Mechanisms of resistance to high and low linear energy transfer radiation in myeloid leukemia cells.
Low linear energy transfer (LET) ionizing radiation (IR) is an important form of therapy for acute leukemias administered externally or as radioimmunotherapy. IR is also a potential source of DNA damage. High LET IR produces structurally different forms of DNA damage and has emerged as potential treatment of metastatic and hematopoietic malignancies. Therefore, understanding mechanisms of resistance is valuable. We created stable myeloid leukemia HL60 cell clones radioresistant to either γ-rays or α-particles to understand possible mechanisms in radioresistance. Cross-resistance to each type of IR was observed, but resistance to clustered, complex α-particle damage was substantially lower than to equivalent doses of γ-rays. The resistant phenotype was driven by changes in: apoptosis; late G2/M checkpoint accumulation that was indicative of increased genomic instability; stronger dependence on homology-directed repair; and more robust repair of DNA double-strand breaks and sublethal-type damage induced by γ-rays, but not by α-particles. The more potent cytotoxicity of α-particles warrants their continued investigation as therapies for leukemia and other cancers.


Functional dissection of a trigger enzyme: mutations of the bacillus subtilis glutamate dehydrogenase RocG that affect differentially its catalytic activity and regulatory properties.
Any signal transduction requires communication between a sensory component and an effector. Some enzymes engage in signal perception and transduction, as well as in catalysis, and these proteins are known as "trigger" enzymes. In this report, we detail the trigger properties of RocG, the glutamate dehydrogenase of Bacillus subtilis. RocG not only deaminates the key metabolite glutamate to form alpha-ketoglutarate but also interacts directly with GltC, a LysR-type transcription factor that regulates glutamate biosynthesis from alpha-ketoglutarate, thus linking the two metabolic pathways. We have isolated mutants of RocG that separate the two functions. Several mutations resulted in permanent inactivation of GltC as long as a source of glutamate was present. These RocG proteins have lost their ability to catabolize glutamate due to a strongly reduced affinity for glutamate. The second class of mutants is exemplified by the replacement of aspartate residue 122 by asparagine. This mutant protein has retained enzymatic activity but has lost the ability to control the activity of GltC. Crystal structures of glutamate dehydrogenases that permit a molecular explanation of the properties of the various mutants are presented. Specifically, we may propose that D122N replacement affects the surface of RocG. Our data provide evidence for a correlation between the enzymatic activity of RocG and its ability to inactivate GltC, and thus give insights into the mechanism that couples the enzymatic activity of a trigger enzyme to its regulatory function.


Endotoxemia in horses. A review of cellular and humoral mediators involved in its pathogenesis.
Endotoxemia remains the leading cause of death in horses, being intimately involved in the pathogenesis of gastrointestinal disorders that cause colic and neonatal foal septicemia. Endotoxins, normally present within the bowel, gain access to the blood across damaged intestinal mucosa, or endotoxemia occurs when gram negative organisms proliferate in tissues. Endotoxins are removed from the circulation by the mononuclear phagocyte system, and the response of mononuclear phagocytes to these lipopolysaccharides (LPS) play an important role in determining the severity of clinical disease. Macrophages become highly activated for enhanced secretory, phagocytic and cidal functions by LPS. Macrophage-derived cytokines are responsible for many of the pathophysiologic consequences of endotoxemia. The arachidonic acid metabolites, prostacyclin and thromboxane A2 likely mediate early hemodynamic dysfunction and the leukotrienes may potentiate tissue ischemia during endotoxemia. Interleukin 1 (IL-1) induces fever and is responsible for the inflammatory cascade, which constitutes the acute phase response. Tumor necrosis factor (TNF), an important proximal mediator of the effects of LPS, acts to initiate events and formation of other molecules that affect shock and tissue injury. Systemic administration of TNF produces most of the physiologic derangements that are associated with endotoxemia and antibodies that are directed against TNF significantly reduce LPS-induced mortality in experimental animals. In response to endotoxins, mononuclear phagocytes express thromboplastin-like procoagulant activity (PCA), which initiates microvascular thrombosis. Both IL-1 and TNF induce PCA expression, creating a positive feedback loop for LPS-induced coagulopathy. A macrophage-derived platelet activating factor contributes to coagulation dysfunction and further stimulates arachidonic acid metabolism. The ultimate consequences of endotoxemia are multiple system organ failure and death. The numerous feedback loops and intertwining cascades of mediators during endotoxemia defy simplistic methods of treatment. The optimal therapy likely involves methods to alter the generation of inflammatory mediators by mononuclear phagocytes.


Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer.
To determine the place of single-agent paclitaxel compared with nonanthracycline combination chemotherapy as front-line therapy in metastatic breast cancer. Patients with previously untreated metastatic breast cancer were randomized to receive either paclitaxel 200 mg/m(2) intravenously (IV) over 3 hours for eight cycles (24 weeks) or standard cyclophosphamide 100 mg/m(2)/d orally on days 1 to 14, methotrexate 40 mg/m(2) IV on days 1 and 8, fluorouracil 600 mg/m(2) IV on days 1 and 8, and prednisone 40 mg/m(2)/d orally on days 1 to 14 (CMFP) for six cycles (24 weeks) with epirubicin recommended as second-line therapy. A total of 209 eligible patients were randomized with a median survival duration of 17.3 months for paclitaxel and 13.9 months for CMFP. Multivariate analysis showed that patients who received paclitaxel survived significantly longer than those who received CMFP (P =.025). Paclitaxel produced significantly less severe leukopenia, thrombocytopenia, mucositis, documented infections (all P <.001), nausea or vomiting (P =.003), and fever without documented infection (P =.007), and less hospitalization for febrile neutropenia than did CMFP (P =.001). Alopecia, peripheral neuropathy, and myalgia or arthralgia were more severe with paclitaxel (all P <.0001). Overall, quality of life was similar for both treatments (P > = .07). Initial paclitaxel was associated with significantly less myelosuppression and fewer infections, with longer survival and similar quality of life and control of metastatic breast cancer compared with CMFP.


[Adolescents and their relationship to health services: a school-based cross-sectional study in Niterói, Rio de Janeiro, Brazil].
This cross-sectional study describes the relationship between adolescents and health services using several indicators (self-reported diseases, self-rated health status, the need and search for health care, health care utilization and fidelity, adherence to medical prescription) and their association with socio-demographic variables. The adolescents (aged 12 to 17 years) were enrolled in schools from a district in Niteroi, Rio de Janeiro State, Brazil. Type of school, representing the participants' socioeconomic status, was associated with all the indicators. Adolescents in public schools tended to rate their health status as fair or poor. They also showed lower odds of reporting health needs, the search for health care, obtaining access, and remaining faithful to health services. Girls rated their health status as fair or poor and sought health care more frequently boys. High adherence to medical prescription of medicines and tests was observed in the sample.


[Actual indications for day-surgery in the treatment of lung neoplasms].
To point out the actual possibilities to apply surgical treatments (diagnostic and therapeutics) for the cure of neoplastic disease of the lungs into an outpatient procedure. After a review of the recent literature, the authors show problems and limits of such a program. The analysis of the invasive diagnostic procedures (video-mediastinoscopy, anterior mediastinotomy, and thoracoscopy) shows that in most cases, a part from the kind of anesthesia, could be done in a short-term hospitalization. On the contrary, for pulmonary resection, all the experiences prove the practicability of the program, but only after careful selection of the patient, deep information of the patient and of his family and mostly, a proved integration between hospital and territory to warranty the continuation of the cures. The Authors believe that, mostly in their country, it is too early for a wide diffusion of new form of hospitalization different from the traditional one for the treatment of neoplastic disease of the lung.


Enzyme-controlled, nutritive hydrogel for mesenchymal stromal cell survival and paracrine functions.
Culture-adapted human mesenchymal stromal cells (hMSCs) are appealing candidates for regenerative medicine applications. However, these cells implanted in lesions as single cells or tissue constructs encounter an ischemic microenvironment responsible for their massive death post-transplantation, a major roadblock to successful clinical therapies. We hereby propose a paradigm shift for enhancing hMSC survival by designing, developing, and testing an enzyme-controlled, nutritive hydrogel with an inbuilt glucose delivery system for the first time. This hydrogel, composed of fibrin, starch (a polymer of glucose), and amyloglucosidase (AMG, an enzyme that hydrolyze glucose from starch), provides physiological glucose levels to fuel hMSCs via glycolysis. hMSCs loaded in these hydrogels and exposed to near anoxia (0.1% pO2) in vitro exhibited improved cell viability and angioinductive functions for up to 14 days. Most importantly, these nutritive hydrogels promoted hMSC viability and paracrine functions when implanted ectopically. Our findings suggest that local glucose delivery via the proposed nutritive hydrogel can be an efficient approach to improve hMSC-based therapeutic efficacy.


Frequency of abnormal human haemoglobins caused by C----T transitions in CpG dinucleotides.
A large part of human genetic disease apparently arises from deamination of cytosines in methylated CpG dinucleotides. Their mutation rate is known to be high when C is present as 5-methyl-cytosine, but is believed to be normal when it is unmethylated. The beta-globin gene contains five, the gamma-globin gene two, and each of the alpha-globin genes contain 35 CpG's. The CpG's in the beta-and gamma-globin genes are methylated, while those in the alpha-globin genes are undermethylated. One would therefore have expected the CpG's to be a frequent source of mutations in the beta- and gamma-globin genes, but not in the alpha-globin genes. In fact, the evidence points to CpG's being a frequent source of mutations in both the alpha- and beta-globin genes. This suggests either that the mutation rates of both methylated and unmethylated CpG's are abnormally high, which conflicts with published evidence, or that there is a finite chance of some CpG's in the alpha-globin genes of certain individuals being methylated and therefore subject to mutation.


Association of curry consumption with blood lipids and glucose levels.
Curcumin, an active ingredient in turmeric, is highly consumed in South Asia. However, curry that contains turmeric as its main spice might be the major source of curcumin in most other countries. Although curcumin consumption is not as high in these countries as South Asia, the regular consumption of curcumin may provide a significant health-beneficial effect. This study evaluated whether the moderate consumption of curry can affect blood glucose and lipid levels that become dysregulated with age. This study used data obtained from the Korea National Health and Nutrition Examination Survey, conducted from 2012 to 2013, to assess curry consumption frequency as well as blood glucose and blood lipid levels. The levels of blood glucose and lipids were subdivided by age, sex, and body mass index, and compared according to the curry consumption level. The estimates in each subgroup were further adjusted for potential confounding factors, including the diagnosis of diseases, physical activity, and smoking. After adjusting for the above confounding factors, the blood glucose and triglyceride levels were significantly lower in the moderate curry consumption group compared to the low curry consumption group, both in older (> 45) male and younger (30 to 44) female overweight individuals who have high blood glucose and triglyceride levels. These results suggest that curcumin consumption, in an ordinary diet, can have health-beneficial effects, including being helpful in maintaining blood glucose and triglyceride levels that become dysregulated with age. The results should be further confirmed in future studies.


[Hypothenar hammer syndrome: causes, sequelae and diagnostic aspects].
To investigate the reasons and disease course of Hypothenar Hammer Syndrome. Occlusion of the ulnar artery at the level of the hamate bone due to repetitive trauma to the hypothenar eminence is implicated as the cause of the rarely diagnosed hypothenar hammer syndrome (HHS). The thrombotic occlusion and the formation of an aneurysm of the ulnar artery and the superficial palmar arch with possible peripheral embolism of the digital arteries are a direct cause of the chronic damage to the vessel wall. Generally, HHS is diagnosed too late for recanalization to be a viable therapeutic option. From 1996 to 1998 the diagnosis of an HHS was made in 8 patients at our hospital. Etiology, clinical settings and disease course were assessed. Our analysis suggests that HHS may be caused by a single severe trauma in addition to repetitive injuries. The pathogenesis of the syndrome is dependent on the vascular anatomy of the individual hand. Interindividual variations in the arterial supply of the affected hand influences the clinical symptomatology with possible masking of arterial occlusions. An exact investigation concerning the pathogenesis of HHS is a precondition for treating the disease and may help to establish HHS as an occupational disease. MR-angiography may be a new approach for assessing HHS.


A novel model for pyro-electro-catalytic hydrogen production in pure water.
The pyro-electro-catalytic induced generation of hydrogen gas is an environmentally friendly and sustainable way to convert excess thermal energy into a storable form. The main idea is to make use of spontaneous polarization of pyroelectric materials that can be altered by temperature changes. Thus, surface potential changes and subsequent electron exchange with surrounding molecules can be induced. In this work, a fundamental model to describe the behavior of a thermally excited pyroelectric material in pure water is developed. The model combines the fields of pyroelectricity, electrochemistry, diffusion and semiconductor theory. After derivation, it was used to explore some basic questions on pyro-electro-catalytic hydrogen production and the accuracy was tested with experimental data. The results show that p/εr has to be balanced depending on the temperature gradient to maximize the hydrogen production. The validation of the experimental data revealed good agreement.


Development of paediatric quality of inpatient care indicators for low-income countries - A Delphi study.
Indicators of quality of care for children in hospitals in low-income countries have been proposed, but information on their perceived validity and acceptability is lacking. Potential indicators representing structural and process aspects of care for six common conditions were selected from existing, largely qualitative WHO assessment tools and guidelines. We employed the Delphi technique, which combines expert opinion and existing scientific information, to assess their perceived validity and acceptability. Panels of experts, one representing an international panel and one a national (Kenyan) panel, were asked to rate the indicators over 3 rounds and 2 rounds respectively according to a variety of attributes. Based on a pre-specified consensus criteria most of the indicators presented to the experts were accepted: 112/137(82%) and 94/133(71%) for the international and local panels respectively. For the other indicators there was no consensus; none were rejected. Most indicators were rated highly on link to outcomes, reliability, relevance, actionability and priority but rated more poorly on feasibility of data collection under routine conditions. There was moderate to substantial agreement between the two panels of experts. This Delphi study provided evidence for the perceived usefulness of most of a set of measures of quality of hospital care for children proposed for use in low-income countries. However, both international and local experts expressed concerns that data for many process-based indicators may not currently be available. The feasibility of widespread quality assessment and responsiveness of indicators to intervention should be examined as part of continued efforts to improve approaches to informative hospital quality assessment.


[Analysis of independent components for event-related potentials from patients with an established diagnosis of schizophrenia, obsessive-compulsive and depressive disorders].
We investigated the possibility to classify data from patients with different psychiatric disorders on the base of physiological measures of the brain activity. Event-related potentials during the execution of GO/NOGO task were recorded from age matched groups of patients with schizophrenia, major depression and obsessive-compulsive disorder. Separation of independent components for event-related potentials was performed by applying Independent Component Analysis method. Picked out components were used in the method of discriminant analysis to classify the data according to clinical diagnosis. Discriminant analysis of components for event-related potentials allows classifying the data of patients with a suitable amount of matches with an established diagnosis.


Play-based interventions to support social and communication development in autistic children aged 2-8 years: A scoping review.
Play is used by practitioners from across disciplinary backgrounds as a natural and enjoyable context for providing intervention and support in early childhood. In the case of autism interventions, many therapies are based on the association between social play and the development of social skills, language development, and communication skills, as these are often particular areas of challenge for autistic children. However, play is a wide-ranging concept and the extant literature on play-based interventions is large and heterogeneous. This means it is challenging for practitioners and families to navigate the evidence base and make choices about differing intervention strategies. This review aims to provide a comprehensive map of the research on this topic and to develop a conceptual framework to inform clinical decision-making. An initial stakeholder consultation confirmed the relevance of the topic to practitioners and autistic people. A scoping review methodology (preregistered) was used to identify relevant literature. We systematically searched seven databases to find peer-reviewed primary intervention studies of play-based approaches targeting language, social and communication outcomes for autistic children aged 2-8 years. We then summarised the literature using narrative synthesis and Evidence Gap Maps (EGMs). The literature was summarised according to a range of characteristics, including study design, population characteristics, agent of intervention and outcomes measured, among others. These summaries were then used to develop a framework for some key considerations for practitioners appraising play-based approaches. 388 studies met inclusion criteria. Approximately 21% of studies were RCTs, and over 50% had ≤10 participants. Over 45% of studies reported multiple relevant outcomes, with social play skills being the most common single intervention target. Girls and minority background groups are under-represented. A range of intervention types were identified, and some high-level categorisations are proposed.Main contribution: On the basis of the evidence synthesis we suggest important dimensions for appraisal of play-based interventions, including the role of play within an intervention (as a context, a key developmental mechanism, or a component of a larger approach), the underpinning philosophy (e.g. behaviourist or developmental), and the role of the practitioner (providing parent feedback, 1:1 intervention, group facilitation). The wide range of approaches uncovered by this review is a testament to the wonderful diversity inherent to both play and autism. However, research could usefully focus on consolidating the evidence base for existing approaches, rather than aiming for further diversification. Implications: The conceptual framework proposed in this review can help practitioners appraise the literature and aid their advice to families when making shared intervention decisions.


Environmental, social and governance (ESG) performance of firms in the era of geopolitical conflicts.
Do geopolitical conflicts matter for the environmental, social, governance (ESG) and overall ESG performance of firms? We answer this question by studying the impact of geopolitical conflict of a country on the ESG performance, separately and collectively, of firms of that country. We use data from Refinitiv and UCDP/PRIO (Uppsala Conflict Data Program/International Peace Research Institute, Oslo) databases for the period from 2002 to 2021 for 79 countries and we use fixed effects regression as our main methodology. We find that if a country is in a geopolitical conflict, their firms are impacted in the form of lower E, S and G performance and overall ESG performance, with stronger effects for developed countries. This comes on top of the direct costs of geopolitical conflicts. Our results are robust to country, year and firm fixed effects as well as robust to endogeneity as we use Lewbel (2012) estimator to eliminate any chances of endogeneity. We provide first evidence on this topic and it has geopolitical and socioeconomical implications.


Novel electrospun bead-like Ag2MoO4 nanofibers coated on Ni foam for visible light-driven heterogeneous photocatalysis and high-performance supercapacitor electrodes.
Novel Ag2MoO4 nanocomposite fibers were designed to enhance the photocatalytic response and supercapacitor performance of MoO3 grown via the sol-gel electrospinning technique. The Ag2MoO4 nanocomposite fibers exhibit a high specific surface area of 49.3 m2 g-1 comprising nanobeads that aggregate in the fibrous structure. The photodegradation efficiency of Ag2MoO4 was evaluated as 62% under visible light irradiation which improved to 71% with heterogeneous photocatalysis. The Ag2MoO4@Ni foam exhibited a low Rct of 19.6 Ω, and an enhanced specific capacitance of 1445 F g-1 was obtained at 1 A g-1, with 93% of its initial capacitance remaining after 5000 cycles. In addition, the Ag2MoO4//activated carbon asymmetric supercapacitor possesses an excellent energy density of 76.6 W h kg-1 at 743.2 W kg-1 and a noteworthy cycling durability of 91% after 5000 cycles. Our findings demonstrate that the electrospun Ag2MoO4@Ni foam is an important and inexpensive electrode material for supercapacitor applications and visible light-driven heterogeneous photocatalysis, drawing on the synergic effects of Ag and Mo to exhibit much better performance.


Citrullination profile analysis reveals peptidylarginine deaminase 3 as an HSV-1 target to dampen the activity of candidate antiviral restriction factors.
Herpes simplex virus 1 (HSV-1) is a neurotropic virus that remains latent in neuronal cell bodies but reactivates throughout an individual's life, causing severe adverse reactions, such as herpes simplex encephalitis (HSE). Recently, it has also been implicated in the etiology of Alzheimer's disease (AD). The absence of an effective vaccine and the emergence of numerous drug-resistant variants have called for the development of new antiviral agents that can tackle HSV-1 infection. Host-targeting antivirals (HTAs) have recently emerged as promising antiviral compounds that act on host-cell factors essential for viral replication. Here we show that a new class of HTAs targeting peptidylarginine deiminases (PADs), a family of calcium-dependent enzymes catalyzing protein citrullination, exhibits a marked inhibitory activity against HSV-1. Furthermore, we show that HSV-1 infection leads to enhanced protein citrullination through transcriptional activation of three PAD isoforms: PAD2, PAD3, and PAD4. Interestingly, PAD3-depletion by specific drugs or siRNAs dramatically inhibits HSV-1 replication. Finally, an analysis of the citrullinome reveals significant changes in the deimination levels of both cellular and viral proteins, with the interferon (IFN)-inducible proteins IFIT1 and IFIT2 being among the most heavily deiminated ones. As genetic depletion of IFIT1 and IFIT2 strongly enhances HSV-1 growth, we propose that viral-induced citrullination of IFIT1 and 2 is a highly efficient HSV-1 evasion mechanism from host antiviral resistance. Overall, our findings point to a crucial role of citrullination in subverting cellular responses to viral infection and demonstrate that PAD inhibitors efficiently suppress HSV-1 infection in vitro, which may provide the rationale for their repurposing as HSV-1 antiviral drugs.


[Analysis of communication in social networks of the influenza vaccine campaign in Spain].
After arising of anti-vaccine groups and their dissemination, it is necessary to carry out communication campaigns on the benefits of vaccination aimed at citizens, and social networks are a good way to reach a large population. The objective of this article is to determine the communication on Twitter social network during the influenza vaccine campaign in 2018 in Spain. Big data methods were used to collect all tweets about the influenza vaccine during October 23 to December 15. They were determined by cluster analysis, eigenvector and pagerank calculations to determinate who were the most important influencers during the campaign. A total of 9,147 tweets were collected, of which 71.94% were retweets (RT). Ten groups generated 69.92% of the message traffic on vaccines. The main emotion expressed in the messages about vaccines is the fear of consequences if people do not get vaccinated. It was determined that the information on the campaign is favorable to vaccination but is mainly directed by (supposedly) doctors, nurses or anonymous patients who tweet and are followed by many users. The official and institutional campaigns, some of which are re-disseminated in a possibly organized way, are very neglected in the monitoring of society in the networks.


Variable-Focus Liquid Lens Integrated with a Planar Electromagnetic Actuator.
In this paper, we design, fabricate and characterize a new electromagnetically actuated variable-focus liquid lens which consists of two polymethyl methacrylate (PMMA) substrates, a SU-8 substrate, a polydimethylsiloxane (PDMS) membrane, a permanent magnet and a planar electromagnetic actuator. The performance of this liquid lens is tested from four aspects including surface profiling, optical observation, variation of focal length and dynamic response speed. The results shows that with increasing current, the optical chamber PDMS membrane bulges up into a shape with a smaller radius of curvature, and the picture recorded by a charge-coupled device (CCD) camera through the liquid lens also gradually becomes blurred. As the current changes from -1 to 1.2 A, the whole measured focal length of the proposed liquid lens ranges from -133 to -390 mm and from 389 to 61 mm. Then a 0.8 A square-wave current is applied to the electrode, and the actuation time and relaxation time are 340 and 460 ms, respectively. The liquid lens proposed in the paper is easily integrated with microfluidic chips and medical detecting instruments due to its planar structure.


Protection Against Cold Storage-Induced Renal Tubular Cell Apoptosis.
Prolonged cold storage (CS) of donor kidneys is associated with tubular cell apoptosis and caspase-3 activation. We have previously shown that pancaspase inhibition prevents CS-associated tubular apoptosis. Because of the nonspecific nature of pancaspase inhibitors, which block all caspases including proinflammatory caspase-1, the effect of specific caspase-3 inhibition during CS is unknown. X-linked inhibitor of apoptosis (XIAP) is the most potent naturally occurring specific inhibitor of caspase-3. We hypothesized that prolonged CS would decrease XIAP, whereas upregulation of XIAP with the novel compound UCF-101 would protect against caspase-3 activation and tubular cell apoptosis. LLC-PK1 tubular cells and whole kidneys from C57BL/6 mice were subjected to prolonged CS with or without UCF-101, and examined for XIAP, caspase-3, and tubular apoptosis. Tubular cells subjected to prolonged CS in vitro demonstrated significantly decreased XIAP and significantly increased apoptosis, caspase-3 protein and activity. UCF-101 treatment significantly increased XIAP, significantly decreased capsase-3 protein and activity, and protected against apoptosis. To determine the therapeutic significance, whole kidneys were subjected to prolonged CS with UCF-101. UCF-101 significantly increased XIAP in donor kidneys and protected against apoptosis. Prolonged CS of tubular cells in vitro and whole mouse kidneys ex vivo is associated with loss of XIAP and subsequent tubular cell apoptosis. UCF-101 protects against the loss of XIAP during prolonged CS both in vitro and ex vivo, and is associated with significantly reduced tubular cell apoptosis. UCF-101 may represent an attractive approach to improve organ preservation.


Real-time complex temporal response measurements of ultrahigh-speed optical modulators.
We demonstrate a technique for direct, real-time characterization of the complex (amplitude and phase) temporal response of ultrahigh-speed (GHz-bandwidth) optical modulators. The demonstrated technique is based on pulse interferometry combined with time-frequency mapping processes using fiber linear dispersion. A new mechanism is incorporated to overcome the temporal resolution (bandwidth) limitation of the detectable modulation response in our previously reported setup. This mechanism, referred to as 'common-path temporal image magnification', lowers the required detection bandwidth by a factor of more than 10, enabling real-time single-shot waveform acquisition without loss of information using a conventional temporal digitizer. The design specifications of the proposed measurement setup are derived and discussed in detail. As a proof-of-concept experiment, real-time characterization of a complex electro-op c modulation temporal response with time features as fast as approximately 35 ps (modulation bandwidth > 40-GHz) was obtained and displayed at a video rate of 30 frames/sec.


Hazard Characterization of Modified Vaccinia Virus Ankara Vector: What Are the Knowledge Gaps?
Modified vaccinia virus Ankara (MVA) is the vector of choice for human and veterinary applications due to its strong safety profile and immunogenicity in vivo. The use of MVA and MVA-vectored vaccines against human and animal diseases must comply with regulatory requirements as they pertain to environmental risk assessment, particularly the characterization of potential adverse effects to humans, animals and the environment. MVA and recombinant MVA are widely believed to pose low or negligible risk to ecosystem health. However, key aspects of MVA biology require further research in order to provide data needed to evaluate the potential risks that may occur due to the use of MVA and MVA-vectored vaccines. The purpose of this paper is to identify knowledge gaps in the biology of MVA and recombinant MVA that are of relevance to its hazard characterization and discuss ongoing and future experiments aimed at providing data necessary to fill in the knowledge gaps. In addition, we presented arguments for the inclusion of uncertainty analysis and experimental investigation of verifiable worst-case scenarios in the environmental risk assessment of MVA and recombinant MVA. These will contribute to improved risk assessment of MVA and recombinant MVA vaccines.


Coping Strategies Among Undergraduates: Spanish Adaptation and Validation of the Brief-COPE Inventory.
Different studies have highlighted the importance of coping strategies in stressful situations. The Coping Orientation to Problem Experienced (COPE) by Carver et al is one of the instruments that is frequently used for measuring this aspect. The aim of this study was to carry out the cross-cultural adaptation and validation of the Brief-COPE inventory to measure coping strategies in Spanish populations. The linguistic and cultural adaptation of the Brief-COPE was carried out using the back-translation method and, after considering the results of the pilot test, the Spanish version of the instrument was configured, and subsequently administered to a convenient sample of 2135 undergraduates. A confirmatory factor analysis was carried out to examine construct validity of the Spanish adaptation of the brief-COPE; likewise, reliability was analyzed from two approaches, internal consistency and composite reliability. Concurrent validity was also tested. The results showed that the Spanish version of Brief-COPE has adequate reliability values, as well as satisfactory fit indexes for the proposed 14-factor first-order structural model. Likewise, external evidence of the validity of the inventory with the variables perceived stress, level of satisfaction with life, and academic performance is provided. The results suggest that this instrument presents a satisfactory metric quality and, therefore, it could be useful to evaluate coping strategies, which would allow further research on its incidence and consequences on health and psychological functioning.


A serial dilution microfluidic device using a ladder network generating logarithmic or linear concentrations.
In this paper, we propose a serial dilution microfluidic chip which is able to generate logarithmic or linear step-wise concentrations. These concentrations were generated via adjustments in the flow rate of two converging fluids at the channel junctions of the ladder network. The desired dilution ratios are almost independent of the flow rate or diffusion length of molecules, as the dilution device is influenced only by the ratio of volumetric flow rates. Given a set of necessary dilution ratios, whether linear or logarithmic, a serial dilution chip can be constructed via the modification of a microfluidic resistance network. The design principle was suggested and both the logarithmic and linear dilution chips were fabricated in order to verify their performance in accordance with the fluorescence intensity. The diluted concentrations of a fluorescein solution in the microfluidic device evidenced relatively high linearity, and the cytotoxicity test of MCF-7 breast cancer cells via the logarithmic dilution chip was generally consistent with the results generated with manual dilution.


Novel fluid-fluid interface domains in geologic media.
Pore-scale fluid processes in geological media are critical for numerous applications in several fields. Continued improvement of high-resolution image acquisition and processing methods has provided a means to directly characterize pore-scale fluid processes for natural geomedia, and to test the representativeness of theoretical and computational models developed to simulate them. High-resolution synchrotron X-ray microtomography (XMT) combined with advanced 3-D image visualization was used to investigate the impact of larger-scale solid-surface heterogeneity on nonwetting-wetting (air-water) interfacial area for two natural geomedia (a sand and a soil). The studies revealed the presence of air-water interfaces associated with water residing within macroscopic features such as pits and crevices on the surfaces of the solids. The diameters of the features ranged from tens to 100's of μm for the sand, and the aggregate associated air-water interfacial area was estimated to represent ∼12% of the maximum capillary interfacial area. These features and respective fluid interfaces, which are not considered in standard conceptualizations of fluid distribution in geomedia, may have an impact on pore-scale physical and biogeochemical processes.


Synthesis and characterization of pH-responsive deep eutectic solvent followed by HPLC for trace determination of bisphenol A in water samples.
A microextraction based on pH-responsive deep eutectic solvent combined with high-performance liquid chromatography was developed for the separation, preconcentration, and determination of bisphenol A in water samples. Five deep eutectic solvents were prepared using thymol (hydrogen bond acceptor) and 6-, 8-, 9-, 10-, and 12-carbon carboxylic acids (hydrogen bond donor), and were used as extraction solvent. Herein, by alkalinizing the environment, phase transition takes place, and by adding acid, phase separation and extraction of analytes occur simultaneously. Some important parameters on the extraction such as deep eutectic solvent type, molar ratio of deep eutectic solvent components, deep eutectic solvent volume, potassium hydroxide concentration, hydrochloric acid volume, extraction time, and salt addition were optimized. Under the optimum conditions, intra- and interday precisions of the method based on seven replicate measurements of 10 μg L-1 of bisphenol A in water samples were 2.2% and 4.3%, respectively. The analytical performance of the method showed linearity over the concentration of 0.05-50 μg L-1 with the detection limit of 0.02 μg L-1 . The accuracy of the method was confirmed by spiking different concentrations of bisphenol A in real water samples and obtaining relative recoveries in the range of 92.5%-105.2%.


Comparison of modeled and measured indoor air trichloroethene (TCE) concentrations at a vapor intrusion site: influence of wind, temperature, and building characteristics.
There is a lack of vapor intrusion (VI) models that reliably account for weather conditions and building characteristics, especially at sites where active alternative pathways, such as sewer connections and other preferential pathways, are present. Here, a method is presented to incorporate freely-available models, CONTAM, and CFD0, to estimate site-specific building air exchange rates (AERs) and indoor air contaminant concentrations by accounting for weather conditions and building characteristics at a well-known VI site with a land drain preferential pathway. To account for uncertainty in model input parameters that influence indoor air chlorinated volatile organic compound (CVOC) concentration variability, this research incorporated Monte Carlo simulations and compared model results with retrospective field data collected over approximately 1.5 years from the study site. The results of this research show that mass entry rates for TCE are likely influenced by indoor air pressures that can be modeled as a function of weather conditions (over seasons) and building characteristics. In addition, the results suggest that temporal variability in indoor air TCE concentrations is greatest (modeled and measured) due to the existence of a land drain, which acts as a preferential pathway, from the subsurface to the granular fill beneath the floor slab. The field data and modeling results are in good agreement and provide a rare comparison of field data and modeling results for a VI site. The modeling approach presented here offers a useful tool for decision makers and VI practitioners as they assess these complex and variable processes that have not been incorporated within other VI models.


Calcium, Ammonia, Redox-Active Tyrosine YZ, and Proton-Coupled Electron Transfer in the Photosynthetic Oxygen-Evolving Complex.
A redox-active tyrosine, YZ (Y161 in the D1 polypeptide), is essential in photosystem II (PSII), which conducts photosynthetic oxygen evolution. On each step of the light-driven oxygen evolving reaction, YZ radical is formed by a chlorophyll cation radical. YZ radical is then reduced by a Mn4CaO5 cluster in a proton coupled electron transfer (PCET) reaction. YZ is hydrogen bonded to His190-D1 and to water molecules in a hydrogen-bonding network, involving calcium. This network is sensitive to disruption with ammonia and to removal and replacement of calcium. Only strontium supports activity. Here, we use electron paramagnetic resonance (EPR) spectroscopy to define the influence of ammonia treatment, calcium removal, and strontium/barium substitution on YZ radical PCET at two pH values. A defined oxidation state of the metal cluster (S2) was trapped by illumination at 190 K. The net reduction and protonation of YZ radical via PCET were monitored by EPR transients collected after a 532 nm laser flash. At 190 K, YZ radical cannot oxidize the Mn4CaO5 cluster and decays on the seconds time scale by recombination with QA-. The overall decay half-time and biexponential fits were used to analyze the results. The reaction rate was independent of pH in control, calcium-reconstituted PSII (Ca-PSII). At pH 7.5, the YZ radical decay rate decreased in calcium-depleted (CD-PSII) and barium/strontium-reconstituted PSII (Ba-PSII, Sr-PSII), relative to Ca-PSII. At pH 6.0, the YZ radical decay rate was not significantly altered in CD-PSII and Sr-PSII but decreased in Ba-PSII. A two-pathway model, involving two competing proton donors with different pKa values, is proposed to explain these results. Ammonia treatment decreased the YZ decay rate in Ca-PSII, Sr-PSII, and CD-PSII, consistent with a reaction that is mediated by the hydrogen-bonding network. However, ammonia treatment did not alter the rate in Ba-PSII. This result is interpreted in terms of the large ionic radius of barium and the elevated pKa of barium-bound water, which are expected to disrupt hydrogen bonding. In addition, evidence for a functional interaction between the S2 protonated water cluster (Wn+) and the YZ proton donation pathway is presented. This interaction is proposed to increase the rate of the YZ PCET reaction.


The experience of first-time Hong Kong Chinese fatherhood: A qualitative exploratory study.
The father's involvement in childrearing can positively influence health outcomes not only for the man himself but also for his partner and their children. However, the experience of first-time fatherhood is limited in Chinese communities. The aim of this study is to explore men's experience of first-time fatherhood and coping in Hong Kong. An exploratory qualitative design was used. A purposive sample of 44 first-time Chinese fathers who had participated in a couple-based cognitive-behavioral intervention for postnatal depression were recruited for telephone interviews at 1-3 months postpartum. Data were collected by a semistructured interview guide and analyzed using thematic analysis. The process involved in men's transition to first-time fatherhood reveals four major themes: changes in daily life, new paternal roles and responsibilities, availability of resources to enhance adaptation, and coping strategies. The findings have implications for health care professionals and policy-makers in the provision of comprehensive perinatal care and family-friendly policies to aid men's transition to first-time fatherhood in Chinese communities.


Wine Resveratrol: From the Ground Up.
The ability of the grapevine to activate defense mechanisms against some pathogens has been shown to be linked to the synthesis of resveratrol and other stilbenes by the plant (inducible viniferins). Metabolized viniferins may also be produced or modified by extracellular enzymes released by the pathogen in an attempt to eliminate undesirable toxic compounds. Because of the important properties of resveratrol, there is increasing interest in producing wines with higher contents of this compound and a higher nutritional value. Many biotic and abiotic elicitors can trigger the resveratrol synthesis in the berries, and some examples are reported. Under the same elicitation pressure, viticultural and enological factors can substantially affect the resveratrol concentration in the wine. The production of high resveratrol-containing grapes and wines relies on quality-oriented viticulture (suitable terroirs and sustainable cultural practices) and winemaking technologies that avoid degradation of the compound. In general, the oenological practices commonly used to stabilize wine after fermentation do not affect resveratrol concentration, which shows considerable stability. Finally the paper reports on two sirtuin genes (SIRT) expressed in grapevine leaves and berries and the role of resveratrol on the deacetylation activity of the encoded enzymes.


Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3-TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study.
Pioglitazone (PIO) is a peroxisome proliferator-activated receptor (PPAR)γ agonist insulin-sensitiser with anti-inflammatory and anti-atherosclerotic effects. Our objective was to evaluate the effect of low-dose PIO (15 mg/day) on glucose metabolism and inflammatory state in obese individuals with type 2 diabetes. A randomised, double-blind, placebo-controlled, mechanistic trial was conducted on 29 patients with type 2 diabetes treated with metformin and/or sulfonylurea. They were randomised to receive PIO or placebo (PLC) for 6 months, in a 1:1 ratio. Participants were allocated to interventions by central office. All study participants, investigators and personnel performing measurements were blinded to group assignment. At baseline and after 6 months patients underwent: (1) OGTT; (2) muscle biopsy to evaluate expression of TNF-α, tissue inhibitor of metalloproteases 3 (TIMP-3) levels, TNF-α converting enzyme (TACE) expression and enzymatic activity; (3) euglycaemic-hyperinsulinaemic clamp; (4) measurement of plasma high-sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor type-1 (PAI-1), TNF-α, IL-6, monocyte chemotactic protein-1 (MCP-1), adiponectin and fractalkine (FRK). The interventions were PIO 15 mg/day vs placebo and the main outcomes measured were absolute changes in whole-body insulin sensitivity, insulin secretion and inflammatory state. Fifteen participants were randomized to receive PIO and 14 participants were randomized to receive PLC. Eleven participants completed the study in the PIO group and nine participants completed the study in the PLC group and were analysed. Fasting plasma glucose and HbA1c decreased modestly (p < 0.05) after PIO and did not change after PLC. M/I (insulin-stimulated whole-body glucose disposal), adipose tissue insulin resistance (IR) index, insulin secretion/IR (disposition) index and insulinogenic index improved significantly after PIO, but not after PLC. Circulating MCP-1, IL-6, FRK, hsCRP and PAI-1 levels decreased in PIO- as compared with PLC-treated patients, while TNF-α did not change. TNF-α protein expression and TACE enzymatic activity in muscle were significantly reduced by PIO but not PLC. Adiponectin levels increased significantly after PIO as compared with PLC treatment. Given that the mean TACE enzymatic activity level at baseline in the PIO group was 0.29 ± 0.07 (fluorescence units [FU]), and at end of study decreased to 0.05 vs 0.14 in the PLC group, the power to reject the null hypothesis that the population means of the PIO and PLC groups are equal after 6 months is greater than 0.80. Given that M/I was 2.41 ± 0.35 μmol kg(-1) min(-1) (pmol/l)(-1) at baseline and increased by 0.55 in the PIO and 0.17 in the PLC groups, the power to reject the null hypothesis that the population means of the PIO and PLC groups are equal after 6 months is greater than 0.85. The type I error probability associated with this test of this null hypothesis is 0.05. No serious adverse events occurred in either group. Low-dose PIO (15 mg/day) improves glycaemic control, beta cell function and inflammatory state in obese patients with type 2 diabetes. Clinical.Trial.gov NCT01223196. This study was funded by TAKEDA.


Prognostic significance of intratumoral blood vessel invasion in pathologic stage IA non-small cell lung cancer.
The 5-year survival rate of pathologic stage IA non-small cell lung cancer (NSCLC) is excellent; however, up to 10% of patients with pathologic stage IA NSCLC still relapse postoperatively and die. This study retrospectively analyzed the clinicopathologic features of patients with pathologic stage IA NSCLC to identify the prognostic factors and investigate the effect of a combination of intratumoral vessel invasion and tumor size. From December 1991 to December 2003, 217 consecutive patients with stage IA NSCLC were selected, and disease-free survival (DFS) was analyzed. Intratumoral blood vessel invasion (BVI) was identified as an independent poor prognostic factor (p = 0.0006). The relative risk for patients with BVI was 4.599 times higher than that for patients without BVI (95% confidence interval, 1.913 to 11.056). According to the new T N M system, the difference in DFS between the patients with and without BVI was statistically significant, not only in tumors exceeding 2 cm (T1b with BVI vs T1b without BVI, p = 0.0020) but also in tumors smaller than 2 cm (T1a with BVI vs T1a without BVI, p < 0.0001). The survival curve of T1b patients without BVI was similar to that of T1a patients without BVI (p = 0.0892). Distant recurrence was frequently observed in both T1a and T1b patients with BVI. BVI is an independent poor prognostic factor in patients with pathologic stage IA NSCLC. These T1a and T1b patients with BVI both might benefit from adjuvant chemotherapy.


A frame semantic overview of NLP-based information extraction for cancer-related EHR notes.
There is a lot of information about cancer in Electronic Health Record (EHR) notes that can be useful for biomedical research provided natural language processing (NLP) methods are available to extract and structure this information. In this paper, we present a scoping review of existing clinical NLP literature for cancer. We identified studies describing an NLP method to extract specific cancer-related information from EHR sources from PubMed, Google Scholar, ACL Anthology, and existing reviews. Two exclusion criteria were used in this study. We excluded articles where the extraction techniques used were too broad to be represented as frames (e.g., document classification) and also where very low-level extraction methods were used (e.g. simply identifying clinical concepts). 78 articles were included in the final review. We organized this information according to frame semantic principles to help identify common areas of overlap and potential gaps. Frames were created from the reviewed articles pertaining to cancer information such as cancer diagnosis, tumor description, cancer procedure, breast cancer diagnosis, prostate cancer diagnosis and pain in prostate cancer patients. These frames included both a definition as well as specific frame elements (i.e. extractable attributes). We found that cancer diagnosis was the most common frame among the reviewed papers (36 out of 78), with recent work focusing on extracting information related to treatment and breast cancer diagnosis. The list of common frames described in this paper identifies important cancer-related information extracted by existing NLP techniques and serves as a useful resource for future researchers requiring cancer information extracted from EHR notes. We also argue, due to the heavy duplication of cancer NLP systems, that a general purpose resource of annotated cancer frames and corresponding NLP tools would be valuable.


Surprising evidence of pelvic growth (widening) after skeletal maturity.
Following an increase in length and width during childhood and adolescence, skeletal growth is generally assumed to stop. This study investigates the influence of aging on the dimensions of the pelvis and the L4 lumbar vertebra during adulthood. The dimensions of the pelvis, L4 vertebra, and femoral heads were calculated for 246 patients who had received pelvic and abdominal Computed Tomography scans from the UNC Health Care System. Linear regression analysis determined the significance of relationships between age and width of the pelvis. There was a strong correlation between increasing patient age and increasing width of the pelvis at the trochanters, (0.333 mm/year of age p<0.0001), at the iliac wings, (0.371 mm/year of age p < 0.0002), and between the femoral heads, indicating that the bony pelvis widens over 20 mm between the ages of 20 and 80. The pelvic inlet did not enlarge over time while the distance between the hips and the femoral head diameter did significantly increase. The height of L4 did not increase over time, but the L4 width did increase. These correlations were seen in both genders. Surprisingly, our results suggest that the pelvis and L4 vertebra increase in width after skeletal maturity and cessation of longitudinal growth.


Thermodynamics of the size and shape of nanocrystals: epitaxial Ge on Si(001).
The growth and evolution of strained epitaxial Ge on a Si(001) surface provides a rich system for exploring the behavior of strongly interacting nanocrystals. In the temperature regime above 500 degrees C, there are two different (metastable) shapes of defect-free nanocrystals, termed pyramids and domes, that dominate the system depending on the temperature of the substrate during growth and the amount of Ge deposited. In contrast to the usual case considered in nucleation theory, the relaxation of the strain energy at the surface of the nanocrystals makes those surfaces stabilizing, i.e. the surface contribution to the free energy of the Ge nanocrystals is negative. Given that the edges of the nanocrystals are destabilizing (positive free energy), the interaction of the surfaces and edges of the nanocrystals in an ensemble renders an internal free energy for the system that has a local minimum with respect to the size (volume) of the nanocrystal. At finite temperatures, this free energy yields a size distribution with a characteristic centroid, width, and skewness for each nanocrystal shape. The smaller pyramids transform into domes when they grow to the point where they can surmount a kinetic energy barrier between the two structures. However, the Ge nanocrystals also effectively repel one another strongly via the strain fields that are produced in the Si substrate. This repulsive interaction makes the ensemble of Ge nanocrystals a highly nonideal thermodynamic system and, in turn, makes the free energies of the nanocrystals a function of their number density, or equivalently a function of the amount of Ge deposited. The interplay of the stabilizing effect of the nanocrystal surfaces and the destabilizing influence of their repulsive interactions yields a complex behavior for the nanocrystal-size distributions that can nonetheless be modeled using simple thermodynamic expressions.


Paradoxical air embolism during neurosurgery.
Four cases of air embolism which occurred during neurosurgical procedures in the sitting position are described, in whom the signs could be due to air in the coronary or cerebral arteries. It is suggested that, during venous air embolism in the sitting position, a significant number of patients are haemodynamically at risk from paradoxical air embolism, and that the serious consequences of venous air embolism in neurosurgery may be due to this.


Functional cross-talk between distant domains of chikungunya virus non-structural protein 2 is decisive for its RNA-modulating activity.
Chikungunya virus (CHIKV) non-structural protein 2 (nsP2) is a multifunctional protein that is considered a master regulator of the viral life cycle and a main viral factor responsible for cytopathic effects and subversion of antiviral defense. The C-terminal part of nsP2 possesses protease activity, whereas the N-terminal part exhibits NTPase and RNA triphosphatase activity and is proposed to have helicase activity. Bioinformatics analysis classified CHIKV nsP2 into helicase superfamily 1. However, the biochemical significance of a coexistence of two functionally unrelated modules in this single protein remains unknown. In this study, recombinant nsP2 demonstrated unwinding of double-stranded RNA in a 5'-3' directionally biased manner and RNA strand annealing activity. Comparative analysis of NTPase and helicase activities of wild type nsP2 with enzymatic capabilities of different truncated or N-terminally extended variants of nsP2 revealed that the C-terminal part of the protein is indispensable for helicase functionality and presumably provides a platform for RNA binding, whereas the N-terminal-most region is apparently involved in obtaining a conformation of nsP2 that allows for its maximal enzymatic activities. The establishment of the protocols for the production of biochemically active CHIKV nsP2 and optimization of the parameters for helicase and NTPase assays are expected to provide the starting point for a further search of possibilities for therapeutic interventions to suppress alphaviral infections.


Targeted Therapy for Locally Advanced or Metastatic Urothelial Cancer (mUC): Therapeutic Potential of Sacituzumab Govitecan.
Urothelial carcinoma is the second most frequent genitourinary malignancy. Despite the poor prognosis, new treatment options have emerged and have expanded the therapeutic landscape for the disease. Although major improvements have been achieved, many patients experience rapid disease progression and low responses in subsequent lines of therapy. Sacituzumab govitecan is an ADC that targets Trop-2, which is highly expressed in urothelial cancers. Promising results in early clinical trials have led to further drug development which confirmed encouraging efficacy. Sacituzumab govitecan has been given accelerated approval in 2021 for patients with locally advanced and metastatic urothelial cancer who previously received a platinum containing chemotherapy and either a programmed death receptor-1 or programmed death ligand inhibitor. The results are promising, with encouraging efficacy and safety, however responses are not universal. There is a growing comprehension of mechanisms of resistance and predictive biomarkers that are crucial to improving outcomes. In this review, we summarize the current knowledge on antibody-drug conjugates and the clinical findings that led to the approval of Sacituzumab govitecan and discuss the therapeutic potential of new combinations, mechanisms of resistance and predictive biomarkers.


Graphene-Boron Nitride-Graphene Cross-Point Memristors with Three Stable Resistive States.
Two-dimensional (2D) material-based memristors have shown several properties that are not shown by traditional ones, such as high transparency, robust mechanical strength and flexibility, superb chemical stability, enhanced thermal heat dissipation, ultralow power consumption, coexistence of bipolar and threshold resistive switching, and ultrastable relaxation when used as electronic synapse (among others). However, several electrical performances often required in memristive applications, such as the generation of multiple stable resistive states for high-density information storage, still have never been demonstrated. Here, we present the first 2D material-based memristors that exhibit three stable and well-distinguishable resistive states. By using a multilayer hexagonal boron nitride (h-BN) stack sandwiched by multilayer graphene (G) electrodes, we fabricate 5 μm × 5 μm cross-point Au/Ti/G/h-BN/G/Au memristors that can switch between each two or three resistive states, depending on the current limitation (CL) and reset voltage used. The use of graphene electrodes plus a small cross-point structure are key elements to observe the tristate operation, which has not been observed in larger (100 μm × 100 μm) devices with an identical Au/Ti/G/h-BN/G/Au structure nor in similar small (5 μm × 5 μm) devices without graphene interfacial layers (i.e., Au/Ti/h-BN/Au). Basically, we generate an intermediate state between the high resistive state and the low resistive state (LRS), named soft-LRS (S-LRS), which may be related to the formation of a narrower conductive nanofilament across the h-BN because of the ability of graphene to limit metal penetration (at low CLs). All the 2D materials have been fabricated using the scalable chemical vapor deposition approach, which is an immediate advantage compared to other works using mechanical exfoliated 2D materials.


[Definition, classification and diagnosis of chronic venous insufficiency - part II].
Venous insufficiency can be defined as a fixed venous outflow disturbance of the limbs. It is caused by the malfunction of the venous system, that may or may not be associated with venous valvular insufficiency and may involve the superficial or deep venous system of the lower limbs, or both. The CEAP scale includes clinical, etiologic, anatomic and pathophysiologic aspects and has been used in the assessment of venous insufficiency Clinical classification comprises of 7 groups. It takes into account the appearance of the skin of the lower limbs, presence of edema, teleangiectasis and varicose ulcers. CLINICAL GRADING: Group C0 - no visible changes in the clinical examination; Group C1 - telangiectasis, reticular veins, redness of the skin around the ankles; Group C2 - varicose veins, Group C3 - the presence of edema without skin changes; Group C4 - lesions dependent of venous diseases (discoloration, blemishes, lipodermatosclerosis); C5 Group - skin changes described above with signs of healed venous ulcers; Group C6 - skin lesions such as in groups C1 to C4 plus active venous ulcers. ETIOLOGICAL CLASSIFICATION INCLUDES: Ec - congenital defects of the venous system, Ep - primary pathological changes of the venous system, without identification of their causes; Es - secondary causes of venous insufficiency of known etiology (post-thrombotic, post-traumatic, etc.). There are many methods of assessing the venous system. One of the most accurate methods is an ascending phlebography which is especially useful in determining detailed anatomy of the venous system, venous patency and identification of perforans veins. The second method may be a descending phlebography useful in determining the venous reflux and morphology of venous valves. Another radiological method is varicography in which the injection of the contrast medium directly into the veins is performed. It is especially useful in the ,,mapping" of venous connections. Trans-uterine phlebography when contrast medium is injected into the bottom of the uterus and its flow is observed, is a very rare test. A similar method is used in a selective phlebography of the ovarian vein and internal iliac vein. This examination is performed when there is a suspicion of connections between varicose veins of the inferior extremities and the pelvis, in case of the occluded iliac and femoral veins. However these tests are highly invasive, causing a lot of discomfort and are connected with numerous complications, particularly the development of venous thromboembolism. An invasive study but not exposing to the emission of ionizing radiation, is a measurement of the marching pressure (known also as ambulatory venous pressure - AVP). Ultrasound Doppler is the "gold standard" in the diagnosis of venous system. Color Doppler technique is irreplaceable due to its non-invasiveness, availability constantly improving of the ultrasound machines and is the method of choice in pregnancy Unfortunately clinical correlation of Doppler ultrasound and thrombosis is bad. Invasive methods, which include various types of phlebographies, have been reserved only for cases of very high diagnostic doubt.


Reliability and validity of a simulation-based acute care skills assessment for medical students and residents.
Medical students and residents are expected to be able to manage a variety of critical events after training, but many of these individuals have limited clinical experiences in the diagnosis and treatment of these conditions. Life-sized mannequins that model critical events can be used to evaluate the skills required to manage and treat acute medical conditions. The purpose of this study was to develop and test simulation exercises and associated scoring methods that could be used to evaluate the acute care skills of final-year medical students and first-year residents. The authors developed and tested 10 simulated acute care situations that clinical faculty at a major medical school expects graduating physicians to be able to recognize and treat at the conclusion of training. Forty medical students and residents participated in the evaluation of the exercises. Four faculty members scored the students/residents. The reliability of the simulation scores was moderate and was most strongly influenced by the choice and number of simulated encounters. The validity of the simulation scores was supported through comparisons of students'/residents' performances in relation to their clinical backgrounds and experience. Acute care skills can be validly and reliably measured using a simulation technology. However, multiple simulated encounters, covering a broad domain, are needed to effectively and accurately estimate student/resident abilities in acute care settings.


Pioneering immunotherapy for food allergy: clinical outcomes and modulation of the immune response.
There is no approved therapy for food allergies, which affect 12 million people in the United States and millions more worldwide. In the last few years, our research team at Duke has begun to develop protocols to treat peanut and other food allergies. Two distinct therapies are being developed. Oral immunotherapy (OIT), which relies on ingestion of increasing amounts of the allergenic food, has been used to successfully desensitize more than 50 peanut allergic subjects. Sublingual immunotherapy (SLIT) involves placing small quantities of peanut allergens under the tongue and has shown promise in our initial placebo-controlled clinical trial. Immunologic changes associated with OIT and SLIT include reduction in mast cell reactivity as determined by skin prick test size, decreased basophil responses, decreased specific-IgE, increased IgG4, and induction of regulatory T cells. Development of these immunotherapy strategies has generated much excitement in the food allergy community; however, further studies are needed before these approaches are ready for clinical use.


Thyroid hormone receptor expression in the human hypothalamus and anterior pituitary.
In the present study, we describe for the first time the distribution of thyroid hormone receptor (TR) isoforms in the human postmortem hypothalamus and anterior pituitary using immunocytochemistry. We used a set of polyclonal antisera raised against the specific isoforms of the human TR. The distribution of TR alpha 1, alpha 2, beta 1, and beta 2 was studied in consecutive sections of six hypothalami and pituitaries. Staining intensity showed strong interindividual variation but was consistently present in the infundibular nucleus, paraventricular nucleus, and supraoptic nucleus. In addition, strong TR immunoreactivity was observed in the anterior pituitary. Neuropeptide Y and proopiomelanocortin mRNA-positive cells in the infundibular nucleus, which were studied in three other hypothalami, appeared not to express TRs, and thus, the neurons expressing TRs in the human mediobasal hypothalamus remain to be characterized.


Harm reduction theories and strategies for control of human immunodeficiency virus: a review of the literature.
To provide a comprehensive review of the literature on harm reduction theories and strategies related primarily to licit and illicit drug use. Although human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) disease transmission is well understood, it continues to spread, particularly among injection drug users (IDUs). Despite early indications that HIV would be contained within the IDU community, it is spreading to non-IDU sexual partners and to children of IDUs, threatening a more widespread epidemic. An examination of research studies and theoretical writings including reviews and policy papers published in English between 1990 and 2000. Harm reduction does not seek to eliminate drug use; it focuses on minimizing the personal and social harms and costs associated with drug use and spread of HIV. It seeks to ameliorate conditions surrounding drug use responsible for the spread of HIV in the IDU community: unequal access to health services; sharing of infected needles; racial and social discrimination; poverty; exposure to street violence; inadequate housing; lack of employment; poor general or mental health and other demographic and social determinants. Some controversial harm reduction strategies are described: methadone maintenance programmes, illegal drugs dispensing under controlled conditions, needle exchanges, HIV testing, vein maintenance, safe-sex and would-care programmes. The main challenge is to get IDUs to protect themselves against HIV when suffering physical and social privations and addiction needs. Diverse perspectives on harm reduction are problematic with consequences for success of drug use initiatives. Practical, ethical and theoretical complexities exist but further research is needed to build support for a harm-reduction orientation in practice and policy formulation.


Power analysis in randomized clinical trials based on item response theory.
Patient relevant outcomes, measured using questionnaires, are becoming increasingly popular endpoints in randomized clinical trials (RCTs). Recently, interest in the use of item response theory (IRT) to analyze the responses to such questionnaires has increased. In this paper, we used a simulation study to examine the small sample behavior of a test statistic designed to examine the difference in average latent trait level between two groups when the two-parameter logistic IRT model for binary data is used. The simulation study was extended to examine the relationship between the number of patients required in each arm of an RCT, the number of items used to assess them, and the power to detect minimal, moderate, and substantial treatment effects. The results show that the number of patients required in each arm of an RCT varies with the number of items used to assess the patients. However, as long as at least 20 items are used, the number of items barely affects the number of patients required in each arm of an RCT to detect effect sizes of 0.5 and 0.8 with a power of 80%. In addition, the number of items used has more effect on the number of patients required to detect an effect size of 0.2 with a power of 80%. For instance, if only five randomly selected items are used, it is necessary to include 950 patients in each arm, but if 50 items are used, only 450 are required in each arm. These results indicate that if an RCT is to be designed to detect small effects, it is inadvisable to use very short instruments analyzed using IRT. Finally, the SF-36, SF-12, and SF-8 instruments were considered in the same framework. Since these instruments consist of items scored in more than two categories, slightly different results were obtained.


Comprehensive behavioral and physiologic assessment of peripheral and central auditory function in individuals with mild traumatic brain injury.
Auditory complaints are frequently reported by individuals with mild traumatic brain injury (mTBI) yet remain difficult to detect in the absence of clinically significant hearing loss. This highlights a growing need to identify sensitive indices of auditory-related mTBI pathophysiology beyond pure-tone thresholds for improved hearing healthcare diagnosis and treatment. Given the heterogeneity of mTBI etiology and the diverse peripheral and central processes required for normal auditory function, the present study sought to determine the audiologic assessments sensitive to mTBI pathophysiology at the group level using a well-rounded test battery of both peripheral and central auditory system function. This test battery included pure-tone detection thresholds, word understanding in quiet, sentence understanding in noise, distortion product otoacoustic emissions (DPOAEs), middle-ear muscle reflexes (MEMRs), and auditory evoked potentials (AEPs), including auditory brainstem responses (ABRs), middle latency responses (MLRs), and late latency responses (LLRs). Each participant also received magnetic resonance imaging (MRI). Compared to the control group, we found that individuals with mTBI had reduced DPOAE amplitudes that revealed a compound effect of age, elevated MEMR thresholds for an ipsilateral broadband noise elicitor, longer ABR Wave I latencies for click and 4 kHz tone burst elicitors, longer ABR Wave III latencies for 4 kHz tone bursts, larger MLR Na and Nb amplitudes, smaller MLR Pb amplitudes, longer MLR Pa latencies, and smaller LLR N1 amplitudes for older individuals with mTBI. Further, mTBI individuals with combined hearing difficulty and noise sensitivity had a greater number of deficits on thalamic and cortical AEP measures compared to those with only one/no self-reported auditory symptoms. This finding was corroborated with MRI, which revealed significant structural differences in the auditory cortical areas of mTBI participants who reported combined hearing difficulty and noise sensitivity, including an enlargement of left transverse temporal gyrus (TTG) and bilateral planum polare (PP). These findings highlight the need for continued investigations toward identifying individualized audiologic assessments and treatments that are sensitive to mTBI pathophysiology.


A Homopolymer of Xanthenoxanthene-Based Polycyclic Heteroaromatic for Efficient and Stable Perovskite Solar Cells.
Highly efficient perovskite solar cells typically rely on spiro-OMeTAD as a hole transporter, achieving a 25.7% efficiency record. However, these cells are susceptible to harsh 85°C conditions. Here, we present a peri-xanthenoxanthene-based semiconducting homopolymer (p-TNI2) with matched energy levels and a high molecular weight of 388 kDa, synthesized nearly quantitatively through facile oxidative polymerization. Compared to established materials, p-TNI2 excels in hole mobility, morphology, modulus, and waterproofing. Implementing p-TNI2 as the hole transport layer results in n-i-p perovskite solar cells with an initial average efficiency of 24.6%, rivaling 24.4% for the spiro-OMeTAD control cells under identical conditions. Furthermore, the p-TNI2-based cells exhibit enhanced thermostability at 85°C and operational robustness.


Utilization of social media in floods assessment using data mining techniques.
Floods are among the devastating types of disasters in terms of human life, social and financial losses. Authoritative data from flood gauges are scarce in arid regions because of the specific type of dry climate that dysfunctions these measuring devices. Hence, social media data could be a useful tool in this case, where a wealth of information is available online. This study investigates the reliability of flood related data quality collected from social media, particularly for an arid region where the usage of flow gauges is limited. The data (text, images and videos) of social media, related to a flood event, was analyzed using the Machine Learning approach. For this reason, digital data (758 images and 1413 video frames) was converted into numeric values through ResNet50 model using the VGG-16 architecture. Numeric data of images, videos and text was further classified using different Machine Learning algorithms. Receiver operating characteristics (ROC) curve and area under curve (AUC) methods were used to evaluate and compare the performance of the developed machine learning algorithms. This novel approach of studying the quality of social media data could be a reliable alternative in the absence of real-time flow gauges data. A flash flood that occurred in the United Arab Emirates (UAE) from March 7-11, 2016 was selected as the focus of this study. Random forest showed the highest accuracy of 80.18% among the five other classifiers for images and videos. Precipitation/rainfall data were used to validate social media data, which showed a significant relationship between rainfall and the number of posts. The validity of the machine learning models was assessed using the area under the curve, precision-recall curve, root mean square error, and kappa statistics to confirm the validity and accuracy of the model. The data quality of YouTube videos was found to have the highest accuracy followed by Facebook, Flickr, Twitter, and Instagram. These results showed that social media data could be used when gauge data is unavailable.


Production of penicillic acid and ochratoxin A on poultry feed by Aspergillus ochraceus: temperature and moisture requirements.
A strain of Aspergillus ochraceus Wilhelm, isolated from poultry feed, produced both penicillic acid and ochratoxin A. Studies demonstrating the ability of this fungus to colonize poultry feed and produce these two mycotoxins under various temperatures and moistures indicated that the interaction was complex. The optimal temperature for conidial development did not vary with moisture, but accumulation of both toxins did. A combination of low temperature, 15 or 22 C, and low moisture favored the production of penicillic acid, whereas high temperature, 30 C, and high moisture favored the production of ochratoxin A.


Newer Insights into Prostatic Utricle in Proximal Hypospadias.
Prostatic utricles (PUs) are the remnants of Mullerian ducts found in the male posterior urethra. Enlarged symptomatic utricles are known to be associated with hypospadias. There is a dearth of literature defining an enlarged utricle and also its clinical significance. The aim of this study was to describe anatomical difference of PUs of cases with severe hypospadias and also to find their clinical significance if any. A prospective study was carried out, and all patients with proximal hypospadias were enrolled. Cystoscopy was performed in all cases. Symptomatology, size, and location of PU were recorded. PU of >0.5 cm was considered enlarged. In the present series, a total of 70 cases were included over a period of 2 years. Enlarged utricle was found in 47/70 (67.14%) on cystoscopy. They were wide-mouthed and negotiated 9 Fr/11 Fr cystoscope with ease. Recurrent epididymo-orchitis, recurrent urinary tract infection, and obstructive features were the most common complications requiring intervention. PUs in boys with hypospadias are enlarged as well as wide-mouthed. Most of these remain asymptomatic, but few of them carry the potential of complications. Cystoscopy helps in direct visualization of utricular anatomy, so it should be a preferred investigating modality for investigating a PU.


Childhood absence epilepsy requiring more than one medication for seizure control.
Absence epilepsy is the most common primary generalized epilepsy syndrome encountered in pediatric practice. Treatment is pharmacologically specific and usually successful with a single medication. The objective of this study was to identify any clinical or electroencephalographic features at initial presentation in a consecutive cohort of children with absence epilepsy that may be associated with the need for a second medication. A computerized pediatric neurology database (1991-2007 inclusive) was retrospectively searched for all patients with typical absence seizures, 3 Hz spike and wave on EEG and no apparent symptomatic etiology who were over the age of two years at seizure onset with at least one year of follow-up. All such children were then divided into two groups; a) those requiring a single medication for seizure control (Group 1), and b) those requiring two medications for seizure control despite optimal management with the initial medication as determined by serum drug monitoring (Group 2). Clinical and electrographic features evident at diagnosis were then contrasted between Group 1 and 2. Seventy-five children with absence seizures were initially identified with 52 meeting the study's inclusion and none of the exclusion criteria. Of these 52 children, 43 required a single medication for seizure control (Group 1), while 9 required two or more medications for seizure control (Group 2). A significant difference (p < 0.05) was apparent between Group 1 and 2 with respect to gender (16/43 males vs 8/9 males) and mean age of diagnosis (8.19 years +/- 3.00 vs 6.06 years +/- 2.22). Age of onset of seizures, interval duration of seizures prior to treatment initiation, duration of seizures, presence of automatisms, family history, presence of co-morbid conditions and EEG findings were not found to be significantly different between the two Groups. Male gender and an earlier age of diagnosis is associated with the need for two medications for seizure control in children with absence epilepsy. This observation may suggest the need for more intensive early programmatic follow-up for young male children with newly diagnosed absence epilepsy to effect more rapid attainment of seizure control.


Homotaurine induces measurable changes of short latency afferent inhibition in a group of mild cognitive impairment individuals.
Current treatment options for patients with Alzheimer's disease (AD) are limited at providing symptomatic relief, with no effects on the underlying pathophysiology. Recently, advances in the understanding of the AD pathogenesis highlighted the role of ABeta (Aβ) oligomers particularly interfering with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). These findings led to the development of potential anti-amyloid therapies, and among them homotaurine, a glycosaminoglycan mimetic designed to interfere with the actions of Aβ early in the cascade of amyloidogenic events, and by its γ-aminobutyric acid type (GABA) A receptor affinity. Recently, we showed that AD patients have impaired LTP-like cortical plasticity, as measured by standard theta burst stimulation protocols applied over the primary motor cortex (M1). Furthermore, AD patients have a weakened short latency afferent inhibition (SLAI), a neurophysiological measure of central cholinergic transmission, which changes reflect the cholinergic dysfunction occurring in the pathology. Here, we aimed at investigating whether homotaurine administration could modulate in vivo measured mechanisms of synaptic plasticity, namely LTP and LTD, and also SLAI in a group of mild cognitive impaired patients. We observed that homotaurine administration did not induce relevant changes of both LTP and LTD recordings, while induced changes of SLAI in our group of patients. We suggest that homotaurine effects are dependent on changes of cortical GABA transmission suggesting a potential role for this compound in ameliorating the cholinergic transmission by modulating the inhibitory cortical activity.


Managing myelodysplastic symptoms in elderly patients.
Most patients with myelodysplastic syndromes (MDS) are elderly (median age range 65 to 70 years); as a consequence, the incidence and prevalence of these diseases are rising as the population ages. Physicians are often uncertain about how to identify patients who may benefit from specific treatment strategies. The International Prognostic Scoring System is a widely used tool to assess the risk of transformation to leukemia and to guide treatment decisions, but it fails to take into account many aspects of treating elderly patients, including comorbid illnesses, secondary causes of MDS, prior therapy for MDS, and other age-related health, functional, cognitive, and social problems that affect the outcome and managing of myelodysplastic symptoms. Patients with low-risk disease traditionally have been given only best supportive care, but evidence is increasing that treatment with novel non-conventional drugs such as lenalidomide or methyltransferase inhibitors may influence the natural history of the disease and should be used in conjunction with supportive-care measures. Supportive care of these patients could also be improved in order to enhance their quality of life and functional performance. Elderly patients commonly have multiple medical problems and use medications to deal with these. In addition, they are more likely to have more than one health care provider. These factors all increase the risk of drug interactions and the consequent treatment of toxicities. Manifestations of common toxicities or illnesses may be more subtle in the elderly, owing to age-associated functional deficits in multiple organ systems. Particularly important to the elderly MDS patient is the age-related decline in normal bone marrow function, including the diminished capacity of response to stressors such as infection or myelosuppressive treatments. Through the integration of geriatric and oncological strategies, a personalized approach toward this unique population may be applied. As with many diseases in the elderly, reliance on family members or friends to maintain the prescribed treatments, including travel to and from appointments, may place additional stressors on the patient and his/her support network. Careful evaluation and knowledge of functional status, ability to tolerate treatments, effect of disease progression, and general overall health conditions can provide the best opportunity to support these patients. Immediate assessment of daily living activities may detect deficiencies or deficits that often require early interventions.


Use of rituximab in autoimmune hemolytic anemia associated with non-hodgkin lymphomas.
The association between non-Hodgkin lymphomas and autoimmune disorders is a well-known event. Also autoimmune hemolytic anemia (AHA), although much more frequent in patients with chronic lymphocytic leukemia (CLL), has been described in this group of patients. In recent years, among the more traditional therapeutic options, rituximab, an anti-CD20 monoclonal antibody, has shown interesting results in the treatment of primary AHA. Although this drug has been frequently used for AHA in patients with CLL, much less data are available on its use in NHL patients. However, considering that the main pathogenetic mechanism of AHA in course of lymphoproliferative disorders seems to be an antibody production directly or indirectly mediated by the neoplastic clone, this monoclonal antibody represents an ideal therapeutic approach. In this paper we will briefly describe some biological and clinical features of NHL-patients with AHA. We will then analyze some studies focusing on rituximab in primary AHA, finally reviewing the available literature on the use of this drug in NHL related AHA.


Association of PML-RAR alpha fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: an intergroup molecular study.
In each case of acute promyelocytic leukemia (APL) one of three PML-RAR alpha mRNA types is produced, depending on the break/fusion site in the PML gene that is linked to a common RAR alpha gene segment: a short (S)-form type, PML exon 3 RAR alpha exon 3; a long (L)-form type, PML exon 6 RAR alpha exon 3; or a variable (V)-form type, variably deleted PML exon 6 RAR alpha exon 3. We evaluated whether PML-RAR alpha mRNA type is associated with distinct pretreatment clinical characteristics and therapeutic outcome in previously untreated adult APL patients registered to protocol INT 0129 by the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Cancer and Leukemia Group B. Of 279 clinically eligible cases, 230 were molecularly evaluable, and of these, 111 were randomized to receive remission induction therapy with all-trans retinoic acid (ATRA) and 119 with conventional chemotherapy. Nine cases not excluded by central pathology review were PML-RAR alpha negative, and notably, none of five of these cases treated with ATRA achieved complete remission (CR). Among 221 PML-RAR alpha-positive cases, there were 82 S-form cases (37%), 121 L-form cases (55%), and 18 V-form cases (8%). Before any antileukemic therapy, the S-form type, compared with the L-form type, was associated with higher values for the white blood cell (WBC) count (median 2,500/microL v 1,600/microL; P = .009), the percentage of blood blasts plus promyelocytes (median 29% v 8.5%; P = .03), and the absolute blood blasts plus promyelocytes (884/microL v 126/microL; P = .019). Also, an increased percentage of S-form versus L-form cases had the M3 variant phenotype, 24% v 12% (P = .036). There were no differences between S-form and L-form cases in either CR rate (79% v 69%; P = .14) or disease free survival distribution (multivariate analysis adjusting for the association of S-form type and higher WBC count; P = .40). We conclude that the S-form type is associated with previously-identified adverse risk WBC parameters but that the identification of the S-form or L-form type of PML-RAR alpha mRNA, per se, does not predict clinical outcome or add to the value of an increased WBC count as a negative prognostic indicator in APL patients.


Promoter methylation of p16 associated with Helicobacter pylori infection in precancerous gastric lesions: a population-based study.
To investigate the relationship between p16 methylation and Helicobacter pylori infection in precancerous gastric lesions, a population-based study was conducted in Linqu County, a high-risk area of gastric cancer in China. Methylation status of p16 was evaluated by methylation-specific polymerase chain reaction in 920 subjects with precancerous gastric lesions. H. pylori status was determined by 13C-urea breath test and the density of H. pylori in biopsy specimens used for detecting methylation status was assessed by the modified Giemsa stain. The frequency of p16 methylation was significantly higher in subjects with H. pylori positive than those with H. pylori negative in each category of gastric lesion (p<0.001, respectively). Compared with H. pylori negative, the odds ratios (ORs) of p16 methylation were markedly elevated in subjects with H. pylori positive for superficial gastritis (OR, 9.45; 95% confidence interval [CI]: 2.94-30.41), chronic atrophic gastritis (OR, 15.92; 95%CI: 7.60-33.36), intestinal metaplasia (OR, 4.46; 95%CI: 2.44-8.13), indefinite dysplasia (OR, 3.67; 95%CI: 1.90-7.10), and dysplasia (OR, 2.48; 95%CI: 1.02-5.99). Moreover, the frequencies of p16 methylation increased steadily with the severity of H. pylori density in gastric mucosa. Compared with H. pylori negative, the OR of p16 methylation was 1.02-16.13 times higher in subjects with mild H. pylori infection, and 2.69-38.73 times higher in those with moderate/severe infection, respectively. Our findings indicate that p16 methylation was significantly associated with H. pylori infection in precancerous gastric lesions, suggesting that H. pylori infection could potently induce methylation of p16 CpG island.


Glial and neuronal antibodies in patients with idiopathic intracranial hypertension.
Headache and visual disturbances are the main presenting symptoms of idiopathic intracranial hypertension (IIH) characterized by increased intracranial pressure (ICP) with an unknown cause. We aimed to investigate the antibodies against optic neuritis-associated glial antigens, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) and uncharacterized neuronal membrane antigens in IIH patients. Consecutive patients diagnosed according to Friedman revised diagnostic criteria and control subjects were included after their consent. All serum samples were analyzed for antibodies against AQP4 and MOG using cell-based immunofluorescent assays and for uncharacterized neuronal membrane antigens by indirect immunocytochemistry utilizing live neurons. Sera of 34 patients with IIH and 40 control subjects were investigated but none of the patients showed AQP4 and MOG antibodies. However, serum IgG of five IIH patients showed reactivity against membrane antigens of rat hippocampal and cortical neurons. Interestingly, three out of these five patients had nonspecific white matter lesions on MRI, whereas only four of all other patients had these lesions (p = 0.048). AQP4 and MOG antibodies do not seem to have a role in the pathophysiology of IIH. However, association of immunocytochemistry findings with the presence of white matter lesions may suggest that immunological factors contribute to the pathogenesis of IIH in at least some of the patients.


Long-term results of emergency portacaval shunt for bleeding esophageal varices in unselected patients with alcoholic cirrhosis.
A prospective evaluation of emergency protacaval shunt has been conducted in 180 unselected, consecutive patients with cirrhosis and bleeding varices who were operated on between 1963 and 1978. An extensive diagnostic work-up was completed within three to seven hours of admission to the emergency department, and the shunt operation was undertaken within a mean of 7.81 hours. A program of lifelong follow-up was conducted such that the current status of 97% of the patients is known. On each patient, 220 categories of data were collected and entered into a computer program for analysis. On admission, 49% of the patients had jaundice, 53% had ascites, 19% had encephalopathy, 30% had severe muscle wasting and 100% had abnormal BSP retention. Administration of a bolus dose of vasopressin by the systemic intravenous route temporarily controlled the varix hemorrhage in 95% of patients, and emergency shunt permanently controlled the bleeding in 98%. Maximum perfusion pressure in the portal vein prior to shunt did not correlate with survival rate or incidence of encephalopathy after shunt. The operative survival rate was 58%, the five-year actuarial survival rate is 38% and the 12-year actuarial survival rate is 30%. Encephalopathy was observed in 31.5% of the patients, but was severe enough to require chronic dietary protein restriction in only 7%. The portacaval shunt remained patent in 99% of patients. Of the survivors, 48% abstained from alcohol, 60% resumed gainful employment or housekeeping, and two-thirds were judged to be in excellent or good condition after one and five years. Preoperative factors that adversely influenced survival rate were ascites, SGOT >/= 100 units, BSP retention >50%, hypokalemic alkalosis, blood transfusion requirement >/= 5 L, and consumption of alcohol within seven day[unk] of admission. In comparison with our previous prospective studies, emergency portacaval shunt produced a significantly greater long-term survival rate than either emergency medical therapy or emergency varix ligation, followed by elective shunt. During the past four years, 80% of 49 unselected patients have survived emergency shunt, and the four year actuarial survival rate is 69%.


Spotlight on inhaled ciprofloxacin and its potential in the treatment of non-cystic fibrosis bronchiectasis.
Non-cystic fibrosis bronchiectasis (NCFB) is a severe chronic illness characterized by irreversible dilation of airways and thickening of bronchial walls, chronic inflammation, repeated infections, and progressive obstruction of the airways. In contrast to cystic fibrosis bronchiectasis (CFB), which is a well-defined genetic disorder, NCFB is a heterogeneous disease caused by many different medical entities. Inhaled antibiotics are effective for patients with CFB, but their efficacy in NCFB has not been proven. The main pathogens involved in the colonization of patients with bronchiectasis are Haemophilus influenza, Moraxella catarrhalis, Staphylococcus aureus, and Pseudomonas aeruginosa. The latter is associated with increased morbidity and mortality. In addition, in NCFB, P. aeruginosa strains are frequently more resistant than those in CFB. At present, there are no approved inhaled antibiotic therapies for NCFB patients. Inhaled ciprofloxacin has been under investigation in the last few years. In two phase II randomized, double-blind, placebo-controlled trials, the use of inhaled ciprofloxacin was significantly associated with reduction in sputum bacterial density and greater eradication rates. In four phase III randomized, double-blind, placebo-controlled trials, the results regarding the time of the first exacerbation and the rate of exacerbations were inconsistent. Specifically, ORBIT-4 and RESPIRE-1 trials showed clinical benefit (prolongation of the time of the first exacerbation and reduced rate of exacerbations in the treatment group compared to the placebo group), whereas the ORBIT-3 and RESPIRE-2 failed to achieve their primary endpoints. The RESPIRE-1 was the first trial that examined the 14-days on/off course separate from the standard 28-days on/off regimen, which is based on CFB protocol treatments. The current data on the efficacy of inhaled ciprofloxacin are encouraging, but further evaluation is needed to determine the appropriate target group and the ideal duration of treatment.