ER). Because proteasome inhibitors also blocked ER-associated degradation (ERAD) of unassembled AChR subunits, the data indicate that the additional AChRs were assembled from subunits normally targeted for ERAD. Our data show that AChR surface expression is regulated by the UPS through ERAD, whose activity determines oligomeric receptor assembly efficiency.


[Quality rating of follow-up examinations conducted on breast cancer patients].
For breast centre certification, follow-up care data have to be presented, although the further treatment is carried out outside of the hospital. An analysis of 2062 patients with their first operation (breast cancer and carcinoma in situ) occurring between 1.1.1984 and 31.12.1998 has been conducted. The tracking of follow-up results ended on 1.7.2007. The survival of breast cancer patients appears to be superior in the pure clinical register than with cross-linking with additional registers (Epidemiological Cancer Register and registration of address office). The outcome of this is that the completed feedback of the cases of death (Cancer Register) and of living patients (registration of address office) increases the qualitative statement. The compliance with the data security laws may be ensured by pseudo-anonymisation.


Environmental public health tracking of childhood asthma using California health interview survey, traffic, and outdoor air pollution data.
Despite extensive evidence that air pollution affects childhood asthma, state-level and national-level tracking of asthma outcomes in relation to air pollution is limited. Our goals were to evaluate the feasibility of linking the 2001 California Health Interview Survey (CHIS), air monitoring, and traffic data; estimate associations between traffic density (TD) or outdoor air pollutant concentrations and childhood asthma morbidity; and evaluate the usefulness of such databases, linkages, and analyses to Environmental Public Health Tracking (EPHT). We estimated TD within 500 feet of residential cross-streets of respondents and annual average pollutant concentrations based on monitoring station measurements. We used logistic regression to examine associations with reported asthma symptoms and emergency department (ED) visits/hospitalizations. Assignment of TD and air pollution exposures for cross-streets was successful for 82% of children with asthma in Los Angeles and San Diego, California, Counties. Children with asthma living in high ozone areas and areas with high concentrations of particulate matter < 10 microm in aerodynamic diameter experienced symptoms more frequently, and those living close to heavy traffic reported more ED visits/hospitalizations. The advantages of the CHIS for asthma EPHT include a large and representative sample, biennial data collection, and ascertainment of important socio-demographic and residential address information. Disadvantages are its cross-sectional design, reliance on parental reports of diagnoses and symptoms, and lack of information on some potential confounders. Despite limitations, the CHIS provides a useful framework for examining air pollution and childhood asthma morbidity in support of EPHT, especially because later surveys address some noted gaps. We plan to employ CHIS 2003 and 2005 data and novel exposure assessment methods to re-examine the questions raised here.


Solid-State Order and Charge Mobility in [5]- to [12]Cycloparaphenylenes.
We report a computational study of mesoscale morphology and charge-transport properties of radially π-conjugated cycloparaphenylenes ([ n]CPPs) of various ring sizes ( n = 5-12, where n is the number of repeating phenyl units). These molecules are considered structural constituents of fullerenes and carbon nanotubes. [ n]CPP molecules are nested in a unique fashion in the solid state. Molecular dynamics simulations show that while intramolecular structural stability (order) increases with system size, intermolecular structural stability decreases. Density functional calculations reveal that reorganization energy, an important parameter in charge transfer, decreases as n is increased. Intermolecular charge-transfer electronic couplings in the solid state are relatively weak (due to curved π-conjugation and loose intermolecular contacts) and are on the same order of magnitude (∼10 meV) for each system. Intrinsic charge-carrier mobilities were simulated from kinetic Monte Carlo simulations; hole mobilities increased with system size and scaled as ∼ n4. We predict that disordered [ n]CPPs exhibit hole mobilities as high as 2 cm2/(V·s). Our computations show a strong correlation between reorganization energy and hole mobility (μ ∼ λ-4). Quantum mechanical calculations were performed on cofacially stacked molecular pairs for varying phenyl units and reveal that orbital delocalization is responsible for both decreasing reorganization energies and electronic couplings as n is increased.


Meningitis epidemics in Africa: a brief overview.
Every year, meningococcal meningitis causes thousands of deaths within the meningitis belt in sub-Saharan African countries. Large epidemic waves occur with a periodicity of 5-12 years. The waves do correspond to molecular changes in the expression of capsular or subcapsular antigens, which allow the bug to spread in susceptible populations. Serogroup A remains the major killer, even if in 2002, serogroup W135 ST-11 emerged in Burkina Faso, causing an important epidemic. However, the surveillance in the following years has showed a decrease in the W135 incidence and a clear predominance of serogroup A. Moreover, a new serogroup A strain belonging to ST-2859 seems to emerge and does represent a new threat for the coming seasons. In a vaccine perspective, and especially in the context of the development of an A conjugate vaccine; it is the key to strengthen the surveillance systems and to include molecular epidemiology as a tool for monitoring the molecular evolution of Neisseria meningitidis in Africa.


Adult neural stem cells and central nervous system repair.
It has long been believed that the adult mammalian central nervous system does not regenerate after injury. However, recent advances in the field of stem cell biology, including the identification of Musashi-1-positive neural stem cells (NSCs) or NSC-like cells, has provided new insight for the development of novel therapeutic strategies aimed at inducing regeneration in the damaged central nervous system (CNS). The major strategies for inducing regeneration in the damaged CNS can be classified into two subgroups: (1) activation of endogenous neural stem cells and (2) cell transplantation therapies. In this paper, we would like to summarize our recent findings on the functions of the neural RNA-binding protein Musashi-l expressed in neural stem cells in relation to insult-induced neurogenesis, and therapeutic interventions for spinal cord injury, especially focusing on the treatment of spinal cord injury in the acute phase with anti-IL-6 receptor blocking antibody.


[Pathophysiology of primary Sjögren's syndrome].
Primary Sgögren's syndrome (SSP) is one of the most common connective tissue disorder with an estimated prevalence between 0.6 and 1.7% of the general population. Lymphocytic infiltration of salivary gland is easily accessible favoring the diagnosis, and clinical and fundamental research. However, while many advances have been obtained in the recent decades, the pathophysiology of SSP remains unclear combining environmental factors with genetic predisposition. A central role tends to be attributed to salivary gland epithelial cells, originally designated as "innocent bystanders" and to B cells through the intervention of survey factors like BAFF. New T cells subsets are also carefully studied, particularly natural T regulatory and Th17 cells. They could indeed represent new therapeutic targets.


Hyperventilation-induced changes in periodic oscillations in forehead skin blood flow measured by laser Doppler flowmetry.
Rhythmic oscillations in forehead skin blood flow were studied with the laser Doppler technique in thirteen healthy subjects. During voluntary hyperventilation, a three-fold increase in relative amplitude of the spontaneous rhythmic oscillations in forehead skin blood flow was observed, whereas mean blood flow decreased by 15%. During hyperventilation, the relative amplitude of the oscillations was on average 36% of the mean blood flow value. The mean incidence of the oscillations increased significantly, from 68% of the measuring time before, to 96% of the measuring time during hyperventilation. The oscillation frequency was not affected by hyperventilation. Before, during and after hyperventilation the average oscillation frequency was 0.140 Hz (8.4 min-1), 0.145 Hz (8.7 min-1) respectively. The application of heat or a local anaesthetic to the skin attenuated the relative amplitude of the oscillations in forehead skin blood flow during hyperventilation as well as before and after.


Selection and Characterization of Palmitic Acid Responsive Patients with an OXPHOS Complex I Defect.
Mitochondrial disorders are genetically and clinically heterogeneous, mainly affecting high energy-demanding organs due to impaired oxidative phosphorylation (OXPHOS). Currently, effective treatments for OXPHOS defects, with complex I deficiency being the most prevalent, are not available. Yet, clinical practice has shown that some complex I deficient patients benefit from a high-fat or ketogenic diet, but it is unclear how these therapeutic diets influence mitochondrial function and more importantly, which complex I patients could benefit from such treatment. Dietary studies in a complex I deficient patient with exercise intolerance showed increased muscle endurance on a high-fat diet compared to a high-carbohydrate diet. We performed whole-exome sequencing to characterize the genetic defect. A pathogenic homozygous p.G212V missense mutation was identified in the TMEM126B gene, encoding an early assembly factor of complex I. A complementation study in fibroblasts confirmed that the p.G212V mutation caused the complex I deficiency. The mechanism turned out to be an incomplete assembly of the peripheral arm of complex I, leading to a decrease in the amount of mature complex I. The patient clinically improved on a high-fat diet, which was supported by the 25% increase in maximal OXPHOS capacity in TMEM126B defective fibroblast by the saturated fatty acid palmitic acid, whereas oleic acid did not have any effect in those fibroblasts. Fibroblasts of other patients with a characterized complex I gene defect were tested in the same way. Patient fibroblasts with complex I defects in NDUFS7 and NDUFAF5 responded to palmitic acid, whereas ACAD9, NDUFA12, and NDUFV2 defects were non-responding. Although the data are too limited to draw a definite conclusion on the mechanism, there is a tendency that protein defects involved in early assembly complexes, improve with palmitic acid, whereas proteins defects involved in late assembly, do not. Our data show at a clinical and biochemical level that a high fat diet can be beneficial for complex I patients and that our cell line assay will be an easy tool for the selection of patients, who might potentially benefit from this therapeutic diet.


Achilles tendon thickening does not affect elasticity and functional outcome after surgical repair of Achilles rupture: A retrospective study.
Previous studies have confirmed that Achilles tendon occurs Achilles thickening after repair surgery of the rupture. Although this mechanism has been elucidated in the laboratory, there are few reports on its impact on clinical function. We designed a retrospective study to investigate the Achilles thickening after Achilles tendon rupture repair and its correlation between the elasticity and postoperative function. In this retrospective analysis, patients who underwent surgical treatment for acute Achilles tendon rupture from April 2016 to April 2020 were included. All the patients were regularly followed up at 3 months, 1 year, and 2 years after surgery. American Orthopaedic Foot Ankle Surgeon (AOFAS) scale and Leppilahti score were used to evaluate functional outcomes. Achilles elasticity was measured by ultrasound shear wave of elasticity. Achilles thickening was calculated as maximal transverse and longitudinal diameter in cross-sectional plane of magnetic resonance scan. Sample t-tests was used for different follow-up periods. Correlation between Achilles thickening and other factors were analyzed using Pearson's method. p < 0.05 indicates a statistically significant difference. AOFAS scale and Leppilahti score at 1 year were significantly higher than at 3 months postoperatively (both p < 0.001). These functional scales were also improved at 2-year follow-up significantly (both p < 0.001). The dorsiflexion difference showed gradually recovery in each follow-up period (t = -17.907, p < 0.001). The elasticity of the Achilles appeared to continuously decreases during the postoperative follow-up period in all position sets (p < 0.001). In thickening evaluation, the cross-sectional area of the thickest plane of Achilles was significantly higher at 1 year postoperatively (310.5 ± 25.2) mm2 than that at 3 months postoperatively ((278.0 ± 26.2) mm2, t = -8.219, p < 0.001) and became thinner in 2-year magnetic resonance scan ((256.1 ± 15.1) mm2, t = 16.769, p < 0.001). The correlations between Achilles thickening, elasticity, and functional outcome did not show statistical significance (p > 0.05) in every follow-up period. Achilles tendon thickens after surgery in the 1st year, but begins to gradually return to thinning about 2 years after surgery. There was no significant correlation between the increase and decrease of thickening and the patients' clinical function scores, Achilles elasticity, and bilateral ankle dorsiflexion difference.


Low urinary kallikrein rats: different sensitivity of verapamil on hypertensive response to central acute cadmium administration.
Essential hypertension is a common disease caused by a combination of genetic and environmental factors. Cadmium (Cd), an important environmental pollutant, is able to induce hypertension in humans. In rats, intracerebroventricular (icv) Cd administration causes a sustained increase in arterial blood pressure. The kallikrein-kinin system appears an important regulator of cardiovascular function and rats with low renal excretion of kallikrein differ from normal-kallikrein Wistar rats in their pressor response to icv Cd. To clarify these differences in pressor response, we evaluated the protective effect of a calcium antagonist following the administration of 10 microg Cd icv. Pre-treatment with increasing doses of verapamil (100, 150200 microg) in normal-kallikrein rats produced a blocking of the hypertensive effects of Cd, even at the lower doses. In low-kallikrein rats we observed a dose-dependent inhibition of hypertensive effects at 100 and 150 microg, while at 200 microg there was, paradoxically, an increase in pressor values. Our results suggest that a genetically-determined defect in urinary kallikrein excretion leads to different modulation of brain calcium channels antagonists in the hypertensive response to icv Cd. This different sensitivity of low-kallikrein rats suggests that the hypertensive effect of icv Cd is, at least in part, the result of blocking the calcium channels, but is also sensitive to a new hemodynamic equilibrium, such as that present in low kallikrein rats, and probably intervenes as a modulator at the central level in other as yet not well identified systems, also linked to the hypotensive pathways, which may be activated in certain conditions.


Sex-specific alterations in NOS regulation of vascular function in aorta and mesenteric arteries from spontaneously hypertensive rats compared to Wistar Kyoto rats.
The present study tested the hypothesis that spontaneously hypertensive rats (SHR) have impaired nitric oxide synthase (NOS)-mediated regulation of vascular function versus Wistar-Kyoto rats (WKY). Aorta and small mesenteric arteries were studied from male and female SHR (M SHR and F SHR) and WKY (M WKY and F WKY). Phenylephrine (PE)-induced vasoconstriction was greater in aorta of M SHR versus all others (P < 0.05); there were neither sex nor strain differences in PE contraction in mesenteric arteries. The NOS inhibitor l-Nitro-Arginine Methyl Ester (l-NAME) increased PE-induced vasoconstriction in all rats, although the increase was the least in male SHR (P < 0.05), revealing a blunted vasoconstrictor buffering capacity of NOS. l-NAME increased sensitivity to PE-induced constriction only in mesenteric arteries of SHR, although, the maximal percent increase in contraction was comparable among groups. ACh-induced relaxation was also less in aorta from M SHR versus all others (P < 0.05). ACh relaxation was comparable among groups in mesenteric arteries, although SHR exhibited a greater NOS component to ACh-induced relaxation than WKY. To gain mechanistic insight into sex and strain differences in vascular function, NOS activity and NOS3 protein expression were measured. Aortic NOS activity was comparable between groups and M SHR had greater NOS3 expression than M WKY. In contrast, although vascular function was largely maintained in mesenteric arteries of SHR, NOS activity was less in SHR versus WKY. In conclusion, M SHR exhibit a decrease in NOS regulation of vascular function compared to F SHR and WKY, although this is not mediated by decreases in NOS activity and/or expression.


Physical activity attenuates but does not eliminate coronary heart disease risk amongst adults with risk factors: EPIC-CVD case-cohort study.
This study aimed to evaluate the association between physical activity and the incidence of coronary heart disease (CHD) in individuals with and without CHD risk factors. EPIC-CVD is a case-cohort study of 29 333 participants that included 13 582 incident CHD cases and a randomly selected sub-cohort nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Self-reported physical activity was summarized using the Cambridge physical activity index (inactive, moderately inactive, moderately active, and active). Participants were categorized into sub-groups based on the presence or the absence of the following risk factors: obesity (body mass index ≥30 kg/m2), hypercholesterolaemia (total cholesterol ≥6.2 mmol/L), history of diabetes, hypertension (self-reported or ≥140/90 mmHg), and current smoking. Prentice-weighted Cox regression was used to assess the association between physical activity and incident CHD events (non-fatal and fatal).Compared to inactive participants without the respective CHD risk factor (referent), excess CHD risk was highest in physically inactive and lowest in moderately active participants with CHD risk factors. Corresponding excess CHD risk estimates amongst those with obesity were 47% [95% confidence interval (CI) 32-64%] and 21% (95%CI 2-44%), with hypercholesterolaemia were 80% (95%CI 55-108%) and 48% (95%CI 22-81%), with hypertension were 80% (95%CI 65-96%) and 49% (95%CI 28-74%), with diabetes were 142% (95%CI 63-260%), and 100% (95%CI 32-204%), and amongst smokers were 152% (95%CI 122-186%) and 109% (95%CI 74-150%). In people with CHD risk factors, moderate physical activity, equivalent to 40 mins of walking per day, attenuates but does not completely offset CHD risk.


[Evaluation of vitamin C and E concentration--some nonenzymatic indicators of antioxidant protective barrier in pregnant women].
Many peroxidation processes taking place in organisms both in normal and pathological conditions are initiated among others by free radicals. Organisms developed many protective mechanisms to fight with detrimental effects of free radical activity. The aim of the study was to evaluate antioxidant protective barrier by determination of concentrations of some non-enzymatic parameters such as L-ascorbic acid and tocopherol in blood plasma, and to correlate assessed values with basic lipoprotein parameters. The study was carried out in 144 pregnant women in the second and third trimester. The subject were divided into four groups: diabetic pregnancy, pregnancy induced hypertension, diabetic pregnancy with hypertension, and healthy pregnant women. The study results show that pregnancy induced hypertension, diabetic pregnancy and diabetic pregnancy with hypertension are the factors which disturb lipoprotein metabolism and may cause atherosclerotic changes. Higher concentrations of alpha-tocopherol and L-ascorbic acid in plasma in diabetic pregnancy with hypertension may be an important factor which adopts woman's organism to oxidation stress in complicated pregnancy.


[Giant-cell tumor of the bone].
The giant-cell tumor of bone (GCT) is an aggressive benign, potentially malignant lesion, which biological behaviour is unpredictable. Its aggressivity is usually increasing through the recurrences and is related to the mitotic activity, the excessive metalloproteinase expression and to the alterations in different oncogens of the tumor cells. Statistically, 80% of the GCT-s have a benign course, with a local recurrence rate of 10-50%; about 10% of GCT-s undergo malignant transformation through their recurrences and 1-4% give pulmonary metastases even in case of a benign histology. Despite of the frequent recurrences, adequate treatment results in 96% to 98% cure in patients with GCT. The goal of surgery should be both in primary and recurrent cases: joint-sparing and careful curettage with use of adjuvants (bone cement and phenol, etc.) for decreasing the rate of recurrences. Resection is only in case of extensive joint destruction or malignancy indicated. Radiotherapy with modern supervoltage equipment minimalized the occurrence of secondary malignant transformation, however, its use is only in locations difficult for surgery (vertebra, sacrum, pelvis) recommended.


Milk matters: soluble Toll-like receptor 2 (sTLR2) in breast milk significantly inhibits HIV-1 infection and inflammation.
The majority of infants who breastfeed from their HIV-positive mothers remain uninfected despite constant and repeated exposure to virus over weeks to years. This phenomenon is not fully understood but has been closely linked to innate factors in breast milk (BM). Most recently we have focused on one such innate factor, soluble Toll-like receptor 2 (sTLR2) for its significant contribution as an inhibitor of inflammation triggered by bacterial and viral antigens. We hypothesized that sTLR2 in BM inhibits immune activation/inflammation and HIV-1 infection. sTLR2 protein profiles were analyzed in HIV-uninfected BM and showed dramatic variability in expression concentration and predominant sTLR2 forms between women. sTLR2 immunodepleted BM, versus mock-depleted BM, incubated with Pam(3)CSK(4) lead to significant increases in IL-8 production in a TLR2-dependant fashion in U937, HEK293-TLR2, and Caco-2. Importantly, TLR2-specific polyclonal and monoclonal antibody addition to BM prior to cell-free R5 HIV-1 addition led to significantly (P<0.01, P<0.001, respectively) increased HIV-1 infection in TZM-bl reporter cells. To confirm these findings, sTLR2-depletion in BM led to significantly (P<0.001) increased HIV-1 infection in TZM-bl cells. Notably, immunodepletion does not allow for the complete removal of sTLR2 from BM, thus functional testing shown here may underestimate the total effect elicited by sTLR2 against HIV-1 and synthetic bacterial ligand. This study provides evidence for the first time that sTLR2 in BM may provide a dual protective role for infants breastfeeding from their HIV-infected mothers by; (1) immunomodulating pro-inflammatory responses to bacterial ligands, and (2) directly inhibiting cell-free HIV-1 infection. Thus, sTLR2 in BM may be critical to infant health and prove beneficial in decreasing vertical HIV-1 transmission to infants.


Physiological and Transcriptome Analysis Reveal the Regulation Mechanism Underlying the Muscle Quality Effect of Dietary Schisandra chinensis in Triploid Crucian Carp (Carassius auratus).
Schisandra chinensis (sc) is generally demonstrated to improve antioxidant and immune functions in mammal. The present study through physiological and transcriptome analysis revealed alterations in muscle metabolisms of triploid crucian carp (Carassius auratus) cultured at different concentrations of S. chinensis diets (sc0, sc0.125%, sc0.25%, sc0.5%, sc1%, sc2%) after 8 weeks. The serum antioxidant enzyme activities analysis showed that dietary S. chinensis could reduce oxidative stress and increase organismic antioxidant capacity. Meanwhile, the detected results of muscle components presented that the amino acids and two flavor nucleotides of GMP and IMP significantly elevated while muscle crude lipid significantly reduced in S. chinensis feeding groups. In addition, springiness, chewiness, and fiber density in S. chinensis feeding groups muscle were significantly upregulated while muscle fiber diameter and area showed an opposite trend. By comparative transcriptome analysis of the muscles, functional enrichments of differentially expressed genes showed that multiple terms were related to purine metabolism, glycerolipid metabolism, regulation of actin cytoskeleton, and peroxisome. Finally, some key hub genes such as egln, gst, ggct, su1b, pi3kr4, myh9, lpl, gcdh, mylk, and col4a were identified by weighted gene co-expression network analysis. Taken together, our findings facilitate the understanding of the molecular basis underlying the muscle quality effect of dietary S. chinensis in triploid crucian carp, which provides valuable insights into the nutritional strategies of the aquaculture industry.


[Music perception, EEG and musical training].
Changes of EEG during listening to music were studied in two groups of probands, one of them with several years of training on a musical instrument. The EEG was recorded simultaneously from 19 electrodes (10:20 system) against connected ear lobe electrodes. One minute recording periods at rest before and after music were compared with a period of one minute recording during listening to music. 30 seconds of each of these recordings were studied by Fourier analysis. Averaged power and coherence spectra (between transversally adjacent electrodes and between electrodes on homologous regions of both hemispheres) were computed. Broad band parameters were chosen for 5 frequency bands between 4 and 32 Hz. Significant changes of the parameters were represented topographically. During listening to music, a significant reversible decrease of the parameters studied was found: in the musically trained group on both sides, but preponderantly on the right hemisphere, in the non-trained group almost exclusively on the left hemisphere. Moreover, in the trained group, the changes occurred more frequently and involved larger regions of the skull than in the untrained group. In addition, the first group had most changes in the frequency range between 18 and 24 Hz, the second group between 13 and 18 Hz. Finally, comparisons of the changes between the control period before music and music and those between the control period after music and listening to music led to additional conclusions on different strategies of the processing of musical information in musically trained and untrained persons.


Monitoring cardiac amyloidosis with multimodality imaging.
Cardiac amyloidosis (CA) refers to an infiltrative process involving amyloid fibril deposition in the myocardium causing restrictive cardiomyopathy. While various types can affect the heart, the predominant forms are immunoglobulin light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis. This review article explores the expanding field of imaging techniques used to diagnose AL-CA and ATTR-CA, highlighting their usefulness in prognostication and disease surveillance. Echocardiography is often the initial imaging modality to suspect CA and, since the incorporation of nonbiopsy criteria using bone scintigraphy, diagnosing ATTR-CA has become more attainable following exclusion of plasma cell dyscrasia. Cardiac magnetic resonance is progressively emerging as a vital tool for imaging CA, and is used in diagnosis, prognostication, and disease surveillance. The use of cardiac magnetic resonance in AL-CA is discussed, as it has been shown to accurately evaluate organ response to chemotherapy. As novel drug treatments emerge in the realm of ATTR-CA, the use of cardiovascular imaging surveillance to monitor disease progression is discussed, as it is gaining prominence as a critical consideration. The ongoing phase III trials investigating treatments for patients with ATTR-CA, will undoubtedly enhance our understanding of cardiac imaging surveillance.


Diffusive motion of C60 on a graphene sheet.
The motion of a C60 molecule over a graphene sheet at finite temperature is investigated both theoretically and computationally. We show that a graphene sheet generates a van der Waals laterally periodic potential, which directly influences the motion of external objects in its proximity. The translational motion of a C60 molecule near a graphene sheet is found to be diffusive in the lateral directions, while in the perpendicular direction, the motion may be described as diffusion in an effective harmonic potential which is determined from the distribution function of the position of the C60 molecule. We also examine the rotational diffusion of C60 and show that its motion over the graphene sheet is not a rolling motion.


Determinates of tumor response to radiation: tumor cells, tumor stroma and permanent local control.
The causes of tumor response variation to radiation remain obscure, thus hampering the development of predictive assays and strategies to decrease resistance. The present study evaluates the impact of host tumor stromal elements and the in vivo environment on tumor cell kill, and relationship between tumor cell radiosensitivity and the tumor control dose. Five endpoints were evaluated and compared in a radiosensitive DNA double-strand break repair-defective (DNA-PKcs(-/-)) tumor line, and its DNA-PKcs repair competent transfected counterpart. In vitro colony formation assays were performed on in vitro cultured cells, on cells obtained directly from tumors, and on cells irradiated in situ. Permanent local control was assessed by the TCD50 assay. Vascular effects were evaluated by functional vascular density assays. The fraction of repair competent and repair deficient tumor cells surviving radiation did not substantially differ whether irradiated in vitro, i.e., in the absence of host stromal elements and factors, from the fraction of cells killed following in vivo irradiation. Additionally, the altered tumor cell sensitivity resulted in a proportional change in the dose required to achieve permanent local control. The estimated number of tumor cells per tumor, their cloning efficiency and radiosensitivity, all assessed by in vitro assays, were used to predict successfully, the measured tumor control doses. The number of clonogens per tumor and their radiosensitivity govern the permanent local control dose.


Total synthesis and antibacterial testing of the A54556 cyclic acyldepsipeptides isolated from Streptomyces hawaiiensis.
The first total synthesis of all six known A54556 acyldepsipeptide (ADEP) antibiotics from Streptomyces hawaiiensis is reported. This family of compounds has a unique mechanism of antibacterial action, acting as activators of caseinolytic protease (ClpP). Assembly of the 16-membered depsipeptide core was accomplished via a pentafluorophenyl ester-based macrolactamization strategy. Late stage amine deprotection was carried out under neutral conditions by employing a mild hydrogenolysis strategy, which avoids the formation of undesired ring-opened depsipeptide side products encountered during deprotection of acid-labile protecting groups. The free amines were found to be significantly more reactive toward late stage amide bond formation as compared to the corresponding ammonium salts, giving final products in excellent yields. A thorough NMR spectroscopic analysis of these compounds was carried out to formally assign the structures and to aid with the spectroscopic assignment of ADEP analogues. The identity of two of the structures was confirmed by comparison with biologically produced samples from S. hawaiiensis. An X-ray crystallographic analysis of an ADEP analogue reveals a conformation similar to that found in cocrystal structures of ADEPs with ClpP protease. The degree of antibacterial activity of the different compounds was evaluated in vitro using MIC assays employing both Gram-positive and Gram-negative strains and a fluorescence-based biochemical assay.


Up with ecology, down with economy? The consolidation of the idea of climate change mitigation in the global public sphere.
Building on theories of valuation and evaluation, we develop an analytical framework that outlines six elements of the process of consolidation of an idea in the public sphere. We then use the framework to analyse the process of consolidation of the idea of climate change mitigation between 1997 and 2013, focusing on the interplay between ecological and economic evaluations. Our content analysis of 1274 articles in leading newspapers in five countries around the globe shows that (1) ecological arguments increase over time, (2) economic arguments decrease over time, (3) the visibility of environmental nongovernmental organizations as carriers of ecological ideas increases over time, (4) the visibility of business actors correspondingly decreases, (5) ecological ideas are increasingly adopted by political and business elites and (6) a compromise emerges between ecological and economic evaluations, in the form of the argument that climate change mitigation boosts, rather than hinders economic growth.


A prospective study of lumbo-pelvic coordination in patients with non-chronic low back pain.
Despite the current knowledge about abnormalities in the lumbo-pelvic coordination of patients with non-specific low back pain (LBP), it is unclear how such abnormalities change with time. Timing and magnitude aspects of lumbo-pelvic coordination during a trunk forward bending and backward return task along with subjective measures of pain and disability were collected at three-time points over a six-month period from 29 patients who had non-chronic LBP at the time of enrollment in the study. To enable investigation of abnormalities in lumbo-pelvic coordination of patients, we also included lumbo-pelvic coordination data of age and gender-matched back healthy individuals from an earlier study of our group. Finally, differences in lumbo-pelvic coordination between patients with moderate-severe LBP (i.e., those whose level of pain was ≥ 4 (out of 10) at all three data collection sessions; n = 8) and patients with low-moderate LBP (n = 21) were investigated. There were clear distinctions in measures of lumbo-pelvic coordination between patients with low-moderate and moderate-severe LBP. Contrary to our expectation, however, the abnormalities in magnitude aspects of lumbo-pelvic coordination were larger (F > 4.84, P < 0.012) in patients with low-moderate LBP. These abnormalities in patients with low-moderate LBP, compared to controls, included larger (>12°) pelvic and thoracic rotations as well as smaller (>10°) lumbar flexion. The abnormal lumbo-pelvic coordination of patients with non-specific LBP, observed at baseline, persisted (F < 1.96, P > 0.156) or worsen (F > 3.48, P < 0.04) over the course of study period despite significant improvement in their pain (18% decrease; F = 12.10, P < 0.001) and disability (10% decrease; F = 4.39, P = 0.017). Distinct but lingering abnormalities in lumbo-pelvic coordination, observed in patients with low-moderate and moderate-severe LBP, might have a role in persistence and/or relapse of symptoms in patients with non-specific LBP. Such inferences, however, should further be studied in future via investigation of the relationship between abnormalities in lumbo-pelvic coordination and clinical presentation of LBP.


The Strengths and Difficulties Questionnaire: the self-report version in American urban and suburban youth.
This study examined the factor structure of the Strengths and Difficulties Questionnaire (SDQ) in urban inner-city and suburban general population samples of American youth. The SDQ was administered to 4,661 predominantly minority urban youth (mean age = 13.0 years, SD = 2.02) and 937 predominantly Caucasian suburban youth (mean age = 14.0 years, SD = 1.56). The authors examined SDQ factor structure using structural equation modeling techniques. The fit for the 5-factor models in both samples was very good (comparative fit index = .96-.97). However, the factor loadings and, correspondingly, the scale reliabilities for most of the SDQ scales (except for Emotional Problems) were low, which suggests poor specificity of the items. Subsequent exploratory and confirmatory factor analyses suggested that a 3-factor structure had a comparable model fit and better internal consistency of the scales. The study concluded that, although the SDQ scales do conform reasonably well to a 5-factor model, the scales are unsatisfactory in other respects and that, in its present form, the instrument has inadequate psychometric characteristics. Future research is needed for further scale development.


What do review papers conclude about food and dietary patterns?
Nutrients and other bioactive constituents of foods may interact with each other and the surrounding food matrix in complex ways. Therefore, associations between single nutrients and chronic disease may be difficult to identify and interpret, but when dietary patterns (DPs) are examined the combination of many food factors will be considered. An explorative literature search of published review articles was conducted to obtain a fuller understanding of current DPs in epidemiological research, to discuss pros and cons of DPs in nutrition research, and to identify results of studies linking DPs to chronic disease risk in adults. Randomized feeding trials providing the experimental diets to study participants have repeatedly demonstrated that diets based on current dietary recommendations are associated with important health benefits. Systematic reviews of feeding trials and prospective population studies of DPs and chronic disease risk reach similar conclusions regardless of the methodology used to construct DPs. However, to date only a few review articles of DP studies have followed a systematic process using independent reviewers with strict inclusion, exclusion, and study quality criteria. Diets with plenty of plants foods, fish, and seafood that preferably include vegetable oils and low-fat dairy products are associated with a lower risk of most chronic diseases. In contrast, Western-type DPs with food products low in essential nutrients and high in energy, like sugar-sweetened beverages, sweets, refined cereals and solid fats (e.g. butter), and high in red and processed meats, are associated with adverse health effects. An emphasis on high-quality original research, and systematic reviews following a structured process to objectively select and judge studies, is needed in order to enforce a strong future knowledge base regarding DPs and chronic disease.


Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells.
Aberrant Notch signalling has been linked to many cancers including choroid plexus (CP) tumours, a group of rare and predominantly paediatric brain neoplasms. We developed animal models of CP tumours, by inducing sustained expression of Notch1, that recapitulate properties of human CP tumours with aberrant NOTCH signalling. Whole-transcriptome and functional analyses showed that tumour cell proliferation is associated with Sonic Hedgehog (Shh) in the tumour microenvironment. Unlike CP epithelial cells, which have multiple primary cilia, tumour cells possess a solitary primary cilium as a result of Notch-mediated suppression of multiciliate differentiation. A Shh-driven signalling cascade in the primary cilium occurs in tumour cells but not in epithelial cells. Lineage studies show that CP tumours arise from monociliated progenitors in the roof plate characterized by elevated Notch signalling. Abnormal SHH signalling and distinct ciliogenesis are detected in human CP tumours, suggesting the SHH pathway and cilia differentiation as potential therapeutic avenues.


Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies.
Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.


Candidate DNA replication initiation regions at human trinucleotide repeat disease loci.
The positions of DNA replication initiation regions (IRs) at three human trinucleotide repeat (TNR) disease loci were examined in order to characterize the role played by IRs in explaining the known locus-specific variation in TNR instability levels. Using three different normal cell lines, candidate IRs were identified at the HD, SCA-7 and SBMA loci. At each locus the IR is less than 3.6 kb from the CAG/CTG repeat tract. Preliminary studies with a cell line homozygous for an HD disease mutation indicated no change in the position of the candidate IR in spite of the mutation. Comparison with experimental results from model systems suggests that a complex relationship may exist between instability and the proximity and/or orientation of the repeats with respect to an IR.


Ovulation synchrony after follicle ablation in mares.
Two experiments were performed to determine the efficacy of ultrasound-guided transvaginal follicle ablation for synchronizing ovarian function in mares. The experiments were initiated at random stages of the oestrous cycle in control (nonablated) and follicle-ablated mares. On day 0, all follicles > or =10 mm in diameter were punctured, aspirated and curettaged in ablated mares, and, on day 4, two doses of PGF2alpha were administered with a 12 h interval between the doses to both ablated and nonablated (control) mares. In Expt 1, hCG was administered to the ablated mares on the first or second day after the largest follicle was > or =30 mm in diameter. In Expt 2, hCG was administered to ablated mares 6 days after PGF2alpha administration, at which time the largest follicle was expected to be > or =30 mm in diameter. FSH concentrations increased initially and decreased subsequently in the ablated mares, and the ablation-induced wave (first detection of a follicle > or =10 mm in diameter) was observed 1.9 days after ablation and was synchronous (1-3 days) in 90% of mares. In both Expts 1 and 2, the uniformity of follicular wave emergence among follicle-ablated mares resulted in significantly better synchrony of ovulation after PGF2alpha administration compared with that of control mares. The variation in the interval from PGF2alpha administration to ovulation in ablated mares was reduced further by hCG administration. In the ablation + hCG groups, ovulation synchrony occurred 6-10 days after PGF2alpha administration in Expt 1 (13/16, 81%) and 7-8 days after PGF2alpha administration in Expt 2 (7/8, 88%). The extended period of ovulation in Expt 1 compared with that of Expt 2 (5 versus 2 days) was inherent in the experimental design, as hCG was not administered in Expt 1 until the largest follicle reached > or =30 mm in diameter, whereas in Expt 2 the experimental design was modified such that hCG was administered 6 days after PGF2alpha administration. As a result, in Expt 2 all but one mare in the ablation + hCG group ovulated within a 2 day period; 75% (6/8) ovulated on day 8 after PGF2alpha administration. Combined data from Expts 1 and 2 revealed that 96% (22/23) of the follicle-ablated mares ovulated within 48 h of hCG administration. Significantly more double ovulations were detected in follicle-ablated mares (10/41, 24%) than in control mares (1/21, 5%). The relatively high degree of ovulation synchrony obtained among mares in the present study indicates that this procedure can be used as an alternative method to synchronize ovarian function in horses.


Effects of a novel antitumor depsipeptide, FR901228, on human breast cancer cells.
Human breast cancer MCF7 and MDA-MB231 cells were used to investigate the biological and molecular activities of a novel naturally occurring agent, FR901228 (FR), that possesses a potent antitumor activity against human and murine tumor cells. Investigation of the cytotoxicity of FR and induction of internucleosomal DNA degradation in FR-treated cultures revealed that FR induced apoptotic-like cell death of MCF7 and MDA-MB231 cells. In FR-treated apoptotic cultures, flow cytometry revealed that there was a significant decrease of cells in S phase of the cell cycle. In FR-treated cells there was an increased expression of p21Cip1 and phosphorylation of Bcl-2 as determined by Western immunoblotting, and a novel cytoplasmic kinase of 33 kDa, p33 kinase, as determined by the in-gel kinase assay using myelin basic protein (MBP) as a substrate. Increased expression of p21CiP1, phosphorylation of Bcl-2, and activation of p33 MBP kinase may play part of the key mechanism for FR-induced apoptosis.


Marine food pollutants as a risk factor for hypoinsulinemia and type 2 diabetes.
Some persistent environmental chemicals are suspected of causing an increased risk of type 2 diabetes mellitus, a disease particularly common after the age of 70. This concern was examined in a cross-sectional study of elderly subjects from a fishing population with elevated contaminant exposures from seafood species high in the food chain. Clinical examinations of 713 Faroese residents aged 70-74 years (64% of eligible population) included fasting plasma concentrations of glucose and insulin, and glycosylated hemoglobin. Lifetime exposure to persistent environmental chemicals from pilot whale and other traditional food was estimated from a dietary questionnaire and by analysis of blood samples for polychlorinated biphenyls (PCBs) and related food contaminants. Septuagenarians with type 2 diabetes or impaired fasting glycemia tended to have higher PCB concentrations and higher past intake of traditional foods, especially during childhood and adolescence. In nondiabetic subjects, the fasting insulin concentration decreased by 7% (95% CI = -12% to -2%) for each doubling of the PCB concentration after adjustment for sex and body mass index at age 20. Conversely, the fasting glucose concentration increased by 6% (-1% to 13%) for each doubling in PCB. Similar associations were seen in subjects without impaired fasting glycemia, while further adjustment for current body mass index and lipid metabolism parameters attenuated some of the associations. Impaired insulin secretion appears to constitute an important part of the type 2 diabetes pathogenesis associated with exposure to persistent lipophilic food contaminants.


Enhancement of TWIK-related acid-sensitive potassium channel 3 (TASK3) two-pore domain potassium channel activity by tumor necrosis factor α.
TASK3 two-pore domain potassium (K2P) channels are responsible for native leak K channels in many cell types which regulate cell resting membrane potential and excitability. In addition, TASK3 channels contribute to the regulation of cellular potassium homeostasis. Because TASK3 channels are important for cell viability, having putative roles in both neuronal apoptosis and oncogenesis, we sought to determine their behavior under inflammatory conditions by investigating the effect of TNFα on TASK3 channel current. TASK3 channels were expressed in tsA-201 cells, and the current through them was measured using whole cell voltage clamp recordings. We show that THP-1 human myeloid leukemia monocytes, co-cultured with hTASK3-transfected tsA-201 cells, can be activated by the specific Toll-like receptor 7/8 activator, R848, to release TNFα that subsequently enhances hTASK3 current. Both hTASK3 and mTASK3 channel activity is increased by incubation with recombinant TNFα (10 ng/ml for 2-15 h), but other K2P channels (hTASK1, hTASK2, hTREK1, and hTRESK) are unaffected. This enhancement by TNFα is not due to alterations in levels of channel expression at the membrane but rather to an alteration in channel gating. The enhancement by TNFα can be blocked by extracellular acidification but persists for mutated TASK3 (H98A) channels that are no longer acid-sensitive even in an acidic extracellular environment. TNFα action on TASK3 channels is mediated through the intracellular C terminus of the channel. Furthermore, it occurs through the ASK1 pathway and is JNK- and p38-dependent. In combination, TNFα activation and TASK3 channel activity can promote cellular apoptosis.


Robot-assisted anterior lumbar interbody fusion (ALIF) using retroperitoneal approach.
Over the past few years, robot-assisted surgery has become increasingly popular, affecting virtually all surgical fields. It has been proven to overcome pitfalls of laparoscopic procedures, such as high complication rates and steep learning curve. We have, therefore, performed experimental anterior lumbar interbody fusion (ALIF) using retroperitoneal approach in swine model to test the feasibility of robot-assisted surgery in spinal surgery. In this report, we describe the setup with the da Vinci surgical system, operative method, result and discuss technical aspects and the future of robot-assisted ALIF. Experimental retroperitoneal dissection using robotic surgical system was successfully performed with great visual cue, minimal retraction and minimal bleeding. Although retroperitoneal approach for spinal fusion has never been attempted with robotic surgical system, we could demonstrate the possibility with swine model. Further studies and development of appropriate instruments will bring minimally invasive spine surgery to a new era.


p73 Interacts with human immunodeficiency virus type 1 Tat in astrocytic cells and prevents its acetylation on lysine 28.
Human immunodeficiency virus type 1 (HIV-1) Tat is a potent transcriptional activator of the HIV-1 promoter and also has the ability to modulate a number of cellular regulatory circuits including apoptosis. Tat exerts its effects through interaction with viral as well as cellular proteins. Here, we studied the influence of p73, a protein that is implicated in apoptosis and cell cycle control, on Tat functions in the central nervous system. Protein interaction studies using immunoprecipitation followed by Western blot and glutathione S-transferase pull-down assays demonstrated the association of Tat with p73. Tat bound to the N-terminal region of p73 spanning amino acids 1 to 120, and this interaction required the cysteine-rich domain (amino acids 30 to 40) of Tat. Association of p73 with Tat prevented the acetylation of Tat on lysine 28 by PCAF. Functional studies including RNA interference showed that p73 inhibited Tat stimulation of the HIV-1 promoter. Furthermore, p73 prevented the interaction of Tat with cyclin T1 in vitro but not in vivo. These findings suggest possible new therapeutic approaches, using p73, for Tat-mediated AIDS pathogenesis.