Synthesis of a zwitterionic silane and its application in the surface modification of silicon-based material surfaces for improved hemocompatibility.
A phosphorylcholine-like silane coupling agent bearing zwitterionic molecular structure was synthesized and studied. The chemical structure of this silane coupling agent was characterized by FTIR, 1H NMR and 31P NMR. The zwitterionic structure was successfully constructed onto the surface of silicon as a self-assembled layer (SAL). Static water contact angle, and atomic force microscopy (AFM) were used to investigate the wettability and surface topography of the modified silicon surfaces. Static water contact angle results indicated that the hydrophilicity of the surfaces could be effectively improved by the modification with this zwitterionic silane coupling agent. The changes of the topography and water contact angle of the modified surfaces with different incubation periods in PBS solution were also measured to evaluate the stability of the SALs. Blood compatibility of the modified surfaces were evaluated by testing the full-blood activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT), as well as by observing the adhered blood platelets onto the surface. The modified surfaces showed prolonged clotting time and fewer adherent platelets, revealing that the blood compatibility was evidently improved by the modification using this zwitterionic silane.


Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation.
Suppressor of cytokine signaling (SOCS) proteins are feedback inhibitors of the JAK/STAT pathway. SOCS3 has a crucial role in inhibiting STAT3 activation, cytokine signaling, and inflammatory gene expression in macrophages/microglia. To determine the role of SOCS3 in myeloid cells in neuroinflammation, mice with conditional SOCS3 deletion in myeloid cells (LysMCre-SOCS3(fl/fl)) were tested for experimental autoimmune encephalomyelitis (EAE). The myeloid-specific SOCS3-deficient mice are vulnerable to myelin oligodendrocyte glycoprotein (MOG)-induced EAE, with a severe, nonresolving atypical form of disease. In vivo, enhanced infiltration of inflammatory cells and demyelination is prominent in the cerebellum of myeloid-specific SOCS3-deficient mice, as is enhanced STAT3 signaling and expression of inflammatory cytokines/chemokines and an immune response dominated by Th1 and Th17 cells. In vitro, SOCS3-deficient macrophages exhibit heightened STAT3 activation and are polarized toward the classical M1 phenotype. SOCS3-deficient M1 macrophages provide the microenvironment to polarize Th1 and Th17 cells and induce neuronal death. Furthermore, adoptive transfer of M2 macrophages into myeloid SOCS3-deficient mice leads to delayed onset and reduced severity of atypical EAE by decreasing STAT3 activation, Th1/Th17 cells, and proinflammatory mediators in the cerebellum. These findings indicate that myeloid cell SOCS3 provides protection from EAE through deactivation of neuroinflammatory responses.


Compositional evolution of the emplaced fuel source in the vadose zone field experiment at Airbase Verløse, Denmark.
A field experiment was performed in a sandy vadose zone, studying the fate of an emplaced fuel-NAPL source, composed of 13 hydrocarbons and a tracer. The UNIFAC model was used to testthe nonideal behavior of the source, and the numerical model MIN3P was used for assessing the effect of biodegradation on source evolution. The diffusive loss to the surrounding vadose zone and the atmosphere created temporary gradients in mole fractions of the individual compounds within the source NAPL. The evolution of the source composition corresponded in general with expectations based on Raoult's Law, with the exception thatthe mole fractions of aromatic compounds in the source NAPL decreased faster than fractions of aliphatic compounds of similar volatility. Calculation of activity coefficients (y) using the UNIFAC model implied nonideal conditions, with composition-dependent gammas different from 1. Positive deviations were calculated for the aromatic compounds. The effect of biodegradation on source depletion, evaluated by numerical modeling, was greater for the aromatic as compared to the aliphatic compounds. Hence, the faster depletion of the aromatic relative to aliphatic compounds of similar volatility is both a result of the nonideality of the mixture and a result of partitioning and biodegradation in the pore-water. Vapor concentrations of the compounds in the source were in reasonable agreement with predictions based on the modified Raoult's Law with the UNIFAC predicted gammas and the NAPL composition for the most volatile compounds. For the less volatile compounds, the measured vapor concentrations were lower than predicted with the largest deviations for the least volatile compounds. This field experiment illustrated that nonideal behavior and bioenhanced source depletion need to be considered at multicomponent NAPL spill sites.


Intra-oral myofascial therapy versus education and self-care in the treatment of chronic, myogenous temporomandibular disorder: a randomised, clinical trial.
Myogenous temporomandibular disorders (TMD) are considered to be a common musculoskeletal condition. No studies exist comparing intra-oral myofascial therapies to education, self-care and exercise (ESC) for TMD. This study evaluated short-term differences in pain and mouth opening range between intra-oral myofascial therapy (IMT) and an ESC program. Forty-six participants with chronic myogenous TMD (as assessed according to the Research Diagnostic Criteria Axis 1 procedure) were consecutively block randomised into either an IMT group or an ESC group. Each group received two sessions per week (for five weeks) of either IMT or short talks on the anatomy, physiology and biomechanics of the jaw plus instruction and supervision of self-care exercises. The sessions were conducted at the first author's jaw pain and chiropractic clinic in Sydney, Australia. Primary outcome measures included pain at rest, upon opening and clenching, using an eleven point ordinal self reported pain scale. A secondary outcome measure consisted of maximum voluntary opening range in millimetres. Data were analysed using linear models for means and logistic regression for responder analysis. After adjusting for baseline, the IMT group had significantly lower average pain for all primary outcomes at 6 weeks compared to the ESC group (p < 0.001). These differences were not clinically significant but the IMT group had significantly higher odds of a clinically significant change (p < 0.045). There was no significant difference in opening range between the IMT and ESC groups. Both groups achieved statistically significant decreases in all three pain measures at six weeks (p ≤ 0.05), but only the IMT group achieved clinically significant changes of 2 or more points. This study showed evidence of superiority of IMT compared to ESC over the short-term but not at clinically significant levels. Positive changes over time for both IMT and ESC protocols were noted. A longer term, multi-centre study is warranted. Australian and New Zealand Clinical Trials Registry ACTRN12610000508077.


[Consultations with specialists in private practice in a Norwegian district].
After the Norwegian hospital reform of 2002, there has been increased acceptance of private-sector health-care providers. Still, the use of specialist services in private practice is less well documented. This article explores the use of private specialist health care in the south-east of Norway. The article is based on several sources of data, including data from the Norwegian Patient Register and from the National Insurance Administration on reimbursements. Also a survey was sent out to a sample of general practitioner; in-depth interviews were carried out with a sample of hospital physicians and private specialists. The article shows that private specialists with contract with Helse Øst provided 151 consultations per 1000 inhabitants over the period September to November 2003, while the public outpatient clinics provided 186 consultations. The service provision varies geographically and between specialties. In one county the use of private specialists is 174 consultations per 1000 inhabitants; in another it is 80 per 1000 inhabitants. Private-sector specialists within the fields of eye, ear-nose-throat and skin provided two thirds of all outpatient services in their respective fields. The results indicate that the services of specialists in private practice should be more focused on and discussed in relation to integrated healthcare and the relationship between specialised hospital services and primary healthcare.


Antimicrobial effects of Medicines for Malaria Venture Pathogen Box compounds on strains of Neisseria gonorrhoeae.
Therapeutic options for Neisseria gonorrhoeae are limited due to emerging global resistance. New agents and treatment options to treat patients with susceptible and multi-extensively drug-resistant N. gonorrhoeae is a high priority. This study used an in vitro approach to explore the antimicrobial potential, as well as synergistic effects of Medicine for Malaria Venture (MMV) Pathogen Box compounds against ATCC and clinical N. gonorrhoeae strains. Microbroth dilution assay was used to determine pathogen-specific minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the Pathogen Box compounds against susceptible and resistant N. gonorrhoeae strains, with modification, by adding PrestoBlue HS Cell Viability Reagent. A checkerboard assay was used to determine synergy between the active compounds and in conjunction with ceftriaxone. Time-kill kinetics was performed to determine if the compounds were either bactericidal or bacteriostatic. The Pathogen Box compounds: MMV676501, MMV002817, MMV688327, MMV688508, MMV024937, MMV687798 (levofloxacin), MMV021013, and MMV688978 (auranofin) showed potent activity against resistant strains of N. gonorrhoeae at an MIC and MBC of ≤10 µM. Besides the eight compounds, MMV676388 and MMV272144 were active against susceptible N. gonorrhoeae strains, also at MIC and MBC of ≤10 µM. All the compounds were bactericidal and were either synergistic or additive with fractional inhibitory concentration index ranging between 0.40 and 1.8. The study identified novel Pathogen Box compounds with potent activity against N. gonorrhoeae strains and has the potential to be further investigated as primary or adjunctive therapy to treat gonococcal infections.


Radiologic characteristics of primitive neuroectodermal tumors in children.
Radiographic findings are reviewed in 31 children with primitive neural ectodermal tumors seen at the Hospital for Sick Children from 1962 through 1983. Seventeen children were initially evaluated with computed tomography (CT). Ten of these had both CT studies and angiography. The tumors were large, irregular, typically iso- to hyperdense, and showed dense, heterogeneous contrast enhancement. Cysts were present in 65% and calcifications in 71% of cases. The angiographic findings were nonspecific, ranging from avascular to markedly vascular. Although these tumors were usually found in the cerebral hemisphere, particularly the frontal lobes, two cases are included of tumors arising elsewhere: one in the pineal and one in the suprasellar region. Epidemiologic data are reviewed.


Aligning the AACP Strategic Engagement Agenda with Key Federal Priorities in Health: Report of the 2016-17 Argus Commission.
The Argus Commission identified three major federal priorities related to health care, including the precision medicine initiative, the Cancer Moonshot and the opioid abuse epidemic. Current activities at the federal level were summarized and an analysis of activities within the profession, and academic pharmacy specifically, was prepared. The implications for pharmacy education, research and practice are compelling in all three areas. Recommendations, suggestions and two policy statements aim to optimize the attention to these priorities by the academy. Further, aligning the AACP Strategic Engagement agenda with the opportunities and threats acknowledged in the analysis is essential.


Low cost reconstructive options after musculoskeletal tumour resection in developing countries. Affordable, effective and durable alternatives.
Over the last two, three decades, the overall survival rates for non-metastatic malignant tumours of the bone have dramatically improved. This has become possible due to the recent advances and multidisciplinary approach towards these diseases, specifically the advent of multi-agent chemotherapy and radiotherapy. Limb salvage has now become the norm in the treatment of musculoskeletal tumours without compromising on the overall survival and recurrence of the disease. In the era of metal, prosthetic reconstruction has become the standard procedure specifically in the large tumours which involve the joints as this method of reconstruction helps in joint mobility and early weight-bearing. Considering the costs and resource constraints, multiple cost-effective, stable, durable reconstruction options have evolved over the last decade and these have also shown favourable func tional outcomes without compromising on the amount of resection and risk of local recurrence. The current literature review was planned to discuss various cost-effective, durable reconstructive options and their advantages and disadvantages. These include Van ness rotationplasty, allograft, autograft, devitalised tumour bone and Masqueletor induced membrane technique . .


Effect of tanshinone IIA on oxidative stress and apoptosis in a rat model of fatty liver.
Oxidative stress is a crucial factor associated with fatty liver disease, which raises the possibility of using antioxidants to improve liver steatosis. Tanshinone IIA (TSIIA) is a traditional Chinese medicine that has been reported to have antioxidant effects in vitro. The present study aimed to investigate whether TSIIA possesses antioxidant effects in vivo and whether TSIIA was able to improve liver steatosis. Hence, the ability of TSIIA to protect rats from liver disease was explored, particularly in regard to antioxidant activity. Rats were fed a high-lipid diet for 90 days, causing severe liver steatosis, both morphologically and biochemically. An increase in reactive oxygen species (ROS) in the liver was exhibited in addition to significantly elevated serum lipids and malondialdehyde (MDA). Furthermore, hepatocyte apoptosis was measured by Hoechst staining, reverse transcription-quantitative polymerase chain reaction and western blot analysis and an increase in hepatocyte apoptosis rate was indicated in mice on a high-fat diet. Following intraperitoneal injection of TSIIA (10 mg/kg/day), liver steatosis was significantly inhibited. In rats receiving TSIIA treatment, less ROS were indicated in the liver and significantly decreased levels of MDA (P<0.05) in serum were exhibited, whereas significantly increased activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX) were observed (P<0.05 and P<0.01, respectively). In addition, the rate of hepatocyte apoptosis was significantly decreased in the TSIIA group (P<0.01). However, TSIIA elicited no effect on serum lipid profiles. These results suggest that TSIIA attenuates oxidative stress by decreasing ROS and MDA production and enhancing the activity of T-SOD and GSH-PX, which may contribute to the inhibition of apoptosis and amelioration of liver steatosis.


Effect of hyperbaric oxygen on tissue distribution of mononuclear cell subsets in the rat.
In a previous study we found a significant temporary decrease in the ratio of CD4/CD8 (helper, inducer/suppressor, cytotoxic) T lymphocytes in the peripheral blood of healthy human volunteers after exposure to a single commonly used profile of hyperbaric oxygen (HBO). The transient nature of the changes suggested redistribution of T-cell subsets. The purpose of the present study was to verify such a redistribution and to locate possible target organs in an animal model. A single exposure of rats to HBO (0.28 MPa) induced a highly significant rapid decrease in the CD4/CD8 ratio in peripheral blood count (P < 0.0001), confirming our previous findings in humans. HBO also induced a significant increase in the CD4/CD8 ratio in the lungs and lymph nodes (P < 0.001) and a significant decrease in the ratio in the spleen (P < 0.01). Furthermore, exposure to HBO induced a significant increase in T cells bearing surface interleukin-2 receptors in the blood, spleen, lungs, and lymph glands (P < 0.001) and a significant decrease in T cells expressing alpha beta-receptors in the lungs (P < 0.001) and lymph glands (P < 0.05). Our findings suggest rapid T-cell activation after a brief exposure to HBO, with shifts of CD4 and CD8 subsets and variations in T-cell receptor type. These rapid changes in the parameters of cell-mediated immunity may represent the activation of protective mechanisms against the toxic effect of oxygen or the early stages of pulmonary oxygen toxicity.


A longitudinal study of parent-reported sensory responsiveness in toddlers at-risk for autism.
Atypical sensory responsivity and sensory interests are now included in the DSM 5 diagnostic criteria for autism spectrum disorder (ASD) under the broad domain of restricted and repetitive behavior (RRB). However, relatively little is known about the emergence of sensory-related features and their relation to conventionally defined RRB in the first years of life. Prospective, longitudinal parent-report data using the Sensory Experiences Questionnaire (SEQ) were collected for 331 high-risk toddlers (74 of whom met diagnostic criteria for ASD at age 2) and 135 low-risk controls. Longitudinal profiles for SEQ scores were compared between groups across ages 12-24 months. Associations between SEQ measures and measures of RRB subtypes (based on the Repetitive Behavior Scale, Revised) were also examined. Longitudinal profiles for all SEQ scores significantly differed between groups. SEQ scores were elevated for the ASD group from age 12 months, with differences becoming more pronounced across the 12-24 month interval. At both 12 and 24 months, most measures derived from the SEQ were significantly associated with all subtypes of RRB. These findings suggest that differences in sensory responsivity may be evident in high-risk infants later diagnosed with ASD in early toddlerhood, and that the magnitude of these differences increases over the second year of life. The high degree of association between SEQ scores and RRB supports the conceptual alignment of these features but also raises questions as to explanatory mechanisms.


[ANMCO Position paper: Antithrombotic treatment of patients with atrial fibrillation undergoing intracoronary stenting and/or acute coronary syndromes].
Patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) with or without acute coronary syndromes (ACS) represent a subgroup with a challenging pharmacological management. Indeed, if on the one hand antithrombotic therapy should reduce the risk related to recurrent ischemic events and/or stent thrombosis, on the other hand care should be taken to avoid major bleeding events. In recent years, several trials, which overall included more than 12 000 patients, have been conducted demonstrating the safety of different therapeutic combinations of oral antiplatelet and anticoagulant agents. In the present ANMCO position paper we propose a decision-making algorithm on antithrombotic strategies based on scientific evidence and expert consensus to be adopted in the periprocedural phase, at the time of hospital discharge and in the long-term follow-up of patients with AF undergoing PCI with/without ACS.


Improved detection of hepatic metastases with pulse-inversion US during the liver-specific phase of SHU 508A: multicenter study.
To compare conventional B-mode ultrasonography (US) alone with the combination of conventional B-mode US and contrast material-enhanced (SHU 508A) late-phase pulse-inversion US for the detection of hepatic metastases by using dual-phase spiral computed tomography (CT) as the standard of reference. One hundred twenty-three patients underwent conventional US, US in the liver-specific phase of SHU 508A, and single-section spiral CT. US and CT images were assessed by blinded readers. Differences in sensitivity, specificity, and the number and smallest size of metastases at conventional and contrast-enhanced US were compared by using CT as the standard of reference. Lesion conspicuity was assessed objectively (quantitatively) and subjectively by one reader before and after contrast material administration. In 45 of 80 (56%) patients with metastases, more metastases were seen at contrast-enhanced US than at conventional US. In three of these patients, conventional US images appeared normal. The addition of contrast-enhanced US improved sensitivity for the detection of individual metastases from 71% to 87% (P <.001). On a patient basis, sensitivity improved from 94% to 98% (P =.44), and specificity improved from 60% to 88% (P <.01). Contrast enhancement improved the subjective conspicuity of metastases in 66 of 75 (88%) patients and the objective contrast by a mean of 10.8 dB (P <.001). Contrast-enhanced US showed more metastases than did CT in seven patients, and CT showed more than did contrast-enhanced US in one of 22 patients in whom an independent reference (magnetic resonance imaging, intraoperative US, or pathologic findings) was available. Contrast-enhanced US improved sensitivity and specificity in the detection of hepatic metastases.


Lipopolysaccharide-induced IL-1 beta production by human uterine macrophages up-regulates uterine epithelial cell expression of human beta-defensin 2.
The uterine endometrium coordinates a wide spectrum of physiologic and immunologic functions, including endometrial receptivity and implantation as well as defense against sexually transmitted pathogens. Macrophages and epithelial cells cooperatively mediate innate host defense against bacterial invasion through the generation of immunologic effectors, including cytokines and antimicrobial peptides. In this study, we demonstrate that stimulation of peripheral blood monocytes and uterine macrophages with bacterial LPS induces the production of biologically active proinflammatory IL-1beta. High doses of estradiol enhance LPS-induced IL-1beta expression in an estrogen receptor-dependent manner. Furthermore, both peripheral blood monocyte- and uterine macrophage-derived IL-1beta induce secretion of antimicrobial human beta-defensin 2 by uterine epithelial cells. These data indicate dynamic immunologic interaction between uterine macrophages and epithelial cells and implicate a role for estradiol in the modulation of the immune response.


The generalized influence blocking maximization problem.
Given a network N and a set of nodes that are the starting point for the spread of misinformation across N and an integer k, in the influence blocking maximization problem the goal is to find k nodes in N as the starting point for a competing information (say, a correct information) across N such that the reach of the misinformation is minimized. In this paper, we deal with a generalized version of this problem that corresponds to a more realistic scenario, where different nodes have different costs and the counter strategy has a "budget" for picking nodes for a solution. Our experimental results show that the success of a given strategy varies substantially depending on the cost function in the model. In particular, we investigate the cost function implicitly used in all previous works in the field (i.e., all nodes have cost 1), and a cost function that assigns higher costs to higher-degree nodes. We show that, even though strategies that perform well in these two diverse cases are very different from each other, both correlate well with simple (but different) strategies: greedily choose high-degree nodes and choose nodes uniformly at random. Furthermore, we show properties and approximations results for the influence function in several diffusion models .


Motivational trade-offs and modulation of nociception in bumblebees.
Insects are traditionally thought to respond to noxious stimuli in an inflexible manner, without the ability to modulate their behavior according to context. We investigated whether bumblebees' attraction to high sucrose solution concentrations reduces their avoidance of noxious heat. Bees were given the choice between either unheated or noxiously heated (55 °C) feeders with different sucrose concentrations and marked by different colors. Bees avoided noxious feeders when the unheated feeders contained high sucrose concentrations, but progressively increased feeding from noxious feeders when the sucrose concentration at unheated feeders decreased. This shows a motivational trade-off of nociceptive responses. Bees used learned color cues for their decisions, and thus the trade-off was based on processing in the brain, rather than just peripheral processing. Therefore, bees can use contextual information to modulate nociceptive behavior. This ability is consistent with a capacity for pain experiences in insects.


Satellite-derived estimates of forest leaf area index in southwest Western Australia are not tightly coupled to interannual variations in rainfall: implications for groundwater decline in a drying climate.
There is increasing concern that widespread forest decline could occur in regions of the world where droughts are predicted to increase in frequency and severity as a result of climate change. The average annual leaf area index (LAI) is an indicator of canopy cover and the difference between the annual maximum and minimum LAI is an indicator of annual leaf turnover. In this study, we analyzed satellite-derived estimates of monthly LAI across forested coastal catchments of southwest Western Australia over a 12 year period (2000-2011) that included the driest year on record for the last 60 years. We observed that over the 12 year study period, the spatial pattern of average annual satellite-derived LAI values was linearly related to mean annual rainfall. However, interannual changes to LAI in response to changes in annual rainfall were far less than expected from the long-term LAI-rainfall trend. This buffered response was investigated using a physiological growth model and attributed to availability of deep soil moisture and/or groundwater storage. The maintenance of high LAIs may be linked to a long-term decline in areal average underground water storage and diminished summer flows, with an emerging trend toward more ephemeral flow regimes.


Effects of feeding fish meal to cows on digestibility, milk production, and milk composition.
Holstein cows in early lactation, producing about 30 kg/d of milk, were fed high energy diets containing 5% Megalac. Three protein treatments, soybean meal diet (16% CP), fish meal diet (16% CP), and soybean meal-fish meal diet (20% CP) were compared in a change-over design. Digestibilities of DM, gross energy, CP, and ADF were not affected significantly by protein treatments. The fish meal diet decreased DMI but increased milk and SCM production compared with the soybean meal diet. Daily production of milk, SCM, and milk components (fat, protein, and lactose) were highest and BW gain lowest for the high protein soybean meal-fish meal diet. The fish meal and soybean meal-fish meal diets increased fat percentage but decreased lactose percentage of milk compared with soybean meal diet. This suggests that, for each diet, the energy supply was adequate, and the observed changes were the effects of protein (i.e., AA) supply to the cows. Thus, there seems to be good reason to feed a good quality undegradable protein like fish meal to cows producing more than 30 kg/d of milk.


Vestibular implants: Hope for improving the quality of life of patients with bilateral vestibular loss.
The vestibular system plays an essential role in crucial tasks such as postural control, gaze stabilization, and spatial orientation. Currently, there is no effective treatment for a bilateral loss of the vestibular function (BVL). The quality of life of affected patients is significantly impaired. During the last decade, our group has explored the potential of using electrical stimulation to artificially restore the vestibular function. Our vestibular implant prototype consists of a custom modified cochlear implant featuring one to three vestibular electrodes implanted in the proximity of the ampullary branches of the vestibular nerve; in addition to the main cochlear array. Special surgical techniques for safe implantation of these devices have been developed. In addition, we have developed stimulation strategies to generate bidirectional eye movements as well as the necessary interfaces to capture the signal from a motion sensor (e.g., gyroscope) and use it to modulate the stimulation signals delivered to the vestibular nerves. To date, 24 vestibular electrodes have been implanted in 11 BVL patients. Using a virtual motion profile to modulate the "baseline" electrical stimulation, vestibular responses could be evoked with 21 electrodes. Eye movements with mean peak eye velocities of 32°/s and predominantly in the plane of the stimulated canal were successfully generated. These are within the range of normal compensatory eye movements during walking and were large enough to have a significant effect on the patients' visual acuity. These results indicate that electrical stimulation of the vestibular nerve has a significant functional impact; eye movements generated this way could be sufficient to restore gaze stabilization during essential everyday tasks such as walking. The innovative concept of the vestibular implant has the potential to restore the vestibular function and have a central role in improving the quality of life of BVL patients in the near future.


p53 and WAF1 are induced and Rb protein is hypophosphorylated during cell growth inhibition by the thymidylate synthase inhibitor ZD1694 (Tomudex).
In a previous study, we found that treatment of HCT-8 cells with ZD1694, a specific antifolate-based thymidylate synthase inhibitor, resulted in DNA fragmentation. In this study, we have demonstrated the dose- and time-dependent induction of DNA fragmentation accompanied by elevation of p53 and WAF1 protein expression by ZD1694. WAF1 mRNA showed a time-dependent increase, whereas p53 mRNA was not found to be significantly overexpressed. The initial increase in WAF1 mRNA was detected at 4 hr, but increased WAF1 protein expression was detected 8-24 hr after a 2-hr exposure. The amount of total and hypophosphorylated pRb seems to be rising greatly after ZD1694 exposure. The effects of ZD1694 on the expression of E2F1 and formation of the E2F1-Rb complex were investigated after a 2-hr drug exposure (IC90). The results showed a time-dependent decrease in E2F1 mRNA and protein expression; an increase in the abundance of the E2F-Rb complex could be demonstrated beginning 4 hr after drug exposure by a gel shift assay. Kinetic analysis showed increased availability of hypophosphorylated pRb for inhibition of E2F, which could indirectly result from WAF1-induced inhibition cyclin-dependent kinase activity. Whereas thymidylate synthase inhibition by ZD1694 was rapid in onset and maintained for at least 24 hr after drug treatment, drug-induced cellular growth inhibition was significant 24 hr after drug exposure. The increased abundance of hypophosphorylated pRb and binding to transcription factor E2F-1 is consistent with ZD1694-induced cell growth inhibition in HCT-8 cells. Therefore, the observed effect on downstream events after effective inhibition of thymidylate synthase may offer the critical determinants of response to ZD1694.


Cardiac injuries--a clinical and autopsy profile.
One hundred two patients sustaining cardiac injuries over a 4-year period were analysed to highlight the natural history of the cardiac injuries. There were 45 blunt, 36 stab, and 21 gunshot injuries. The injury involved the ventricle in 85, atrium in seven, pulmonary artery in five cases, and resulted in crush injury to the heart in the remaining five cases. Thirty-three patients (32.3%) died on the scene and 58 (56.9%) died during the transportation. Only 11 patients (10.8%) reached the hospital alive, and ten of these patients survived following thoracotomy and repair of the cardiac injury. The factors influencing the natural course of cardiac injury were analysed: 2.2% of patients with blunt cardiac trauma reached the hospital alive compared to 19.4% with stab and 14.3% with gunshot injuries; ventricular injuries had a greater prehospital mortality compared to atrial or pulmonary artery injuries; 11.3% of patients sustaining injury to right ventricle reached the hospital alive compared to 3% of those with left ventricular injuries. These data emphasize the need for rapid transport, immediate recognition, and aggressive surgical management, to make a favourable impact on the natural history of cardiac injuries.


Transcriptome analysis and transient transformation suggest an ancient duplicated MYB transcription factor as a candidate gene for leaf red coloration in peach.
Leaf red coloration is an important characteristic in many plant species, including cultivars of ornamental peach (Prunus persica). Peach leaf color is controlled by a single Gr gene on linkage group 6, with a red allele dominant over the green allele. Here, we report the identification of a candidate gene of Gr in peach. The red coloration of peach leaves is due to accumulation of anthocyanin pigments, which is regulated at the transcriptional level. Based on transcriptome comparison between red- and green-colored leaves, an MYB transcription regulator PpMYB10.4 in the Gr interval was identified to regulate anthocyanin pigmentation in peach leaf. Transient expression of PpMYB10.4 in tobacco and peach leaves can induce anthocyain accumulation. Moreover, a functional MYB gene PpMYB10.2 on linkage group 3, which is homologous to PpMYB10.4, is also expressed in both red- and green-colored leaves, but plays no role in leaf red coloration. This suggests a complex mechanism underlying anthocyanin accumulation in peach leaf. In addition, PpMYB10.4 and other anthocyanin-activating MYB genes in Rosaceae responsible for anthocyanin accumulation in fruit are dated to a common ancestor about 70 million years ago (MYA). However, PpMYB10.4 has diverged from these anthocyanin-activating MYBs to generate a new gene family, which regulates anthocyanin accumulation in vegetative organs such as leaves. Activation of an ancient duplicated MYB gene PpMYB10.4 in the Gr interval on LG 6, which represents a novel branch of anthocyanin-activating MYB genes in Rosaceae, is able to activate leaf red coloration in peach.


Sweet's syndrome and non-Hodgkin's lymphoma: the first report of this association.
A 58-year-old woman developed Sweet's syndrome one week after a flu-like illness. She was later found to have a centrocytic/centroblastic non-Hodgkins lymphoma. Six courses of chemotherapy were given during which the lesions of Sweet's syndrome resolved completely. As far as we are aware this is the first report of the association of Sweet's syndrome with a lymphoma.


Effect of Experience and Training on the Concordance and Precision of Strain Measurements.
This study sought to show the degree to which experience and training affect the precision and validity of global longitudinal strain (GLS) measurement and to evaluate the variability of strain measurement after feedback. The application of GLS for the detection of subclinical dysfunction has been recommended in an expert consensus document and is being used with increasing frequency. The role of experience in the precision and validity of GLS measurement is unknown, as is the efficacy of training. Fifty-eight readers, divided into 4 groups on the basis of their experience with GLS, calculated GLS from speckle strain analysis of 9 cases with various degrees of image quality. Intraclass correlation coefficients (ICCs), mean difference, SD, and coefficient of variation (CV) were compared against the measurements of a reference group that had experience with >1,000 cases of strain measurement. Individualized feedback was distributed, and repeat measurements were performed by 40 readers. Comparisons with the baseline variation provided information about whether feedback was effective. The ICC for GLS was significantly greater than that for ejection fraction regardless of image quality. Experience with strain measurement affected the concordance in strain values among the readers; the group with the highest level of experience showed significantly better ICC than those with no experience, although the ICC of the inexperienced readers was still very good (0.996 vs. 0.975; p = 0.0002). As experience increased, the mean difference, SD, and CV became significantly smaller. The CV of segmental strain analysis showed significant improvement after training, regardless of experience. The favorable interobserver agreement of GLS makes it more attractive than ejection fraction for follow-up of left ventricular function by multiple observers. Although experience is important, the precision of GLS was high for all groups. Training appears to be of most value for the assessment of segmental strain.


A Review of Pulmonary Arterial Hypertension Treatment in Extracorporeal Membrane Oxygenation: A Case Series of Adult Patients.
Little data is published describing the use of medications prescribed for pulmonary arterial hypertension (PAH) in patients receiving extracorporeal membrane oxygenation (ECMO). Even though many patients with PAH may require ECMO as a bridge to transplant or recovery, little is reported regarding the use of PAH medications in this setting. This retrospective case series summarizes the clinical experience of 8 patients with PAH receiving ECMO and reviews medication management in the setting of ECMO. Eight PAH patients, 5 of whom were female, ranging in age from 21 to 61 years old, were initiated on ECMO. Veno-arterial (VA) ECMO was used in 4 patients, veno-venous (VV) ECMO and hybrid ECMO configurations in 2 patients respectively. Common indications for ECMO included cardiogenic shock, bridge to transplant, and cardiac arrest. All patients were on intravenous (IV) prostacyclin therapy at baseline. Refractory hypotension was noted in 7 patients of whom 5 patients required downtitration or discontinuation of baseline PAH therapies. Three patients had continuous inhaled epoprostenol added during their time on ECMO. In patients who were decannulated from ECMO, PAH therapies were typically resumed or titrated back to baseline dosages. One patient required no adjustment in PAH therapy while on ECMO. Two patients were not able to be decannulated from ECMO. The treatment of critically ill PAH patients is challenging given a variety of factors that could affect PAH drug concentrations. In particular, PAH patients on prostacyclin analogues placed on VA ECMO appear to have pronounced systemic vasodilation requiring vasopressors which is alleviated by temporarily reducing the intravenous prostacyclin dose. Patients should be closely monitored for potential need for rapid titrations in prostacyclin therapy to maintain hemodynamic stability.


QTLs for uniform grain dimensions and germination selected during wheat domestication are co-located on chromosome 4B.
A major locus on the long arm of wheat chromosome 4B controls within-spikelet variation in both grain size and seed dormancy, the latter an important survival mechanism likely eliminated from wild wheat during domestication. Seed dormancy can increase the probability of survival of at least some progeny under unstable environmental conditions. In wild emmer wheat, only one of the two grains in a spikelet germinates during the first rainy season following maturation; and this within-plant variation in seed dormancy is associated with both grain dimension differences and position within the spikelet. Here, in addition to characterizing these associations, we elucidate the genetic mechanism controlling differential grain dimensions and dormancy within wild tetraploid wheat spikelets using phenotypic data from a wild emmer × durum wheat population and a high-density genetic map. We show that in wild emmer, the lower grain within the spikelet is about 30 % smaller and more dormant than the larger, upper grain that germinates usually within 3 days. We identify a major locus on the long arm of chromosome 4B that explains >40 % of the observed variation in grain dimensions and seed dormancy within spikelets. This locus, designated QGD-4BL, is validated using an independent set of wild emmer × durum wheat genetic stocks. The domesticated variant of this novel locus on chromosome 4B, likely fixed during the process of wheat domestication, favors spikelets with seeds of uniform size and synchronous germination. The identification of locus QGD-4BL enhances our knowledge of the genetic basis of the domestication syndrome of one of our most important crops.


Fine-scale variation in vector host use and force of infection drive localized patterns of West Nile virus transmission.
The influence of host diversity on multi-host pathogen transmission and persistence can be confounded by the large number of species and biological interactions that can characterize many transmission systems. For vector-borne pathogens, the composition of host communities has been hypothesized to affect transmission; however, the specific characteristics of host communities that affect transmission remain largely unknown. We tested the hypothesis that vector host use and force of infection (i.e., the summed number of infectious mosquitoes resulting from feeding upon each vertebrate host within a community of hosts), and not simply host diversity or richness, determine local infection rates of West Nile virus (WNV) in mosquito vectors. In suburban Chicago, Illinois, USA, we estimated community force of infection for West Nile virus using data on Culex pipiens mosquito host selection and WNV vertebrate reservoir competence for each host species in multiple residential and semi-natural study sites. We found host community force of infection interacted with avian diversity to influence WNV infection in Culex mosquitoes across the study area. Two avian species, the American robin (Turdus migratorius) and the house sparrow (Passer domesticus), produced 95.8% of the infectious Cx. pipiens mosquitoes and showed a significant positive association with WNV infection in Culex spp. mosquitoes. Therefore, indices of community structure, such as species diversity or richness, may not be reliable indicators of transmission risk at fine spatial scales in vector-borne disease systems. Rather, robust assessment of local transmission risk should incorporate heterogeneity in vector host feeding and variation in vertebrate reservoir competence at the spatial scale of vector-host interaction.


Clinical review 65. Evaluation and treatment of the patient with a pituitary incidentaloma.
Incidental pituitary adenomas are being found commonly with our improved neuroradiological imaging procedures. Screening for hormone oversecretion by these tumors appears to be warranted. For patients with macroadenomas, patients should also be screened for hypopituitarism. In the absence of visual field abnormalities or hypothalamic/stalk compression, it may be appropriate to observe such patients carefully with repeated CT or MRI scans. A limited amount of data suggests that significant tumor enlargement will occur in less than 15% of patients with microadenomas (7). However, all macroadenomas must start out as microadenomas, so periodic follow-up is indicated to assess this possibility. Macroadenomas, by their very existence at the time of detection, have already indicated a propensity for growth. Over the limited period of follow-up in the two series reported, significant growth occurred in almost one third of patients with macroadenomas (7, 8). Hemorrhage into such tumors is uncommon, but anticoagulation may predispose to this complication. When there is no evidence of visual field deficits, an attempt at medical therapy with a dopamine agonist is reasonable, realizing that only about 10% of such patients will respond with a decrease in tumor size. Surgery is indicated if there is evidence of tumor enlargement, especially when such growth is accompanied by compression of the optic chiasm, cavernous sinus invasion, or the development of pituitary hormone deficiencies.


Obesity is a risk factor for thyroid cancer in a large, ultrasonographically screened population.
Obesity is a well-known risk factor for many cancers, including those of the esophagus, colon, kidney, breast, and skin. However, there are few reports on the relationship between obesity and thyroid cancer. We conducted this study to determine whether obesity is a risk factor for thyroid cancer by systematically screening a selected population by ultrasonography. We obtained data from 15,068 subjects that underwent a routine health checkup from 2007 to 2008 at the Health Screening and Promotion Center of Asan Medical Center. Thyroid ultrasonography was included in the checkup, and suspicious nodules were examined by ultrasonography-guided aspiration. Those with a history of thyroid disease or family history of thyroid cancer were excluded from this study. In total, 15,068 subjects, 8491 men and 6577 women, were screened by thyroid ultrasonography. Fine-needle aspiration cytology was performed in 1427 of these patients based on the predefined criteria and thyroid cancer was diagnosed in 267 patients. The prevalence of thyroid cancer in women was associated with a high BMI (per 5 kg/m(2) increase) (odds ratios (OR)=1.63, 95% CI 1.24-2.10, P<0.001), after adjustment for age, smoking status, and TSH levels. There was no positive correlation between the prevalence of thyroid cancer in men and a high BMI (OR=1.16, 95% CI 0.85-1.57, P=0.336). There was no association between age, fasting serum insulin, or basal TSH levels and thyroid cancer in either gender. Obesity was associated with a higher prevalence of thyroid cancer in women when evaluated in a routine health checkup setting. This association between risk factor and disease was unrelated to serum insulin and TSH levels. Additional studies are needed to understand the mechanism(s) behind the association of obesity with thyroid cancer risk.


Extracts from two frequently consumed spices--cumin (Cuminum cyminum) and turmeric (Curcuma longa)--inhibit platelet aggregation and alter eicosanoid biosynthesis in human blood platelets.
In the traditional Indian system of medicine, Ayurveda, several spices and herbs are claimed to possess medicinal properties, such as being antithrombotic, antiatherosclerotic, hypolipidemic, anti-inflammatory etc. Earlier we have reported that extracts from several spices behave as antiaggregatory agents and inhibit eicosanoid synthesis. Similar studies with extracts prepared from cumin (Cuminum cyminum) and turmeric (Curcuma longa) were undertaken. Ethereal extract of both cumin and turmeric inhibited arachidonate-induced platelet aggregation. Extracts from these spices inhibited thromboxane B2 production from exogenous (14C) arachidonic acid (AA) in washed platelets; a simultaneous increase in the formation of lipoxygenase-derived products was observed. Less TxB2 was produced in blood samples treated with turmeric extract when they were allowed to clot. Turmeric extract inhibited incorporation of (14C)AA into platelet phospholipids and deacylation of AA-labelled phospholipids on stimulation with calcium ionophore A23187. Cumin extract was devoid of such effects. Extracts from the two spices reduced the formation of (14C)TxB2 from AA-labelled platelets when they were challenged with A23187. The anti-inflammatory property of turmeric may, in part, be explained by its effect on eicosanoid biosynthesis.


Antioxidants in dermatology.
The skin cells continuously produce, through cellular respiration, metabolic processes or under external aggressions, highly reactive molecules oxidation products, generally called free radicals. These molecules are immediately neutralized by enzymatic and non-enzymatic systems in a physiological and dynamic balance. In situations where this balance is broken, various cellular structures, such as the cell membrane, nuclear or mitochondrial DNA may suffer structural modifications, triggering or worsening skin diseases. several substances with alleged antioxidant effects has been offered for topical or oral use, but little is known about their safety, possible associations and especially their mechanism of action. The management of topical and oral antioxidants can help dermatologist to intervene in the oxidative processes safely and effectively, since they know the mechanisms, limitations and potential risks of using these molecules as well as the potential benefits of available associations.


Adult age-dependent differences in resting-state connectivity within and between visual-attention and sensorimotor networks.
Healthy aging is accompanied by structural and functional changes in the brain, among which a loss of neural specificity (i.e., dedifferentiation) is one of the most consistent findings. Little is known, however, about changes in interregional integration underlying a dedifferentiation across different functional systems. In a large sample (n = 399) of healthy adults aged from 18 to 85 years, we analyzed age-dependent differences in resting-state (RS) (task-independent) functional connectivity (FC) of a set of brain regions derived from a previous fMRI study. In that study, these regions had shown an age-related loss of activation specificity in visual-attention (superior parietal area 7A and dorsal premotor cortex) or sensorimotor (area OP4 of the parietal operculum) tasks. In addition to these dedifferentiated regions, the FC analysis of the present study included "task-general" regions associated with both attention and sensorimotor systems (rostral supplementary motor area and bilateral anterior insula) as defined via meta-analytical co-activation mapping. Within this network, we observed both selective increases and decreases in RS-FC with age. In line with regional activation changes reported previously, we found diminished anti-correlated FC for inter-system connections (i.e., between sensorimotor-related and visual attention-related regions). Our analysis also revealed reduced FC between system-specific and task-general regions, which might reflect age-related deficits in top-down control possibly leading to dedifferentiation of task-specific brain activity. Together, our results underpin the notion that RS-FC changes concur with regional activity changes in the healthy aging brain, presumably contributing jointly to age-related behavioral changes.


Effect of cell salvage on bleeding, transfusion of blood products, and bleeding parameters in patients undergoing liver transplantation with intraoperative massive blood transfusion.
Autologous transfusion using a cell saver system has been used in liver transplantation with controversial outcomes. Its efficiency in patients with massive intraoperative transfusion has not been studied yet. This study aimed to evaluate effect of cell salvage (CS) on intraoperative bleeding and transfusion practices in liver transplantation with massive intraoperative transfusion. Consecutive patients aged ≥18 years with intraoperative massive blood transfusion (≥ 6 units) between March 2014 and September 2020 were included. Patients subjected to CS were grouped as CS, whereas other patients were grouped as control. Number of transfused red blood cells was study's primary outcome. There were 38 and 32 patients in CS and control groups, respectively. Median blood loss was significantly lower in CS group than in control group (2500 mL vs. 4000 mL, p = 0.010). There were significantly more transfusions of red blood cells, fresh frozen plasma, platelets, and cryoprecipitates in CS group (p < 0.05). Postoperative median hemoglobin levels were determined as 4.8 g/dL and 8.2 g/dL in CS and control groups (p < 0.001). The decrease in postoperative hemoglobin levels compared to preoperative values was significantly higher in the CS group (p < 0.001). The mortality rate in postoperative first year was significantly higher in CS group than in control group (36.8% vs. 12.5%, p = 0.041). Use of CS in patients undergoing liver transplantation with massive intraoperative transfusion did not improve clinical and transfusion-related outcomes. In conclusion, its usage can be questionable given the absence of any clinical benefit and presence of poor outcomes.


Emergency Foot-and-Mouth Disease Vaccines A Malaysia 97 and A22 Iraq 64 Offer Good Protection against Heterologous Challenge with A Variant Serotype A ASIA/G-IX/SEA-97 Lineage Virus.
The continuous emergence of foot-and-mouth disease virus (FMDV) serotype A variants in South East Asia is of concern for international FMDV antigen banks, especially when in vitro tests predict a low antigenic match. A vaccination-challenge study was performed by using two emergency FMDV vaccines with A22 Iraq 64 (A22 IRQ) and A Malaysia 97 (A MAY 97) strains, against challenge with a variant strain of FMDV A/Asia/G-IX/SEA-97 lineage at 7- and 21-day post-vaccination (dpv). At 7 dpv, three of five female calves vaccinated with A MAY 97 and four of five vaccinated with A22 IRQ did not show lesions on the feet and were considered protected, while at 21 dpv all five calves were protected with each vaccine, indicating equal efficacy of both vaccine strains. Calves were protected despite relatively low heterologous neutralizing antibody titers to the challenge virus at the time of challenge. All the calves developed antibodies to the non-structural proteins, most likely due to the direct intradermolingual (IDL) inoculation. Only one calf from the A MAY 97-7 group had infectious virus in the serum 1-3-day post-challenge (dpc), while no virus could be isolated from the serum of cattle challenged on 21 dpv. The virus could be isolated from the oral swabs of all calves, 1-7 dpc with viral RNA detected 1-10 dpc. Nasal swabs were positive for virus 1-6 dpc in a small number of calves. The time between vaccination and infection did not have an impact on the number of animals with persistent infection, with almost all the animals showing viral RNA in their oro-pharyngeal fluid (probang) samples up to 35 dpc. Despite the poor in vitro matching data and field reports of vaccine failures, this study suggests that these vaccine strains should be effective against this new A/Asia/G/SEA-97 variant, provided they are formulated with a high antigen dose.


Plasticity as a plastic response: how submergence-induced leaf elongation in Rumex palustris depends on light and nutrient availability in its early life stage.
Plants may experience different environmental cues throughout their development which interact in determining their phenotype. This paper tests the hypothesis that environmental conditions experienced early during ontogeny affect the phenotypic response to subsequent environmental cues. This hypothesis was tested by exposing different accessions of Rumex palustris to different light and nutrient conditions, followed by subsequent complete submergence. Final leaf length and submergence-induced plasticity were affected by the environmental conditions experienced at early developmental stages. In developmentally older leaves, submergence-induced elongation was lower in plants previously subjected to high-light conditions. Submergence-induced elongation of developmentally younger leaves, however, was larger when pregrown in high light. High-light and low-nutrient conditions led to an increase of nonstructural carbohydrates in the plants. There was a positive correlation between submergence-induced leaf elongation and carbohydrate concentration and content in roots and shoots, but not with root and shoot biomass before submergence. These results show that conditions experienced by young plants modulate the responses to subsequent environmental conditions, in both magnitude and direction. Internal resource status interacts with cues perceived at different developmental stages in determining plastic responses to the environment.


Rotenone-induced G2/M cell cycle arrest and apoptosis in a human B lymphoma cell line PW.
Concentrations of rotenone (ROT) that block electron flow through mitochondrial complex I (100 nM) did not significantly alter either cell viability or the growth of PW cells. However, 10- to 50-fold higher concentrations (1-5 microM) were found to induce a dose-dependent cell cycle arrest predominantly at the G2/M stage of the cycle and apoptosis. Apoptosis was dependent on the cell cycle arrest, since apoptosis but not the G2/M arrest was prevented with the broad spectrum caspase inhibitor zVADfmk. Biochemical features of apoptosis included mitochondrial cytochrome c release, reactive oxygen species generation, and the activation of procaspase 3. Thus, ROT inhibition of mitochondrial electron transport may be insufficient to induce apoptosis in PW cells. Instead, apoptosis in these cells occurs as a consequence of disruption of the cell cycle and is only indirectly dependent upon mitochondrial electron transport.


Topological frustration of artificial spin ice.
Frustrated systems, typically characterized by competing interactions that cannot all be simultaneously satisfied, display rich behaviours not found elsewhere in nature. Artificial spin ice takes a materials-by-design approach to studying frustration, where lithographically patterned bar magnets mimic the frustrated interactions in real materials but are also amenable to direct characterization. Here, we introduce controlled topological defects into square artificial spin ice lattices in the form of lattice edge dislocations and directly observe the resulting spin configurations. We find the presence of a topological defect produces extended frustration within the system caused by a domain wall with indeterminate configuration. Away from the dislocation, the magnets are locally unfrustrated, but frustration of the lattice persists due to its topology. Our results demonstrate the non-trivial nature of topological defects in a new context, with implications for many real systems in which a typical density of dislocations could fully frustrate a canonically unfrustrated system.


Catalpol pretreatment attenuates cardiac dysfunction following myocardial infarction in rats.
To investigate the effects and mechanisms of catalpol on cardiac function in rats with isoproterenol (ISO)-induced myocardial infarction (MI). Adult male Wistar rats were divided into four groups: control group, ISO group, catalpol (L, low dose) group, and catalpol (H, high dose) group. Isoproterenol (85 mg/kg) was injected subcutaneously for 2 consecutive days to induce experimental MI. At the end of experiment, the effects of catalpol on cardiac function; apelin levels; apoptosis index; apelin, APJ, Bcl-2, and Bax protein expression; and caspase-3/9 activities were investigated. The rats in the ISO group showed lower left ventricular maximum rate of positive or negative pressure development (±LVdp/dtmax) and left ventricular end-systolic pressure (LVSP) and higher left ventricular end-diastolic pressure (LVEDP) than those in the control group, suggesting severe cardiac dysfunction. Interestingly, catalpol administration significantly ameliorated the ISO-induced cardiac dysfunction. The groups administered low and high dosages catalpol (5 and 10 mg/kg/day, respectively) showed higher ±LVdp/dtmax and LVSP and lower LVEDP than the group administered ISO alone. Catalpol markedly upregulated apelin levels in the plasma and myocardium. Further, catalpol increased the apelin and APJ expression levels in the myocardium of the ISO-treated rats. In addition, catalpol pretreatment inhibited cardiomyocyte apoptosis as indicated by a decrease in the TUNEL-positive cell percentage, alterations in the Bax and Bcl-2 expression levels, and a decline in caspase-3 and caspase-9 activities. Our results revealed that catalpol can improve cardiac function. Its protective effects may be linked to the enhancement of myocardium contractility, regulation of the apelin/APJ pathway, and inhibition of cardiomyocyte apoptosis.


Inner medullary plasma flow in the kidney with ureteral obstruction.
To test the thesis that ureteral obstruction causes medullary ischemia, we determined inner medullary plasma flow (IMPF) in rats with bilateral or unilateral ureteral obstruction, and after relief of obstruction, by the intravenous 125I-albumin infusion technique. A progressive decline in IMPF was observed during obstruction of 18 h duration, greater in bilateral obstruction (7% of normal at 5h) than in unilateral obstruction (28% of normal at 5 h). The elevation in ureteral pressure was greater and more sustained in bilateral obstruction. After relief of obstruction, IMPF rose to 69-78% of normal in both groups within 2 h. Histologic studies showed tubular necrosis in portions of the inner and outer medulla immediately beneath the renal pelvic epithelium after bilateral or unilateral obstruction of 18 h duration, and India ink perfusion studies showed very poor filling of vasa recta in these areas. The concentrating defect in the postobstructive kidney may be related, at least in part, to damage inflicted by medullary ischemia during obstruction.


North Atlantic Subtropical Gyre: SOFAR Floats Tracked by Moored Listening Stations.
In 1980, SOFAR (sound fixing and ranging) floats were tracked acoustically in the western North Atlantic entirely by means of moored autonomous listening stations. During a 5-month period 17 float trajectories were obtained in the eastern (45 degrees to 65 degrees W) Gulf Stream and subtropical gyre interior at depths of 700 and 2000 meters. These mid-depth trajectories suggest a time-varying Gulf Stream with instances of both a narrow, swift, westward recirculation south of the stream and a northeastward penetration into the Newfoundland Basin. A hundredfold increase of eddy kinetic energy was observed at 2000 meters from the gyre interior (south of 30 degrees N) to the Gulf Stream.


Clinical experience with chemoradiotherapy comprising S-1 plus low-dose cisplatin in a patient with stage IV anal cancer.
We report a case of anal cancer in a 58-year-old woman who complained of narrow, bloody stools and anal pain. Physical examination revealed anal stenosis associated with a circular mass arising in the anal canal. Histological examination of biopsy specimens confirmed a diagnosis of moderately differentiated squamous cell carcinoma. Enhanced computed tomography revealed anal cancer invading the levator ani and the vagina, with lymph-node, multiple hepatic, and pulmonary metastases. The patient received two cycle of chemoradiotherapy with S-1 plus low-dose cisplatin with rest for 4 weeks, leading to complete response of the primary lesion and a partial response of the metastatic lesions. Each cycle included oral S-1 (120 mg/body; day 1-21), cisplatin (10 mg/body; day 1-5, 8-12) and radiotherapy (2 Gy/day; day 1-5, 8-12, 15-19). Adverse effects of treatment were mild perineal skin erosion and mild appetite loss, but no hematologic toxicity. Although the patient died 16 months after first admission, chemoradiotherapy with S-1 plus cisplatin is potentially effective for the management of advanced anal cancer.


Correlation Between Optical Coherence Tomography and Photopic Negative Response of Flash Electroretinography in Ganglion Cell Complex Assessment in Glaucoma Patients.
To investigate the correlation between the photopic negative response (PhNR) of the light-adapted flash electroretinography (ERG) and measurements of standard automated perimetry (SAP) and optical coherence tomography (OCT) in assessment of retinal ganglion cells' (RGCs) affection in glaucoma. A cross-sectional study included 40 eyes of glaucoma patients and 40 eyes of age- and gender-matched normal subjects. Participants underwent a complete ophthalmologic assessment, SAP, OCT, and light-adapted flash ERG using the extended PhNR protocol of the International Society for Clinical Electrophysiology of Vision (ISCEV). Glaucomatous eyes were divided into 3 subgroups: mild (n = 15), moderate (n = 11) and severe glaucoma (n = 14) according to the mean deviation (MD) of SAP. Measurements of SAP, OCT and ERG parameters were analyzed, and correlations between PhNR measurements and other study measurements were evaluated. PhNR amplitudes and PhNR/b-wave ratios were significantly reduced in glaucoma cases compared to healthy controls, and they showed a significant and progressive decline across the three glaucoma subgroups (P < 0.05). An exception to this is PT (b-wave peak to PhNR trough) PhNR amplitude where its reduction was statistically non-significant when comparing between controls and mild glaucoma cases (P = 0.178), and between moderate and severe glaucoma cases (P = 0.714). PhNR amplitudes and PhNR/b-wave ratios correlated significantly with SAP and OCT parameters (P < 0.05). PhNR correlates well with SAP and OCT parameters in glaucoma assessment. PhNR could be a valuable supplementary tool for objective assessment of the RGCs' function in glaucoma.


Upstream open reading frames mediate autophagy-related protein translation.
Macroautophagy/autophagy, a highly conserved catabolic pathway that maintains proper cellular homeostasis is stringently regulated by numerous autophagy-related (Atg) proteins. Many studies have investigated autophagy regulation at the transcriptional level; however, relatively little is known about translational control. Here, we report the upstream open reading frame (uORF)-mediated translational control of multiple Atg proteins in Saccharomyces cerevisiae and in human cells. The translation of several essential autophagy regulators in yeast, including Atg13, is suppressed by canonical uORFs under nutrient-rich conditions, and is activated during nitrogen-starvation conditions. We also found that the predicted human ATG4B and ATG12 non-canonical uORFs suppress downstream coding sequence translation. These results demonstrate that uORF-mediated translational control is a widely used mechanism among ATG genes from yeast to human and suggest a model for how some ATG genes bypass the general translational suppression that occurs under stress conditions to maintain a proper level of autophagy.Abbreviations: 5' UTR, 5' untranslated region; Atg, autophagy-related; CDS, coding sequence; Cvt, cytoplasm-to-vacuole targeting; HBSS, Hanks' balanced salt solution; PA, protein A; PE, phosphati-dylethanolamine; PIC, preinitiation complex; PtdIns3K, phosphatidylinositol 3-kinase; qRT-PCR, quantitative reverse transcription PCR; Ubl, ubiquitin-like; uORF, upstream open reading frame; WT, wild-type.


31P-nuclear magnetic resonance analysis of perfused single frog skins.
Perfusion of single frog skins has produced stability of the 31P-nuclear magnetic resonance (NMR) spectra over periods as long as 8 h at room temperature. With this approach, relatively large phosphocreatine (PCr) signals were recorded for each of the 12 frog skins studied. The ratio of the concentration of PCr to ATP was estimated to be 0.76 +/- 0.07, a value an order of magnitude larger than that previously reported. Comparison of the ratio of the intracellular concentrations of inorganic phosphate (Pi) to ATP determined in the present NMR study with that previously estimated by chemical analysis suggests that little intracellular Pi is likely to be immobilized. Inclusion of methylphosphonate in the perfusing solutions permitted simultaneous determination of extracellular and intracellular pH from the NMR spectra alone. The methylphosphonate has been found to be nontoxic. At an extracellular pH of 7.72 +/- 0.04, the intracellular pH was 7.47 +/- 0.06.


Downregulation of microRNA-34 induces cell proliferation and invasion of human mesothelial cells.
Malignant mesothelioma (MM) is an aggressive tumor with a dismal prognosis, and the molecular alterations involved in this disease remain unknown. We previously reported that microRNA-34s (miR-34s) are methylated and downregulated in MM and may play an important role in the carcinogenesis of MM. In this study, we downregulated miR-34s in human mesothelial cells to investigate the cellular effect of miR-34 knockdown. For the cell study, we used LP-9, a human mesothelial cell line, and three human primary-cultured mesothelial cell lines. RNA-based miR-34a, -34b and -34c inhibitors were transfected into these cells, and their effects on proliferation and invasion were evaluated. A scramble RNA oligonucleotide was used as a control. The protein expression status was estimated using western blotting. After miR-34 inhibitor transfection, miR-34a, -34b and -34c were downregulated in all the examined mesothelial cell lines. miR-34 inhibitor transfection significantly increased cell proliferation in all of the mesothelial cell lines, compared with the scramble control. The invasive ability also increased in the miR-34 inhibitor transfectants, compared with the scramble control, in the LP-9 cell line. Western blotting confirmed the upregulation of c-MET, phospho-c-MET, and bcl-2 proteins in LP-9 cells after miR-34 inhibitor transfection. In conclusion, our study showed that the downregulation of miR-34s induced an oncogenic phenotype in non-malignant mesothelial cells. The present study, together with the results of our previous report, strongly suggest that miR-34s play an important role in the early carcinogenic process involved in the transformation of human mesothelial cells to MM.


[Endogenous heparin-like syndrome: analysis of clinical observations].
One of the reasons for non-surgical bleeding is heparin-like syndrome (HLS), under which is understanded presence of heparin effect in the absence of it's exogenous application. The role of endogenous heparins perform glycosaminoglycans -- biologically active substances. HLS is accompanied by endothelium damage and discussed in the network of the systemic inflammatory response syndrome (SIRS). HLS is described in liver future, sepsis, pregnancy and a number of hemoblastosis. Hypocoagulation effect of endogenous heparin localizates in X coagulation factor. The main method of diagnosis - thromboelastography. The use of a specific heparin antidote - Protamine sulfate has not confirmed clinical efficacy. Priority direction in the therapy of - methods of "shunt hemostasis". In this paper, we present the analysis of observations of 4 patients with developed endogenous HLS. In 2 cases (combination of sepsis with hepatic failure in one patient and initial thrombophilia in other) HLS has been accompanied by massive bleeding (massive hemothoraxc with haemorrhagic shock, a massive intraoperative blood loss). For HLS relief in these cases was used prothrombine complex concentrate (PCC) (in the 1st case), recombinant VIIa factor (in the 2nd case). In other cases, HLS (in a patient with multiple myeloma and childbirth in the postpartum period), haemorrhagic syndrome was not so expressed, the treatment was carried out with FFP transfusion.


Barriers to uptake of prevention of mother-to-child transmission of HIV services among mothers of vertically infected HIV-seropositive infants in Makurdi, Nigeria.
Perinatal transmission of human immunodeficiency virus (HIV) continues in Nigeria because of the poor use of prevention of mother-to-child transmission of HIV (PMTCT) services. This study reports on the barriers preventing mothers of vertically infected HIV-seropositive infants to use the PMTCT services at the Federal Medical Centre, Makurdi, Nigeria. This is a descriptive study conducted between January and April, 2014. A quantitative survey was applied to detect barriers along the PMTCT services cascade among 52 mothers of vertically infected HIV-seropositive infants. This includes 22 women who attended antenatal care at the Federal Medical Centre (designated as Group A mothers) and 30 women who did not receive any form of PMTCT service (Group B mothers). The study was supplemented with a focused group discussion involving 12 discussants from the two groups. In the quantitative assessment: among the Group A mothers, falling asleep was the most common reason (n=22, 100%) for missing therapeutic/prophylactic antiretroviral medicine; financial constraint (n=22, 100%) was the most common reason for antenatal care visit defaults; and a lot of the mothers (n=11, 50.0%) did not give nevirapine to their newborns because they delivered at home. Among Group B mothers, unawareness of HIV-seropositive status was the most common reason (n=28, 93.3%) given for not accessing PMTCT services. In the qualitative study: noninvolvement of male partners, stigma and discrimination experienced by HIV-seropositive mothers, financial constraints in couples, involvement of traditional birth attendants in antenatal care and delivery of HIV-infected women, unawareness of HIV-seropositive status by pregnant women, poor health system, and the lack of funding for PMTCT services at private and rural health facilities were the major barriers preventing the use of PMTCT services. In order to reduce the missed opportunities for PMTCT interventions in Makurdi and by extension the Benue State it represents in Nigeria, strong political and financial commitments are needed to overcome the identified barriers.


Detection of p24 antigen with and without immune complex dissociation for longitudinal monitoring of human immunodeficiency virus type 1 infection.
Sequential specimens obtained from 87 multicenter AIDS cohort study participants were tested by three p24 antigen tests. They included a polyclonal enzyme immunoassay (EIA), a monoclonal EIA, and a monoclonal EIA after immune complex dissociation (ICD) of specimens. Subjects were grouped into two categories defined by real-time testing with the polyclonal EIA: 39 had become positive for p24 antigen (antigen converters) during follow-up, and 48 had progressed to AIDS without detectable antigenemia. Twenty-four (61%) antigen converters were positive by ICD-monoclonal EIA about 1 year earlier than by monoclonal EIA. In contrast, only 12 (25%) patients who progressed to AIDS without detectable antigenemia became positive by ICD-p24 EIA before developing AIDS. Thus, the main benefit of ICD treatment may be to detect p24 antigenemia approximately 1 year before the regular assay rather than to identify additional antigenemic people. Quantitative plasma RNA levels were also determined in longitudinal samples from 20 antigen converters and 7 men who developed AIDS without antigenemia. Although mean human immunodeficiency virus type 1 RNA levels were higher in antigen-positive than in antigen-negative samples (P = 0.002), more than half (11 of 20) of the antigen converters had no measurable change in human immunodeficiency virus type 1 RNA associated with change to antigen positivity.


Re-estimated normal hearing threshold levels for pure tones using the calculation procedure of ISO 7029:2017.
The objectives of this study were (1) to re-calculate hearing threshold levels (HTLs) for pure tones as described in an international standard, ISO 7029:2017, and (2) to explain the procedure of how HTLs in the standard had been derived. Pure-tone hearing threshold data used for developing ISO 7029:2017 and additional data sets were combined to re-estimate median HTLs and the distribution of individual HTLs around the median. The calculation was done for audiometric frequencies from 125 Hz to 8000 Hz and extended high frequencies from 9000 Hz to 12,500 Hz for ages from 18 to 80 years. Approximately 9000 men and 20,000 women employed in 15 studies in nine countries. They had been rigorously screened for hearing abnormalities. A new set of median HTLs and distribution around the median was obtained as a function of age for males and females separately and compared with the estimates in ISO 7029. The differences among these threshold values were discussed. The calculation procedure described would help understand how the normative HTLs in ISO 7029:2017 had been obtained. Re-calculated HTLs could serve as a basis for the next edition of the standard that covers a wider range of population.


Foxa2 and Nurr1 synergistically yield A9 nigral dopamine neurons exhibiting improved differentiation, function, and cell survival.
Effective dopamine (DA) neuron differentiation from neural precursor cells (NPCs) is prerequisite for precursor/stem cell-based therapy of Parkinson's disease (PD). Nurr1, an orphan nuclear receptor, has been reported as a transcription factor that can drive DA neuron differentiation from non-dopaminergic NPCs in vitro. However, Nurr1 alone neither induces full neuronal maturation nor expression of proteins found specifically in midbrain DA neurons. In addition, Nurr1 expression is inefficient in inducing DA phenotype expression in NPCs derived from certain species such as mouse and human. We show here that Foxa2, a forkhead transcription factor whose role in midbrain DA neuron development was recently revealed, synergistically cooperates with Nurr1 to induce DA phenotype acquisition, midbrain-specific gene expression, and neuronal maturation. Thus, the combinatorial expression of Nurr1 and Foxa2 in NPCs efficiently yielded fully differentiated nigral (A9)-type midbrain neurons with clearly detectable DA neuronal activities. The effects of Foxa2 in DA neuron generation were observed regardless of the brain regions or species from which NPCs were derived. Furthermore, DA neurons generated by ectopic Foxa2 expression were more resistant to toxins. Importantly, Foxa2 expression resulted in a rapid cell cycle exit and reduced cell proliferation. Consistently, transplantation of NPCs transduced with Nurr1 and Foxa2 generated grafts enriched with midbrain-type DA neurons but reduced number of proliferating cells, and significantly reversed motor deficits in a rat PD model. Our findings can be applied to ongoing attempts to develop an efficient and safe precursor/stem cell-based therapy for PD.


The Scent of the Fly.
(Z)-4-undecenal (Z4-11Al) is the volatile pheromone produced by females of the vinegar fly Drosophila melanogaster. Female flies emit Z4-11Al for species-specific communication and mate-finding. A sensory panel finds that synthetic Z4-11Al has a characteristic flavour, which can be perceived even at the small amounts produced by a single female fly. Since only females produce Z4-11Al, and not males, we can reliably distinguish between single D. melanogaster males and females, according to their scent. Females release Z4-11Al at 2.4 ng/h and we readily sense 1 ng synthetic Z4-11Al in a glass of wine (0.03 nmol/L), while a tenfold concentration is perceived as a loud off-flavour. This corroborates the observation that a glass of wine is spoilt by a single D. melanogaster fly falling into it, which we here show is caused by Z4-11Al. The biological role of Z4-11Al or structurally related aldehydes in humans and the basis for this semiochemical convergence remains yet unclear.


Topical ofloxacin treatment of otorrhea in children with tympanostomy tubes.
To determine the safety and efficacy of ofloxacin otic solution in the treatment of acute otorrhea in children with tympanostomy tubes. Multicenter study with an open-label, prospective ofloxacin arm and retrospective historical and current practice arms. Ear, nose, and throat pediatric and general practice clinics and office-based practices. Children younger than 12 years with acute purulent otorrhea of presumed bacterial origin and tympanostomy tubes. Instillation of 0.3% ofloxacin, 0.25 mL, twice daily for 10 days in the prospective arm; review of medical records in the retrospective arms. The primary index of clinical efficacy was absence (cure) or presence (failure) of otorrhea at 10 to 14 days after therapy. The primary index of microbiologic efficacy (in the ofloxacin arm only) was eradication of pathogens isolated at baseline. Safety was evaluated in the ofloxacin arm only. Significantly more clinically evaluable ofloxacin-treated subjects were cured (84.4%; 119/141) than were historical practice subjects (64.2%; 140/218) (P< or =.001) or current practice subjects (70%; 33/47) (P< or =.03). All baseline pathogens were eradicated in 103 (96.3%) of 107 microbiologically evaluable ofloxacin subjects. Adverse events considered "possibly" or "probably" treatment related occurred in 29 (12.8%) of 226 ofloxacin-treated subjects. Ofloxacin is safe and significantly more effective than treatments used in historical or current practice for acute purulent otorrhea in children with tympanostomy tubes.


Piccolo Directs Activity Dependent F-Actin Assembly from Presynaptic Active Zones via Daam1.
The dynamic assembly of filamentous (F) actin plays essential roles in the assembly of presynaptic boutons, the fusion, mobilization and recycling of synaptic vesicles (SVs), and presynaptic forms of plasticity. However, the molecular mechanisms that regulate the temporal and spatial assembly of presynaptic F-actin remain largely unknown. Similar to other F-actin rich membrane specializations, presynaptic boutons contain a set of molecules that respond to cellular cues and trans-synaptic signals to facilitate activity-dependent assembly of F-actin. The presynaptic active zone (AZ) protein Piccolo has recently been identified as a key regulator of neurotransmitter release during SV cycling. It does so by coordinating the activity-dependent assembly of F-Actin and the dynamics of key plasticity molecules including Synapsin1, Profilin and CaMKII. The multidomain structure of Piccolo, its exquisite association with the AZ, and its ability to interact with a number of actin-associated proteins suggest that Piccolo may function as a platform to coordinate the spatial assembly of F-actin. Here we have identified Daam1, a Formin that functions with Profilin to drive F-actin assembly, as a novel Piccolo binding partner. We also found that within cells Daam1 activation promotes Piccolo binding, an interaction that can spatially direct the polymerization of F-Actin. Moreover, similar to Piccolo and Profilin, Daam1 loss of function impairs presynaptic-F-actin assembly in neurons. These data suggest a model in which Piccolo directs the assembly of presynaptic F-Actin from the AZ by scaffolding key actin regulatory proteins including Daam1.


Hydration of Hybrid Cements at Low Temperatures: A Study on Portland Cement-Blast Furnace Slag-Na2SO4.
Replacement of Portland cement with high volumes of blast furnace slag is known to negatively affect the early-age properties of concrete, particularly at low temperatures. In this study, the effectiveness of Na2SO4 on the mechanical properties, hydration kinetics and microstructure development of a commercial CEM III/B (~69% slag) is investigated at 10 and 20 °C. Na2SO4 enhances compressive strength at both 10 and 20 °C, and at both early (1 and 7 days) and later ages (28 and 90 days). QXRD shows an increase in the degree of alite hydration at 1 day with Na2SO4 addition, while the degree of clinker and slag hydration is similar for all the systems from 7 to 90 days. An increase in ettringite content is observed at all ages in the systems with Na2SO4. Microstructure and pore structure shows densification of hydrates and reduction in porosity on addition of Na2SO4.


Tetraplex formation of a guanine-containing nonameric DNA fragment.
A combination of spectroscopic and calorimetric techniques has been used to characterize the structures formed by a family of short, guanine-containing DNA single strands of the form d[GGTTXTTGG], X = A, C, G, T. In 1 molar NaCl at low temperatures, these molecules do not behave like single strands, but rather exhibit properties consistent with tetraplex formation. The standard state enthalpies, entropies, and free energies for formation of each tetraplex have been measured, as have preliminary nuclear magnetic resonance (NMR) spectra. In 1 molar KCl, the melting behavior of the structure or structures is more complex than in 1 molar NaCl. This observation may be related to the recently proposed "sodium-potassium switch."


Diffuse Micro-Nodules on Peritoneal Surfaces at Donor Organ Procurement: Highlights on the Diagnostic Challenge and Transplant Management.
BACKGROUND Guidelines have been designed to stratify the risk of cancer transmission in donors with a history of or ongoing malignancy, although this evaluation is not always straightforward when unexpected and rare lesions are found. CASE REPORT Here, we present a case of a 41-year-old African female donor who died from a cerebral hemorrhage. Her medical history was unavailable. At procurement, multiple diffuse grayish small nodules were noticed along the peritoneal cavity, some of which were sent to the on-call pathologist for urgent frozen section evaluation. Histology showed a multinodular proliferation of uniform bland-appearing spindle cells, with no evidence of necrosis, nor nuclear atypia or mitoses. The overall picture was consistent with the diagnosis of disseminated peritoneal leiomyomatosis, with overlapping morphology with uterine leiomyoma. Given the rarity of the lesion and the potential for recurrence or malignant degeneration, only the liver and heart were allocated to recipients with life-threatening conditions. The decision was taken in a forcedly limited time and took into account the benefit of transplantation and the risk of disease transmission. CONCLUSIONS This case highlights challenges that transplant teams often have to deal with, as lesions that are difficult to diagnose during donor assessment are usually not covered in guidelines. The acceptance and usage of organs in such cases has to be decided in a team-based fashion, with the collaboration of all the transplant professionals involved to optimally assess the transmission risk, carefully balancing the benefits of transplantation for the recipients and the need to guarantee a reasonable degree of safety.


Ultrastructural localization of rRNA shows defective nuclear export of preribosomes in mutants of the Nup82p complex.
To study the nuclear export of preribosomes, ribosomal RNAs were detected by in situ hybridization using fluorescence and EM, in the yeast Saccharomyces cerevisiae. In wild-type cells, semiquantitative analysis shows that the distributions of pre-40S and pre-60S particles in the nucleolus and the nucleoplasm are distinct, indicating uncoordinated transport of the two subunits within the nucleus. In cells defective for the activity of the GTPase Gsp1p/Ran, ribosomal precursors accumulate in the whole nucleus. This phenotype is reproduced with pre-60S particles in cells defective in pre-rRNA processing, whereas pre-40S particles only accumulate in the nucleolus, suggesting a tight control of the exit of the small subunit from the nucleolus. Examination of nucleoporin mutants reveals that preribosome nuclear export requires the Nup82p-Nup159p-Nsp1p complex. In contrast, mutations in the nucleoporins forming the Nup84p complex yield very mild or no nuclear accumulation of preribosome. Interestingly, domains of Nup159p required for mRNP trafficking are not necessary for preribosome export. Furthermore, the RNA helicase Dbp5p and the protein Gle1p, which interact with Nup159p and are involved in mRNP trafficking, are dispensable for ribosomal transport. Thus, the Nup82p-Nup159p-Nsp1p nucleoporin complex is part of the nuclear export pathways of preribosomes and mRNPs, but with distinct functions in these two processes.


Effect of electroacupuncture on rat ischemic brain injury: importance of stimulation duration.
We explored the optimal duration of electroacupuncture (EA) stimulation for protecting the brain against ischemic injury. The experiments were carried out in rats exposed to right middle cerebral artery occlusion (MCAO) for 60 min followed by 24-hr reperfusion. EA was delivered to "Shuigou" (Du 26) and "Baihui" (Du 20) acupoints with sparse-dense wave (5/20 Hz) at 1.0 mA for 5, 15, 30, and 45 min, respectively. The results showed that 30 min EA, starting at 5 minutes after the onset of MCAO (EA during MCAO) or 5 minutes after reperfusion (EA after MCAO), significantly reduced ischemic infarct volume, attenuated neurological deficits, and decreased death rate with a larger reduction of the ischemic infarction in the former group. Also in the group of EA during MCAO, this protective benefit was positively proportional to the increase in the period of stimulation, that is, increased protection in response to EA from 5- to 30-min stimulation. In all groups, EA induced a significant increase in cerebral blood flow and promoted blood flow recovery after reperfusion, and both blood flow volume and blood cell velocity returned to the preischemia level in a short period of time. Surprisingly, EA for 45 min did not show reduction in the neurological deficits or the infarct volume and instead demonstrated an increase in death rate in this group. Although EA for 45 min still increased the blood flow during MCAO, it led to a worsening of perfusion after reperfusion compared to the group subjected only to ischemia. The neuroprotection induced by an "optimal" period (30 min) of EA was completely blocked by Naltrindole, a δ -opioid receptor (DOR) antagonist (10 mg/kg, i.v.). These findings suggest that earlier EA stimulation leads to better outcomes, and that EA-induced neuroprotection against ischemia depends on an optimal EA-duration via multiple pathways including DOR signaling, while "over-length" stimulation exacerbates the ischemic injury.


PPARγ Pro12Ala interacts with fat intake for obesity and weight loss in a behavioural treatment based on the Mediterranean diet.
The goal of this study was to examine whether the Pro12Ala polymorphism of peroxisome proliferator-activated receptor γ (PPARγ) is associated with insulin resistance, obesity and weight loss and to analyze potential interactions between fat intake and PPARγ polymorphism in a Spanish overweight/obese population. We recruited 1465 subjects enrolled in a behavioural treatment program for obesity based on a Mediterranean diet, which included the following: dietary treatment, physical activity, nutritional education and behavioral techniques. A significant association was found between PPARγ2 Pro12Ala genotype and plasma insulin concentration and homeostasis model assessment insulin resistance. Subjects with the Ala12 genotype had lower insulin levels than those with the Pro12Pro genotype. We detected a gene-diet interaction between the PPARγ Pro12Ala polymorphism and MUFA for BMI and body fat. Furthermore, we detected an interaction between the PPARγ Pro12Ala polymorphism and fat intake for total weight loss (p<0.001). When total fat intake was high, Ala12-carriers exhibited a significantly lower percentage of total weight loss than major-allele-carriers (p=0.037). Data are consistent with previous results showing a protective role for the Ala12 allele against insulin resistance, and replicate an earlier study that detected an interaction between dietary MUFA and PPARγ2 for BMI. Our detection of a gene-diet interaction between PPARγ Pro12Ala and fat intake for weight loss may explain previous discrepancies among different studies.


Evaluation and treatment of altered mental status patients in the emergency department: Life in the fast lane.
Altered mental status (AMS) is a very common emergency case, but the exact etiology of many AMS patients is unknown. Patients often manifest vague symptoms, thus, AMS diagnosis and treatment are highly challenging for emergency physicians. The aim of this study is to provide a framework for the assessment of AMS patients. This assessment should allow providers to better understand the etiology of mental status changes and therefore improve diagnostic skills and management. This is a prospective cohort observational study. We recruited all adult patients with undifferentiated AMS at a single center tertiary care academic emergency department over 24 months (June 2009 to June 2011). Demographic characteristics, clinical manifestations, assessment approaches, causative factors, emergency treatments and outcomes were collected prospectively. In 1934 patients with AMS recruited, accounting for 0.93% of all emergency department (ED) patients, 1 026 (53.1%) were male, and 908 (46.9%) female. Their average age was 51.95±15.71 years. Etiologic factors were neurological (n=641; 35.0%), pharmacological and toxicological (n=421; 23.0%), systemic and organic (n=266; 14.5%), infectious (n=167; 9.1%), endocrine/metabolic (n=145; 7.9%), psychiatric (n=71; 3.9%), traumatic (n=38; 2.1%), and gynecologic and obstetric (n=35; 1.9%). Total mortality rate was 8.1% (n=156). The death rate was higher in elderly patients (≥60) than in younger patients (10.8% vs. 6.9%, P=0.003). Patients with AMS pose a challenge for ED physicians. The most frequently encountered diagnostic categories causing AMS were primary CNS disorders, intoxication, organ system dysfunction, and endocrine/metabolic diseases. AMS has a high fatality rate in the ED. AMS is an important warning signal for ED patients because of its potentially fatal and reversible effects. Prompt evaluation and treatment are essential to decreasing morbidity and mortality associated with AMS.


The interactions of composting and biochar and their implications for soil amendment and pollution remediation: a review.
Compost and biochar, used for the remediation of soil, are seen as attractive waste management options for the increasing volume of organic wastes being produced. This paper reviews the interaction of biochar and composting and its implication for soil amendment and pollution remediation. The interaction of biochar and composting affect each other's properties. Biochar could change the physico-chemical properties, microorganisms, degradation, humification and gas emission of composting, such as the increase of nutrients, cation exchange capacity (CEC), organic matter and microbial activities. The composting could also change the physico-chemical properties and facial functional groups of biochar, such as the improvement of nutrients, CEC, functional groups and organic matter. These changes would potentially improve the efficiency of the biochar and composting for soil amendment and pollution remediation. Based on the above review, this paper also discusses the future research required in this field.


Virtual Reality Surgical Rehearsal and 2-Dimensional Operative Video of a Paramedian Supracerebellar Infratentorial Approach Endoscopic Resection of Pineocytoma: 2-Dimensional Operative Video.
An endoscopic "keyhole" approach to a deep-lying skull base lesion can be a daunting challenge. For the pineal region, the techniques for endoscopic resection of solid tumors in this location are also new.1,2 In such a situation, surgical rehearsal in virtual reality (VR) can significantly improve the surgeon's confidence.3 In this operative video, we demonstrate the use of VR in surgical planning and rehearsal to determine the best approach to a large, solid pineal tumor in a 46-yr-old patient. Using the patient's computed tomography angiography and magnetic resonance imaging, a VR model of his anatomy was created (SNAP VR360 version 3.8.0, Surgical Theater Inc, Cleveland, Ohio). VR rehearsal showed that, with the tumor tucked under the corpus callosum and cradled by the internal cerebral veins and veins of Rosenthal, a supratentorial approach would be suboptimal. Because of the steep angle of the patient's tentorium in the midline, a classic supracerebellar infratentorial (SCIT) approach would be challenging, and thus a paramedian variant of SCIT was chosen.4 For a right-handed surgeon, the left side was used, and the endoscope was docked at the extreme left, out of the main surgical corridor. Shown in the video, the endoscopic resection achieved a complete resection. The histopathological diagnosis was a pineocytoma. No adjuvant treatment is recommended. Given the rarity of pineocytoma,5 the novelty of endoscopic resection of solid tumors in the region, and the challenge of "keyhole" approaches to deep-lying targets, VR rehearsal facilitated the achievement of the surgical goal and avoided the morbidity of a more extensive exposure. Patient consent was obtained prior to the creation of the video and available on request. RHOTON images in the video are from The Rhoton Collection®.


Globe and adnexal trauma at Australian trauma centres.
In multisystem trauma, the assessment and management of globe and adnexal trauma is often complex. Ophthalmology input may assist managing such patients. To understand the role of ophthalmology in tertiary trauma centres we report on the management of globe and adnexal trauma at two tertiary trauma centres in Sydney, Australia. A retrospective case series was completed at Royal North Shore Hospital (RNSH) and Royal Prince Alfred Hospital (RPAH) on patients admitted between January 2015 and December 2019. International Classification of Disease, Tenth Revision codes, diagnostic and procedural coding data were used to identify patients admitted with globe and/or adnexal trauma. Data extracted from medical records included demographics, mechanism of injury, ocular examination and specialist ophthalmic referral. Over 5-years, 773 patients, average age of 53.2years and 62% male, were admitted to RNSH and RPAH with globe and/or adnexal trauma. Most patients (83%) first presented to RNSH or RPAH. The most common mechanism of injury was falls (45%) followed by burns (13%). Two-hundred and thirty-five patients had multisystem trauma, of these patients, 121 (51%) suffered globe trauma with 49 (21%) classified as severe. Three patients were not diagnosed initially due to delayed ophthalmology referral. Falls followed by burns were common causes of globe and adnexal trauma in Sydney, Australia. The presence of orbital/mid-facial injury may indicate a patient has globe trauma. In multisystem trauma, globe trauma may be diagnosed late or not identified. Ophthalmology review has an important role in diagnosing and managing globe trauma in multisystem trauma.