The implementation and sustainment facilitation strategy improved implementation effectiveness and intervention effectiveness: Results from a cluster-randomized, type 2 hybrid trial.
Substance use disorders (SUDs) among people with HIV are both prevalent and problematic. The Substance Abuse Treatment to HIV care project was funded to test the Implementation and Sustainment Facilitation (ISF) strategy as an adjunct to the Addiction Technology Transfer Center (ATTC) strategy for integrating a motivational interviewing-based brief intervention (MIBI) for SUDs within HIV community-based organizations. Using a cluster-randomized, type 2 hybrid trial design, 39 HIV organizations were randomized to either (1) ATTC (n = 19) or (2) ATTC + ISF (n = 20). Each HIV organization identified two staff members to be prepared to implement the MIBI (N = 78). Subsequently, during the implementation phase, HIV organizations in each condition randomized client participants (N = 824) to one of the two intervention conditions: usual care (UC; n = 415) or UC + MIBI (n = 409). Both staff-level outcomes and client-level outcomes were examined. The ISF strategy had a significant impact on the implementation effectiveness (i.e., the consistency and the quality of implementation; β = .65, p = .01) but not on time-to-proficiency (β = -.02) or level-of-sustainment (β = .09). In addition, the ISF strategy was found to have a significant impact on the intervention effectiveness (the effectiveness of the MIBI), at least in terms of significantly decreasing the odds (odds ratio = 0.11, p = .02) of clients using their primary substance daily during follow-up. The ISF strategy was found to be an effective adjunct to the ATTC strategy in terms of implementation effectiveness and intervention effectiveness. It is recommended that future efforts to integrate the project's MIBI for SUD within HIV organizations use the ATTC + ISF strategy. However, given the ISF strategy did not have a significant impact on level-of-sustainment, implementation research testing the extent to which the ATTC + ISF strategy can be significantly enhanced through effective sustainment strategies is warranted. Substance use among people living with HIV is associated with increased mental health problems, worse medication adherence, and worse HIV viral suppression. Increasing substance use-related services in HIV community-based organizations is an important public health need. The Substance Abuse Treatment to HIV care project tested two strategies for helping HIV organizations implement a brief intervention (BI) designed to motivate clients to decrease their substance use. The project also tested if receiving a BI improved clients' outcome. Two staff from each of the 39 participating organizations were taught how to deliver the BI using the Addiction Technology Transfer Center (ATTC) training strategy (online and in-person training, monthly feedback, and coaching). Half of the organizations also received the Implementation and Sustainment Facilitation (ISF) strategy, which included monthly meetings with an ISF coach for the two BI staff and one or more leadership staff from the organization. Organizations that received both the ATTC and ISF strategies delivered more BIs and higher quality BIs than organizations that only received the ATTC strategy. In addition, clients receiving BIs at organizations that received both strategies were more likely to decrease their substance use. However, receiving both strategies did not improve how quickly staff learned to deliver the BI or improve the number of BIs delivered during the project's 6-month sustainment phase. Future research focused on implementing BIs within HIV organizations should consider using the ATTC and ISF strategies while also seeking to enhance the strategies to improve sustainment.


Users' and health service providers' perception on quality of laboratory malaria diagnosis in Tanzania.
Correct diagnosis of malaria is crucial for proper treatment of patients and surveillance of the disease. However, laboratory diagnosis of malaria in Tanzania is constrained by inadequate infrastructure, consumables and insufficient skilled personnel. Furthermore, the perceptions and attitude of health service providers (laboratory personnel and clinicians) and users (patients/care-takers) on the quality of laboratory services also present a significant challenge in the utilization of the available services. This study was conducted to assess perceptions of users and health-care providers on the quality and utilization of laboratory malaria diagnostic services in six districts from three regions in Tanzania. Questionnaires were used to collect information from laboratory personnel, clinicians and patients or care-takers. A total of 63 laboratory personnel, 61 clinicians and 753 patients/care-takers were interviewed. Forty-six (73%) laboratory personnel claimed to be overworked, poorly motivated and that their laboratories were under-equipped. About 19% (N = 12) of the laboratory personnel were lacking professional qualification. Thirty-seven clinicians (60.7%) always requested for blood smear examination to confirm malaria. Only twenty five (41.0%) clinicians considered malaria microscopy results from their respective laboratories to be reliable. Forty-five (73.8%) clinicians reported to have been satisfied with malaria diagnostic services provided by their respective laboratories. Majority (90.2%, N = 679) of the patients or care-takers were satisfied with the laboratory services. The findings show that laboratory personnel were not satisfied with the prevailing working conditions, which were reported to undermine laboratory performance. It was evident that there was no standard criteria for ordering malaria laboratory tests and test results were under-utilized. Majority of the clinicians and patients or care-takers were comfortable with the overall performance of laboratories, but laboratory results were having less impact on patient management.


Comparative hygienic assessment of active ingredients content in the air environment after treatment of cereal spiked crops by combined fungicides.
Introduction: The quality of the air environment significantly affects the health of the population. Chemical plant protection products in the spring and summer time may be the main pollutants of the air environment in rural areas. Chemical plant protection products are dangerous substances of anthropogenic origin. If applying pesticides in high concentrations, the risk of poisoning by active ingredients of pesticide preparations in workers directly contacting with it increases. The aim: Comparative hygienic assessment of active ingredients content in the air environment after treatment of cereal spiked crops by combined fungicides was the aim of the work. Materials and methods: Active ingredients of the studied combined fungicides, samples of air, and swabs from workers' skin and stripes from overalls were materials of the research. Methods of full-scale in-field hygienic experiment, gas-liquid chromatography, high-performance liquid chromatography, as well as statistical and bibliographic methods were used in the research. Results and conclusions: Active ingredients of the studied combined fungicides were not detected in the working zone air and atmospheric air at the levels exceeding the limits of its detection by appropriate chromatography methods. Findings confirmed the air environment safety for agricultural workers and rural population if studied combined fungicides are applied following the hygienically approved suggested application rates and in accordance of good agricultural practice rules. However the possible complex risk for workers after certain studied fungicides application may be higher than acceptable due to the elevated values for dermal effects. The complex risk was higher than acceptable in еру case of aerial spraying of both studied fungicides, meanwhile only one combination of active ingredients revealed possible risk for workers applying fungicides by rod method of cereal spiked crops treatment.


Disparities in Documented Drug Use Disorders Between Transgender and Cisgender U.S. Veterans Health Administration Patients.
Transgender people-those whose gender identity differs from their sex assigned at birth-are at risk for health disparities resulting from stressors such as discrimination and violence. Transgender people report more drug use than cisgender people; however, it is unclear whether they have higher likelihood of drug use disorders. We examined whether transgender patients have increased likelihood of documented drug use disorders relative to cisgender patients in the national Veterans Health Administration (VA). Electronic health record data were extracted for VA outpatients from 10/1/09 to 7/31/17. Transgender status and past-year documentation of drug use disorders (any, opioid, amphetamine, cocaine, cannabis, sedative, hallucinogen) were measured using diagnostic codes. Logistic regression models estimated odds ratios for drug use disorders among transgender compared to cisgender patients, adjusted for age, race/ethnicity and year. Effect modification by presence of ≥1 mental health condition was tested using multiplicative interaction. Among 8,872,793 patients, 8619 (0.1%) were transgender. Transgender patients were more likely than cisgender patients to have any drug use disorder (Adjusted Odds Ratio [aOR] 1.67, 95% confidence interval [CI] 1.53-1.83), amphetamine (aOR 2.22, 95% CI 1.82-2.70), cocaine (aOR 1.59, 95% CI 1.29-1.95), and cannabis (aOR 1.82, 95% CI 1.62-2.05) use disorders. There was no significant interaction by presence of ≥1 mental health condition. Transgender VA patients may have higher likelihood of certain drug use disorders than cisgender VA patients, particularly amphetamine use disorder. Future research should explore mechanisms underlying disparities and potential barriers to accessing treatment and harm reduction services faced by transgender people.


Reproducibility of inverse gas chromatography under infinite dilution: Results and interpretations of an interlaboratory study.
Over the last years, inverse gas chromatography (IGC) proved to be a versatile and sensitive analytical technique for physicochemical properties. However, the comparability of results obtained by different users and devices remains a topic for debate. This is the first time, an interlaboratory study using different types of IGC instruments is reported. Eight organizations with different IGC devices defined a common lab measurement protocol to analyse two standard materials, silica and lactose. All data was collected in a standard result form and has been treated identically with the objective to identify experimentally observed differences and not potentially different data treatments. The calculated values of the dispersive surface energy vary quite significantly (silica: 22 mJ/m2 - 34 mJ/m2, lactose 37 mJ/m2 - 51 mJ/m2) and so do the ISP values and retention volumes for both materials. This points towards significant and seemingly undiscovered differences in the operation of the instruments and the obtained underlying primary data, even under the premise of standard conditions. Variations are independent of the instrument type and uncertainties in flow rates or the injected quantities of probe molecules may be potential factors for the differences. This interlaboratory study demonstrates that the IGC is a very sensitive analytical tool, which detects minor changes, but it also shows that for a proper comparison, the measurement conditions have to be checked with great care. A publicly available standard protocol and material, for which this study can be seen as a starting point, is still needed to judge on the measurements and the resulting parameters more objectively.


Machine-learning assisted confocal imaging of intracellular sites of triglycerides and cholesteryl esters formation and storage.
All living systems are maintained by a constant flux of metabolic energy and, among the different reactions, the process of lipids storage and lipolysis is of fundamental importance. Current research has focused on the investigation of lipid droplets (LD) as a powerful biomarker for the early detection of metabolic and neurological disorders. Efforts in this field aim at increasing selectivity for LD detection by exploiting existing or newly synthesized probes. However, LD constitute only the final product of a complex series of reactions during which fatty acids are transformed into triglycerides and cholesterol is transformed in cholesteryl esters. These final products can be accumulated in intracellular organelles or deposits other than LD. A complete spatial mapping of the intracellular sites of triglycerides and cholesteryl esters formation and storage is, therefore, crucial to highlight any potential metabolic imbalance, thus predicting and counteracting its progression. Here, we present a machine learning assisted, polarity-driven segmentation which enables to localize and quantify triglycerides and cholesteryl esters biosynthesis sites in all intracellular organelles, thus allowing to monitor in real-time the overall process of the turnover of these non-polar lipids in living cells. This technique is applied to normal and differentiated PC12 cells to test how the level of activation of biosynthetic pathways changes in response to the differentiation process.


Fat graft migration causing recurrent cervical cord compression.
Fat graft migration following spinal cord surgery is an uncommon problem. Only few cases of fat graft migration causing cauda equine syndrome, recurrent sciatica, and root compression following lumbar spine surgery have been reported. We report a case of fat graft migration causing symptomatic cervical cord compression. A 45-years-old male with cervical spondylosis underwent anterior C4-5 discectomy and excision of hypertrophied ligament. A dural tear that occurred during the procedure was repaired with fat graft harvested from thigh. Significant improvement in stiffness was noted postoperatively. After 15 days, the patient presented again with worsening lower limbs stiffness. Magnetic resonance imaging of spine was done which revealed displacement of the fat graft causing cervical cord compression. Re-exploration was done and the migrated fat graft was removed. Post operatively patient noticed significant improvement in stiffness in both lower limbs. Autologous fat graft is one of the best materials used in sealing the dural cerebrospinal fluid leak during spinal surgery. However sometimes it may migrate and cause compression of cord and roots with relative symptoms. This complication should be kept in mind as removal of migrated fat graft will relieve these symptoms.


[Microcalorimetry study of pharmacological complexes. The binding of cephalosporins with human serum albumin].
Binding of cephazolin, cephalotin and cephamandol to human serum albumin (HSA) was studied by differential scanning calorimetry. It was shown that the binding resulted in an increase in the protein thermostability, while the cooperative character of the biopolymer solution melting was preserved. The constants of association of the above antibiotics with the primary active site of HSA were estimated, with flow microcalorimetry. The complex formation between cephazolin and the protein carrier was mainly due to the ionic forces. Formation of the hydrogen bond was not excluded. The predominating role of hydrophobic interactions in cephalotin and cephamandol binding was shown.


Acute hepatitis C in a chronically HIV-infected patient: evolution of different viral genomic regions.
To analyze the molecular evolution of different viral genomic regions of HCV in an acute HCV infected patient chronically infected with HIV through a 42-month follow-up. Serum samples of a chronically HIV infected patient that seroconverted to anti HCV antibodies were sequenced, from the event of superinfection through a period of 17 months and in a late sample (42nd month). Hypervariable genomic regions of HIV (V3 loop of the gp120) and HCV (HVR-1 on the E2 glycoprotein gene) were studied. In order to analyze genomic regions involved in different biological functions and with the cellular immune response, HCV core and NS5A were also chosen to be sequenced. Amplification of the different regions was done by RT-PCR and directly sequenced. Confirmation of sequences was done on reamplified material. Nucleotide sequences of the different time points were aligned with CLUSTAL W 1.5, and the corresponding amino acid ones were deduced. Hypervariable genomic regions of both viruses (HVR1 and gp120 V3 loop) presented several nonsynonymous changes but, while in the gp120 V3 loop mutations were detected in the sample obtained right after HCV superinfection and maintained throughout, they occurred following a sequential and cumulative pattern in the HVR1. In the NS5A region of HCV, two amino acid changes were detected during the follow-up period, whereas the core region presented several amino acid replacements, once the HCV chronic infection had been established. During the HIV-HCV superinfection, each genomic region analyzed shows a different evolutionary pattern. Most of the nucleotide substitutions observed are non-synonymous and clustered in previously described epitopes, thus suggesting an immune-driven evolutionary process.


Body mass index (BMI) as a major factor in the incidence of the metabolic syndrome and its constituents in unaffected Taiwanese from 1998 to 2002.
A large health screening program in Taiwan with members who have periodic checks provides an opportunity to track individuals who are healthy at baseline for the emergence of the metabolic syndrome (MS) and its component disorders. The syndrome comprised abdominal obesity assessed by waist circumference, high fasting serum glucose (FSG), high triglyceride (TG), low high density lipoprotein-cholesterol (HDL-C) and high blood pressure. A cohort of 9,785 adults (4,707 men and 5,078 women), aged 19 to 84 years, who were free from the MS at baseline were followed for 4 years from 1998 to 2002. Using Asian criteria for abdominal obesity and reducing the threshold for FSG from >or=110 mg/dL to >or=100 mg/dL, the incidence of MS during the 4-year follow up in the MJ Health Screening Center Study in Taiwan was 12.7% (17.5% for men and 8.3% for women). The incidence of the MS in men exceeded that for women up until 50-59 years and then this gender was reversed in the older age groups pointing to pre-menopausal protection in women. The most evident manifestations of the incident of metabolic abnormalities were high FSG, high blood pressure and high TG, particularly in post-menopausal women. Baseline body mass index and age were the most significant predictors of MS for both men and women, with cigarette smoking significantly predictive in men. Incident information should inform preventive and intervention strategies in Taiwanese, both Chinese and Indigenous, more effectively than MS and its component disorder prevalences.


Angiogenesis is repressed by ethanol exposure during chick embryonic development.
It is now known that excess alcohol consumption during pregnancy can cause fetal alcohol syndrome to develop. However, it is not known whether excess ethanol exposure could directly affect angiogenesis in the embryo or angiogenesis being indirectly affected because of ethanol-induced fetal alcohol syndrome. Using the chick yolk sac membrane (YSM) model, we demonstrated that ethanol exposure dramatically inhibited angiogenesis in the YSM of 9-day-old chick embryos, in a dose-dependent manner. Likewise, the anti-angiogenesis effect of ethanol could be seen in the developing vessel plexus (at the same extra-embryonic regions) during earlier stages of embryo development. The anti-angiogenic effect of ethanol was found associated with excess reactive oxygen species (ROS) production; as glutathione peroxidase activity increased while superoxide dismutase 1 and 2 activities decreased in the YSMs. We further validated this observation by exposing chick embryos to 2,2'-azobis-amidinopropane dihydrochloride (a ROS inducer) and obtained a similar anti-angiogenesis effect as ethanol treatment. Semiquantitative reverse transcription-polymerase chain reaction analysis of the experimental YSMs revealed that expression of angiogenesis-related genes, vascular endothelial growth factor and its receptor, fibroblast growth factor 2 and hypoxia-inducible factor, were all repressed following ethanol and 2,2'-azobis-amidinopropane dihydrochloride treatment. In summary, our results suggest that excess ethanol exposure inhibits embryonic angiogenesis through promoting superfluous ROS production during embryo development.


Central nervous system complications of HIV infection.
Issues relevant to the nervous system garnered substantial attention at the 18th Conference on Retroviruses and Opportunistic Infections. Several topics emerged as areas of importance both for informing current understanding of HIV-related neurologic disorders and their treatment, and for spurring future investigations. Measurable biomarkers of HIV-associated neurocognitive disorder (HAND) were a major theme, with studies ranging from new investigations of known laboratory and imaging markers to identification of novel molecules that might be investigated as potential means to follow disease activity as well as to better understand etiology of disease. Studies of pathogenesis of HAND and simian immunodeficiency virus-mediated neurologic injury added to prior understanding of lentivirus neuropathogenesis. Another broad area of investigation was the interplay between treatment with antiretroviral or adjunctive therapies and biomarkers of HAND. New data were presented on the potential importance of acute and early infection on the integrity of the central nervous system, complemented by studies of the effects of early treatment interventions.


[Requests for microbiological diagnosis by primary care physicians in the Salamanca area].
To assess requests for microbiological analysis made by Primary Care doctors and to evaluate the quality of the procedure by the indicator: proportion of contaminated urine samples. A retrospective crossover study of requests to the Microbiology Laboratory in the University Hospital of Salamanca during 1995. The study covered the Salamanca Health Area, which consists of 35 Health Centres and a catchment population of 358,408. The requests for microbiological diagnosis and results of the 43,317 samples processed were analysed. The data was distributed according to care level and the Area's Health Centres. 9,574 (22%) of the total number of samples received turned out positive, 27.4% of the requests originated in Primary Care (PC). The overall request rate from PC was 33 per 1,000 inhabitants. The microbiological analysis most frequently requested from PC is urine culture. Relationship between request and positives is 4 to 1.


[Corrective osteotomy of the femur in the treatment of the syndromes of dysplastic instability of the hip joint].
On the basis of analysis of short-term outcomes (1-5 years) of treatment of 139 patients (150 joints) with congenital dislocation and oluzation of the thigh, conclusion has been drawn that the application of corrective femur osteotomy with these patients should be limited with the cases of formation of pathology loading of the joint under conditions of negative intercomponental trophism. Restoration of correct anatomical interrelations between the components of the joint can be accompanied by the clinical decompensation of the hip joint state. Position of the cotyloid cavity and epiphysis of the head of the femur is of fundamental importance for further formation of the hip joint and its neck and diaphysis position is of minor importance. When positing indications for corrective femur osteotomy and its efficiency prognostication it is necessary to be orientated towards epidiaphysar and not cervicodiaphysar correlations. Removal of antetorsion of the head of the femur without due regard for the grade of its proximal epiphysis retroversion can lead to the development of external rotary contraction in hip joint.


Inhibition of replicon initiation in human cells following stabilization of topoisomerase-DNA cleavable complexes.
Diploid human fibroblast strains were treated for 10 min with inhibitors of type I and type II DNA topoisomerases, and after removal of the inhibitors, the rate of initiation of DNA synthesis at replicon origins was determined. By alkaline elution chromatography, 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine), an inhibitor of DNA topoisomerase II, was shown to produce DNA strand breaks. These strand breaks are thought to reflect drug-induced stabilization of topoisomerase-DNA cleavable complexes. Removal of the drug led to a rapid resealing of the strand breaks by dissociation of the complexes. Velocity sedimentation analysis was used to quantify the effects of amsacrine treatment on DNA replication. It was demonstrated that transient exposure to low concentrations of amsacrine inhibited replicon initiation but did not substantially affect DNA chainelongation within operating replicons. Maximal inhibition of replicon initiation occurred 20 to 30 min after drug treatment, and the initiation rate recovered 30 to 90 min later. Ataxia telangiectasia cells displayed normal levels of amsacrine-induced DNA strand breaks during stabilization of cleavable complexes but failed to downregulate replicon initiation after exposure to the topoisomerase inhibitor. Thus, inhibition of replicon initiation in response to DNA damage appears to be an active process which requires a gene product which is defective or missing in ataxia telangiectasia cells. In normal human fibroblasts, the inhibition of DNA topoisomerase I by camptothecin produced reversible DNA strand breaks. Transient exposure to this drug also inhibited replicon initiation. These results suggest that the cellular response pathway which downregulates replicon initiation following genotoxic damage may respond to perturbations of chromatin structure which accompany stabilization of topoisomerase-DNA cleavable complexes.


Response of native and exotic longhorn beetles to common pheromone components provides partial support for the pheromone-free space hypothesis.
Longhorn beetles are among the most important groups of invasive forest insects worldwide. In parallel, they represent one of the most well-studied insect groups in terms of chemical ecology. Longhorn beetle aggregation-sex pheromones are commonly used as trap lures for specific and generic surveillance programs at points of entry and may play a key role in determining the success or failure of exotic species establishment. An exotic species might be more likely to establish in a novel habitat if it relies on a pheromone channel that is different to that of native species active at the same time of year and day, allowing for unhindered mate location (i.e., pheromone-free space hypothesis). In this study, we first tested the attractiveness of single pheromone components (i.e., racemic 3-hydroxyhexan-2-one, racemic 3-hydroxyoctan-2-one, and syn-2,3-hexanediol), and their binary and tertiary combinations, to native and exotic longhorn beetle species in Canada and Italy. Second, we exploited trap catches to determine their seasonal flight activity. Third, we used pheromone-baited "timer traps" to determine longhorn beetle daily flight activity. The response to single pheromones and their combinations was mostly species specific but the combination of more than one pheromone component allowed catch of multiple species simultaneously in Italy. The response of the exotic species to pheromone components, coupled with results on seasonal and daily flight activity, provided partial support for the pheromone-free space hypothesis. This study aids in the understanding of longhorn beetle chemical ecology and confirms that pheromones can play a key role in longhorn beetle invasions.


Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective.
During the past decades, metabolism and redox imbalance have gained considerable attention in the cancer field. In addition to the well-known Warburg effect occurring in tumor cells, numerous other metabolic deregulations have now been reported. Indeed, metabolic reprograming in cancer is much more heterogeneous than initially thought. In particular, a high diversity of carbon sources used by tumor cells has now been shown to contribute to this metabolic heterogeneity in cancer. Moreover, the molecular mechanisms newly highlighted are multiple and shed light on novel actors. Furthermore, the impact of this metabolic heterogeneity on tumor microenvironment has also been an intense subject of research recently. Here, we will describe the new metabolic pathways newly uncovered in tumor cells. We will also have a particular focus on Cancer-Associated Fibroblasts (CAF), whose identity, function and metabolism have been recently under profound investigation. In that sense, we will discuss about the metabolic crosstalk between tumor cells and CAF.


Robin: an intuitive wizard application for R-based expression microarray quality assessment and analysis.
The wide application of high-throughput transcriptomics using microarrays has generated a plethora of technical platforms, data repositories, and sophisticated statistical analysis methods, leaving the individual scientist with the problem of choosing the appropriate approach to address a biological question. Several software applications that provide a rich environment for microarray analysis and data storage are available (e.g. GeneSpring, EMMA2), but these are mostly commercial or require an advanced informatics infrastructure. There is a need for a noncommercial, easy-to-use graphical application that aids the lab researcher to find the proper method to analyze microarray data, without this requiring expert understanding of the complex underlying statistics, or programming skills. We have developed Robin, a Java-based graphical wizard application that harnesses the advanced statistical analysis functions of the R/BioConductor project. Robin implements streamlined workflows that guide the user through all steps of two-color, single-color, or Affymetrix microarray analysis. It provides functions for thorough quality assessment of the data and automatically generates warnings to notify the user of potential outliers, low-quality chips, or low statistical power. The results are generated in a standard format that allows ready use with both specialized analysis tools like MapMan and PageMan and generic spreadsheet applications. To further improve user friendliness, Robin includes both integrated help and comprehensive external documentation. To demonstrate the statistical power and ease of use of the workflows in Robin, we present a case study in which we apply Robin to analyze a two-color microarray experiment comparing gene expression in tomato (Solanum lycopersicum) leaves, flowers, and roots.


Hunters' view on the control of African swine fever in wild boar. A participatory study in Latvia.
African swine fever (ASF) has massively spread in recent years and threatens the global pig industry. ASF has been present in Latvia since 2014. Hunters play a major role in the implementation of measures to control ASF and in passive disease surveillance. The probability to detect an ASF-positive wild boar is much higher in animals found dead than in hunted animals. Thus, the willingness and the motivation of hunters to support passive surveillance is of utmost importance. Using participatory methods, this study aimed to assess the acceptability of control measures for ASF in wild boar among hunters. In addition, new approaches to increase hunters' motivation to report wild boar found dead were investigated. A total of ten focus group discussions with hunters from different regions in Latvia were conducted. To assess the quantity and quality of contacts between hunters and stakeholders involved in the control of ASF, relation diagrams were used. Using ranking tools, the trust of the participants in stakeholders to implement control measures successfully was evaluated. Defined control measures were presented to the hunters and their acceptability investigated. An impact diagram and a list of defined motivation options for passive surveillance were offered to identify new ways to increase the willingness of hunters to support passive surveillance actively. A satisfactory and regular relationship was identified between the hunters, the Food and Veterinary Service (FVS) and the State Forest Service (SFS). The hunters' trust in these authorities was high. Although there is no vaccine against ASF, hunters were convinced of the potential of vaccination in controlling ASF. However, building fences was considered as useless and ineffective. To increase the willingness of hunters to support passive surveillance, reducing the infection pressure in the forests was regarded as most motivating. Furthermore, hunters would appreciate a decrease in their costs and workload. The study provides new insight into the concerns and experiences of hunters. Including their views and expectations in the further design and implementation of control and surveillance activities may help to improve current efforts to control ASF in wild boar populations. Although representing the perceptions of Latvian hunters, the main conclusions may be adaptable to adjust ASF control and surveillance in other countries.


Neuropeptides and Behaviors: How Small Peptides Regulate Nervous System Function and Behavioral Outputs.
One of the reasons that most multicellular animals survive and thrive is because of the adaptable and plastic nature of their nervous systems. For an organism to survive, it is essential for the animal to respond and adapt to environmental changes. This is achieved by sensing external cues and translating them into behaviors through changes in synaptic activity. The nervous system plays a crucial role in constantly evaluating environmental cues and allowing for behavioral plasticity in the organism. Multiple neurotransmitters and neuropeptides have been implicated as key players for integrating sensory information to produce the desired output. Because of its simple nervous system and well-established neuronal connectome, C. elegans acts as an excellent model to understand the mechanisms underlying behavioral plasticity. Here, we critically review how neuropeptides modulate a wide range of behaviors by allowing for changes in neuronal and synaptic signaling. This review will have a specific focus on feeding, mating, sleep, addiction, learning and locomotory behaviors in C. elegans. With a view to understand evolutionary relationships, we explore the functions and associated pathophysiology of C. elegans neuropeptides that are conserved across different phyla. Further, we discuss the mechanisms of neuropeptidergic signaling and how these signals are regulated in different behaviors. Finally, we attempt to provide insight into developing potential therapeutics for neuropeptide-related disorders.


Epigenetic Mechanisms in Developmental Alcohol-Induced Neurobehavioral Deficits.
Alcohol consumption during pregnancy and its damaging consequences on the developing infant brain are significant public health, social, and economic issues. The major distinctive features of prenatal alcohol exposure in humans are cognitive and behavioral dysfunction due to damage to the central nervous system (CNS), which results in a continuum of disarray that is collectively called fetal alcohol spectrum disorder (FASD). Many rodent models have been developed to understand the mechanisms of and to reproduce the human FASD phenotypes. These animal FASD studies have provided several molecular pathways that are likely responsible for the neurobehavioral abnormalities that are associated with prenatal alcohol exposure of the developing CNS. Recently, many laboratories have identified several immediate, as well as long-lasting, epigenetic modifications of DNA methylation, DNA-associated histone proteins and microRNA (miRNA) biogenesis by using a variety of epigenetic approaches in rodent FASD models. Because DNA methylation patterns, DNA-associated histone protein modifications and miRNA-regulated gene expression are crucial for synaptic plasticity and learning and memory, they can therefore offer an answer to many of the neurobehavioral abnormalities that are found in FASD. In this review, we briefly discuss the current literature of DNA methylation, DNA-associated histone proteins modification and miRNA and review recent developments concerning epigenetic changes in FASD.


Effects of transoral and transnasal fiberoptic bronchoscopy on oxygenation and cardiac rhythm.
The association of hypoxemia and cardiac arrhythmias with fiberoptic bronchoscopy (FOB) is known. The effects of various methods of inserting the bronchoscope on blood oxygen tensions, the true prevalence of arrhythmias, and the clinical significance of PaO2 and rhythm changes are poorly defined. Arterial blood gas values, oxygen saturation and cardiac arrhythmias detected by 24-hour Holter monitoring were compared in 20 male patients undergoing either transoral or transnasal FOB. No significant difference in oxygen saturation was found; however, PaO2 values fluctuated widely and unpredictably and were significantly higher in the eight patients in the transnasal FOB group. No life-threatening arrhythmias were induced during bronchoscopy; however, because of minor arrhythmias such as sinus tachycardia, the overall frequency of arrhythmias rose from 60% to 65%. The incidence of arrhythmias in this study was similar to that reported during pulmonary function testing.


"Twin meiosis" and other ambivalences in the life cycle of Schizosaccharomyces pombe.
Diploid cells of the yeast Schizosaccharomyces pombe carrying the mating-type allele h(90) are capable of sporulation and copulation. After copulation karyogamy does not always occur. In this case both nuclei will undergo meioses separately (twin meiosis). Asci with eight haploid spores derive from this event. Diploid cells homozygous for the mating-type alleles h(+) or h(-) do not sporulate. However, their nuclei can perform meiosis when they are in a common cytoplasm with a diploid nucleus of compatible mating type.


Sleep Quality as a Mediator in the Relationship Between Perceived Stress and Job Burnout Among Chinese Nurses: A Structural Equation Modeling Analysis.
Background: Job burnout has become an increasing prevailing phenomenon among nurses in both developed and developing countries. There is a paucity of research exploring the relationship between perceived stress (i.e., the level of one's perception or appraisal of stress rather than objective stressful events) and job burnout and no existing literature examining the mediating role of sleep quality in the relationship between these two constructs. The objective of the study was to examine if sleep quality mediates the relationship between perceived stress and job burnout. Methods: Cross-sectional data were collected from a total of 1,013 nurses working in six public tertiary hospitals in China. The self-administered questionnaire included demographic information, the Maslach Burnout Inventory-General Scale, the Pittsburgh Sleep Quality Index and the Perceived Stress Scale. Hierarchical multiple regression (HMR) analyses were performed to examine the contribution of each covariate to the prediction of job burnout. Structural equation modeling (SEM) was employed to test whether the proposed relationships between variables involved existed. Results: Both perceived stress and poor sleep quality exhibited strong positive associations with job burnout among Chinese nurses. The SEM analysis confirmed the direct pathway from perceived stress to burnout and the indirect pathway mediated by sleep quality. The direct effect of perceived stress on job burnout was found to be statistically significant and positive (β = 0.69, p < 0.05). There existed statistically significant effects of sleep quality on both perceived stress (β = 0.48) and job burnout (β = 0.29). The path coefficients of perceived stress on job burnout were significantly reduced (β = 0.56) when sleep quality was modeled as a mediator. The bias-corrected and accelerated bootstrap test revealed that sleep quality had a significant mediating effect on the relationship between perceived stress and job burnout (a * b = 0.139, BCa 95%, CI: 0.110~0.174). Conclusion: Perceived stress might exert significant effects on burnout both directly and indirectly through the mediating role of sleep quality. Efforts to reduce burnout among nurses in clinical settings may benefit from interventions for coping with perceived stress and practices for promoting healthy sleep.


Potential cGAS-STING pathway functions in DNA damage responses, DNA replication and DNA repair.
The major innate immune responder to the DNA of pathogens is the cyclic GMP-AMP (cGAMP) synthase (cGAS) - stimulator of interferon genes (STING) pathway. Most prominently, the outcome of cGAS signalling is the activation of inflammatory transcription through interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kB). In addition, the cGAS-STING pathway can lead to the direct modulation of cellular processes independently of transcription, such as activation of autophagy. Under unperturbed conditions, several mechanisms are in place to prevent the activation of cGAS by self-DNA, chiefly its sequestration on chromatin, which interferes with binding to stimulatory DNA. However, under conditions of genotoxic stress and chromosomal instability, this inhibition breaks down, resulting in the activation of cGAS, which drives sterile inflammation, as well as cell fate and immune responses in cancer. Recently, several studies have suggested that cGAS, STING, or downstream pathway components can also regulate the DNA damage response, DNA damage checkpoint signalling, DNA repair and DNA replication. Here, I review these proposed mechanisms, and discuss some unanswered questions relating to them.


Machine Learning to Study Social Interaction Difficulties in ASD.
Autism Spectrum Disorder (ASD) is a spectrum of neurodevelopmental conditions characterized by difficulties in social communication and social interaction as well as repetitive behaviors and restricted interests. Prevalence rates have been rising, and existing diagnostic methods are both extremely time and labor consuming. There is an urgent need for more economic and objective automatized diagnostic tools that are independent of language and experience of the diagnostician and that can help deal with the complexity of the autistic phenotype. Technological advancements in machine learning are offering a potential solution, and several studies have employed computational approaches to classify ASD based on phenomenological, behavioral or neuroimaging data. Despite of being at the core of ASD diagnosis and having the potential to be used as a behavioral marker for machine learning algorithms, only recently have movement parameters been used as features in machine learning classification approaches. In a proof-of-principle analysis of data from a social interaction study we trained a classification algorithm on intrapersonal synchrony as an automatically and objectively measured phenotypic feature from 29 autistic and 29 typically developed individuals to differentiate those individuals with ASD from those without ASD. Parameters included nonverbal motion energy values from 116 videos of social interactions. As opposed to previous studies to date, our classification approach has been applied to non-verbal behavior objectively captured during naturalistic and complex interactions with a real human interaction partner assuring high external validity. A machine learning approach lends itself particularly for capturing heterogeneous and complex behavior in real social interactions and will be essential in developing automatized and objective classification methods in ASD.


Phenotypic and genotypic characteristics of Trueperella pyogenes isolated from ruminants.
Trueperella pyogenes is an opportunistic pathogen that causes suppurative infections in animals including humans. Data on phenotypic and genotypic properties of T. pyogenes isolated from ruminants, particularly goats and sheep, are lacking. We characterized, by phenotypic and genotypic means, T. pyogenes of caprine and ovine origin, and established their phylogenetic relationship with isolates from other ruminants. T. pyogenes isolates ( n = 50) from diagnostic specimens of bovine ( n = 25), caprine ( n = 19), and ovine ( n = 6) origin were analyzed. Overall, variable biochemical activities were observed among the T. pyogenes isolates. The fimbriae-encoding gene, fimE, and neuraminidase-encoding gene, nanH, were, respectively, more frequently detected in the large ( p = 0.0006) and small ( p = 0.0001) ruminant isolates. Moreover, genotype V ( plo/ nanH/ nanP/ fimA/ fimC) was only detected in the caprine and ovine isolates, whereas genotype IX ( plo/ nanP/ fimA/ fimC/ fimE) was solely present in the isolates of bovine origin ( p = 0.0223). The 16S rRNA gene sequences of all T. pyogenes isolates were clustered with the reference T. pyogenes strain ATCC 19411 and displayed a high degree of identity to each other. Our results highlight phenotypic and genotypic diversity among ruminant isolates of T. pyogenes and reinforce the importance of characterization of more clinical isolates to better understand the pathogenesis of this bacterium in different animal species.


The prevalence of injection-site reactions with disease-modifying therapies and their effect on adherence in patients with multiple sclerosis: an observational study.
Interferon beta (IFNβ) and glatiramer acetate (GA) are administered by subcutaneous (SC) or intramuscular (IM) injection. Patients with multiple sclerosis (MS) often report injection-site reactions (ISRs) as a reason for noncompliance or switching therapies. The aim of this study was to compare the proportion of patients on different formulations of IFNβ or GA who experienced ISRs and who switched or discontinued therapy because of ISRs. The Swiss MS Skin Project was an observational multicenter study. Patients with MS or clinically isolated syndrome who were on the same therapy for at least 2 years were enrolled. A skin examination was conducted at the first study visit and 1 year later. The 412 patients enrolled were on 1 of 4 disease-modifying therapies for at least 2 years: IM IFNβ-1a (n = 82), SC IFNβ-1b (n = 123), SC IFNβ-1a (n = 184), or SC GA (n = 23). At first evaluation, ISRs were reported by fewer patients on IM IFNβ-1a (13.4%) than on SC IFNβ-1b (57.7%; P < 0.0001), SC IFNβ-1a (67.9%; P < 0.0001), or SC GA (30.4%; P = not significant [NS]). No patient on IM IFNβ-1a missed a dose in the previous 4 weeks because of ISRs, compared with 5.7% of patients on SC IFNβ-1b (P = 0.044), 7.1% of patients on SC IFNβ-1a (P = 0.011), and 4.3% of patients on SC GA (P = NS). Primary reasons for discontinuing or switching therapy were ISRs or lack of efficacy. Similar patterns were observed at 1 year. Patients on IM IFNβ-1a had fewer ISRs and were less likely to switch therapies than patients on other therapies. This study may have implications in selecting initial therapy or, for patients considering switching or discontinuing therapy because of ISRs, selecting an alternative option.


Antiproliferative and Antioxidative Bioactive Compounds in Extracts of Marine-Derived Endophytic Fungus Talaromyces purpureogenus.
Endophytic fungi are now recognized as sources of pharmacologically beneficial, novel bioactive compounds. This study was carried out to evaluate antiproliferative and antioxidative potential of a seaweed endophytic fungus Talaromyces purpureogenus. Extracts with different solvents of the fungus grown on different liquid media were assayed for the antiproliferative and antioxidative activities. Tested 6 cancer cell lines, the highest antiproliferative activity was observed in ethyl acetate extract of total culture grown in Potato Dextrose Broth for 28 days in a dose-dependent manner. The highest antioxidative activity was observed in hexane extract of fungal culture grown in Malt Extract Broth for 21 days. Analyzed for secondary metabolites, the extract revealed the presence of phenolics, alkaloids, flavonoids, steroids and terpenoids. Further, Gas Chromatography Mass Spectroscopy (GCMS) analysis of the extract revealed the presence of several compounds including 3-nitropropanoic acid, 4H-pyran-4-one 5-hydroxy-2-(hydroxymethyl), hexadecanoic acid, and octadecanoic acid, known to be cytotoxic or antioxidative. Among different cell lines tested, HeLa cells were the most vulnerable to the treatment of the fungal extract with an IC50 value of 101 ± 1 μg/mL. The extract showed no significant cytotoxicity to the normal human embryonic kidney cell line (HEK 293 T) in the MTT assay. The ethyl acetate extract induced membrane damage and mitochondrial depolarization and thereby apoptosis and cytotoxicity in HeLa cells. The study marks marine-derived endophytes as potential sources for discovery of novel drugs.


Can peripheral blood mononuclear cells be used as a proxy for mitochondrial dysfunction in vital organs during hemorrhagic shock and resuscitation?
Although mitochondrial dysfunction is thought to contribute to the development of posttraumatic organ failure, current techniques to assess mitochondrial function in tissues are invasive and clinically impractical. We hypothesized that mitochondrial function in peripheral blood mononuclear cells (PBMCs) would reflect cellular respiration in other organs during hemorrhagic shock and resuscitation. Using a fixed-pressure HS model, Long-Evans rats were bled to a mean arterial pressure of 40 mmHg. When blood pressure could no longer be sustained without intermittent fluid infusion (decompensated HS), lactated Ringer's solution was incrementally infused to maintain the mean arterial pressure at 40 mmHg until 40% of the shed blood volume was returned (severe HS). Animals were then resuscitated with 4× total shed volume in lactated Ringer's solution over 60 min (resuscitation). Control animals underwent the same surgical procedures, but were not hemorrhaged. Animals were randomized to control (n = 6), decompensated HS (n = 6), severe HS (n = 6), or resuscitation (n = 6) groups. Kidney, liver, and heart tissues as well as PBMCs were harvested from animals in each group to measure mitochondrial oxygen consumption using high-resolution respirometry. Flow cytometry was used to assess mitochondrial membrane potential (Ψm) in PBMCs. One-way analysis of variance and Pearson correlations were performed. Mitochondrial oxygen consumption decreased in all tissues, including PBMCs, following decompensated HS, severe HS, and resuscitation. However, the degree of impairment varied significantly across tissues during hemorrhagic shock and resuscitation. Of the tissues investigated, PBMC mitochondrial oxygen consumption and Ψm provided the closest correlation to kidney mitochondrial function during HS (complex I: r = 0.65; complex II: r = 0.65; complex IV: r = 0.52; P < 0.05). This association, however, disappeared with resuscitation. A weaker association between PBMC and heart mitochondrial function was observed, but no association was noted between PBMC and liver mitochondrial function. All tissues including PBMCs demonstrated significant mitochondrial dysfunction following hemorrhagic shock and resuscitation. Although PBMC and kidney mitochondrial function correlated well during hemorrhagic shock, the variability in mitochondrial response across tissues over the spectrum of hemorrhagic shock and resuscitation limits the usefulness of using PBMCs as a proxy for tissue-specific cellular respiration.


A topological study of chemical bonds under pressure: solid hydrogen as a model case.
It is now well recognized that a fundamental understanding of the rules that govern chemistry under pressure is still lacking. Hydrogen being the "simplest" element as well as a central core to high pressure physics, we undertake a general study of the changes in the chemical bonding under pressure. We start from a simple trimer unit that has been found in high pressure phases, whose behavior has been found to reveal the basics of hydrogen polymerization under pressure. Making use of bond analysis tools, mainly the NCI (noncovalent interactions) index, we show that polymerization takes place in three steps: dipolar attraction, repulsion and bond formation. The use of a 1D Wigner-Seitz radius allowed us to extend the conclusions to 3D networks and to analyze their degree of polymerization. On the one hand, this approach provides new insight into the polymerization of hydrogen. On the other hand, it shows that complicated molecular solids can be understood from cluster models, where correlated methods can be applied, main differences in solid state arising at the transition points, where breaking/forming of bonds happens at once instead of continuously like in the cluster model.


Enhancing leptospirosis control with nanosensing technology: A critical analysis.
Leptospirosis is a serious health problem in tropical areas; thus, animals shed leptospires in the environment. Humans are accidental hosts infected through exposure to contaminating bacteria in the environment. One health strategy can be applied to protect and eliminate leptospirosis because this cooperates and coordinates activities between doctors, veterinarians, and ecologists. However, conventional methods still have limitations. Therefore, the main challenges of leptospirosis control are the high sensing of detection methods to screen and control the pathogens. Interestingly, nano sensing combined with a leptospirosis detection approach can increase the sensitivity and eliminate some limitations. This article reviews nanomaterial development for an advanced leptospirosis detection method, e.g., latex beads-based agglutination test, magnetic nanoparticles enrichment, and gold-nanoparticles-based immunochromatographic assay. Thus, nanomaterials can be functionalized with biomolecules or sensing molecules utilized in various mechanisms such as biosensors. Over the last decade, many biosensors have been developed for Leptospira spp. pathogen and others. The evolution of biosensors for leptospirosis detection was designed for high efficiency and might be an alternative tool. In addition, the high-sensing fabrications are useful for leptospires screening in very low levels, for example, soil or water from the environment.


Factors associated with overweight and obesity in Lebanese male patients with schizophrenia.
To assess the influence of lifestyle factors, antipsychotic medications, and psychosis symptoms on obesity in a group of male patients with schizophrenia in Lebanon. A cross-sectional study conducted between May and July 2018 enrolling 149 male patients with chronic schizophrenia. We found that 59.1% of the patients were obese/overweight. Older age and higher negative and total positive and negative syndrome scale scores were significantly associated with lower body mass index values. This study shed light on some factors associated with obesity in male patients with schizophrenia, which may be targeted for the prevention and management of obesity. Some interventions were proposed such as focusing on patients' physical health, psychiatric treatment, and maintaining a healthy diet and a healthy lifestyle.


Impaired tyrosine phosphorylation and Ca2+ mobilization, but not degranulation, in lyn-deficient bone marrow-derived mast cells.
Signaling through the high affinity IgE receptor (Fc epsilon RI) on mast cells and basophils results in rapid increases in tyrosine phosphorylation on a number of proteins. Fc epsilon RI associates with two classes of the tyrosine kinases, the Src family kinases, such as Lyn, c-Yes, and c-Src, and the Syk kinase. In this work, using primary mast cells derived from wild-type (lyn +/+) and lyn-deficient (lyn -/-) mice, we report that Lyn plays a part in signaling via Fc epsilon RI. Unlike lyn +/+ mast cells, cross-linking of Fc epsilon RI in lyn -/- mast cells failed to induce protein-tyrosine phosphorylation of various substrates, and evoked a delayed and slow Ca2+ mobilization. However, degranulation, adhesion, and production of cytokines occurred normally in lyn -/- mast cells. Our data suggest that the activity of the other Src family kinases, such as c-Src, can complement the role of Lyn in inducing most, but not all, biologic and biochemical responses to Fc epsilon RI cross-linking.


Identification of VAR2CSA domain-specific inhibitory antibodies of the Plasmodium falciparum erythrocyte membrane protein 1 using a novel flow cytometry assay.
VAR2CSA, a member of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family, is a leading candidate for use in vaccines to protect first-time mothers from placental malaria (PM). VAR2CSA, which is comprised of a series of six Duffy binding-like (DBL) domains, binds chondroitin sulfate A (CSA) on placental syncytiotrophoblast. Several recombinant DBL domains have been shown to bind CSA. In order to identify and develop recombinant proteins suitable for clinical development, DBL2X and DBL3X, as well as their respective third subdomain (S3) from the FCR3 parasite clone, were expressed in Escherichia coli, refolded, and purified. All but DBL3X-S3 recombinant proteins bound to CSA expressed on Chinese hamster ovary (CHO)-K1 cells but not to CHO-pgsA745 cells, which are CSA negative as determined by flow cytometry. All but DBL3X-S3 bound to CSA on chondroitin sulfate proteoglycan (CSPG) as determined by surface plasmon resonance (SPR) analysis. Purified IgG from rats and rabbits immunized with these four recombinant proteins bound homologous and some heterologous parasite-infected erythrocytes (IE). Using a novel flow cytometry inhibition-of-binding assay (flow-IBA), antibodies against DBL3X-S3 inhibited 35% and 45% of IE binding to CSA on CHO-K1 cells compared to results for soluble CSA (sCSA) and purified multigravida (MG) IgG, respectively, from areas in Tanzania to which malaria is endemic. Antibodies generated against the other domains provided little or no inhibition of IE binding to CSA on CHO-K1 cells as determined by the flow cytometry inhibition-of-binding assay. These results demonstrate for the first time the ability to identify antibodies to VAR2CSA DBL domains and subdomains capable of inhibiting VAR2CSA parasite-IE binding to CSA by flow cytometry. The flow cytometry inhibition-of-binding assay was robust and provided an accurate, reproducible, and reliable means to identify blocking of IE binding to CSA and promises to be significant in the development of a vaccine to protect pregnant women.


Efficacy of prokinetic agents in improving bowel preparation for colonoscopy.
Colonoscopy plays an important role in the diagnosis and treatment of gastrointestinal illness in both Western countries and Japan. However, preparative bowel cleansing for colonoscopy is frequently troublesome for elderly and/or constipated patients, since they must drink larger volumes of lavage solution for adequate cleansing. We investigated the use of prokinetic agents for improving the efficacy and tolerability of bowel cleansing prior to colonoscopy. 613 patients were divided into two groups according to oral lavage solution used (polyethylene glycol or magnesium citrate), and were further randomized to receive either vehicle (100 ml water) alone, vehicle with 5 mg mosapride citrate, or vehicle with 50 mg itopride hydrochloride 30 min before administration of lavage solution. Experimental parameters included bowel cleansing quality, times to first defecation and completion of bowel cleansing, and incidence of uncomfortable abdominal symptoms during colonoscopy preparation. Administration of mosapride citrate or itopride hydrochloride prior to oral lavage solution did not significantly improve bowel cleansing quality. However, statistically significantly fewer uncomfortable abdominal symptoms were found in patients who received mosapride citrate or itopride hydrochloride versus vehicle alone. Prokinetic agents effectively decreased the incidence of uncomfortable abdominal symptoms experienced during colonoscopy preparation.


Neuromonitoring in the ambulatory anesthesia setting: a pro-con discussion.
Various neurologically focused monitoring modalities such as processed electroencephalography (pEEG), tissue/brain oxygenation monitors (SbO2), and even somatosensory evoked responses have been suggested as having the potential to improve the well tolerated and effective delivery of care in the setting of outpatient surgery. The present article will discuss the pros and cons of such monitors in this environment. There is a paucity of evidence from rigorous, well designed clinical trials demonstrating that the routine use of any neuromonitoring technique in an ambulatory surgery setting leads to meaningful cost savings or a reduction in morbidity or mortality. The use of advanced neuromonitoring techniques (primarily pEEG) may be considered reasonable in two instances: for the prevention of intraoperative awareness during the administration of total intravenous anesthesia coupled with the use of a neuromuscular blocking drug, and for the prevention of relative drug overdose (and possibly postoperative delirium) in the elderly.


[Efficacy and safety of heptral, vitamin B6 and folic acid during toxic hepatitis induced by CCL4].
The aim of this work was to evaluate of efficacy and safety of complex Heptral, Vitamin B6 and Folic Acid in experimental hepatitis therapy compared with monotherapy. Experiments were carried out on pubertal rats. Eperimental hepatitis models were induced by Tetrachlormethane. The tetrachlormethane intoxication was reproduced by subcutaneous injection of CCL(4) 1ml/kg dissolved in 1ml of olive oil. Cytochrome P450, cytochrome b5, reduced glutation,activity of glutationetranspherase and content of ATP in hepatocytes were measured by the spectrophotometric techniques,but content of homocysteine by chromophtography techniques. Under CCL(4) intoxication disturbance of liver detoxication function, energy deficit and surplus of homocysteine were observed. Treatment of the toxic hepatitis with heptral increased the level of cytochrome P450, cytochrome b5, glutation activity of glutationetranspherase glutathione and reduced content of homocysteine. Complex therapy with Heptral and B6 and folic acid reveal more expressive hepatoprotective effect and safety than monotherapy with Heptral. Complex therapy improves not only the parameters of biotransformation (metabolic and conjugation phase), but also normalizes the level of ATP and homocystein. Vitamins B6 and folic acid increases the efficacy and safety of Heptral. This complex was recomended for treatment of hepatitis.


Improved purification process for cholera toxin and its application to the quantification of residual toxin in cholera vaccines.
A simplified method for the purification of cholera toxin was developed. The 569B strain of Vibrio cholerae, a recognized hyper-producer of cholera toxin, was propagated in a bioreactor under conditions that promote the production of the toxin. The toxin was separated from the bacterial cells using 0.2-microm crossflow microfiltration, the clarified toxin was passed through the membrane into the permeate, and the bacterial cells were retained in the retentate. The 0.2-microm permeate was then concentrated 3-fold and diafiltered against 10 mM phosphate buffer, pH 7.6, using 30-kDa crossflow ultrafiltration. The concentrated toxin was loaded onto a cation exchange column, the toxin was bound to the column, and most of the impurities were passed unimpeded through the column. The toxin was eluted with a salt gradient of phosphate buffer, pH7.0, containing 1.0M NaCl. The peak containing the toxin was assayed for cholera toxin and protein and the purity was determined to be 92%. The toxin peak had a low endotoxin level of 3.1 EU/microg of toxin. The purified toxin was used to prepare antiserum against whole toxin, which was used in a G(M1) ganglioside-binding ELISA to determine residual levels of toxin in an oral inactivated whole-cell cholera vaccine. The G(M1) ganglioside-binding ELISA was shown to be very sensitive and capable of detecting as little as 1 ng/ml of cholera toxin.


Alternatives to radioimmunoassay: labels and methods.
We review the following labels used as substitutes for radioisotopes in immunoassay systems: bacteriophages, chemiluminescence precursors, fluorochromes, fluorogens, fluorescence quenchers, enzymes, coenzymes, inhibitors, substrates, various particulates, metal atoms, and stable free radicals. New methods for performing immunoassays with these labels are described where appropriate. Methods that require no separation steps and offer special promise for easy automation are noted.


From social withdrawal to depression: A quasireplication and extension of Boivin, Hymel, and Bukowski (1995).
Tenets of the Boivin et al. (1995) social process model were reexamined with two longitudinal samples using both the original and contemporary analytic strategies. Study goals included reconstructing (e.g., quasireplicating) Boivin et al.'s (1995) original findings and evaluating hypothesized relations across both comparable and longer developmental epochs. Samples included 491 children (245 girls, Mage = 10.0; 80.1% White;19.1% low-, 43.1% middle- or higher-income) followed from grades 4 to 12 and 272 children (148 girls, Mage = 9.61; 84.2% White; 8.2% low-, 17.1% middle-, 74.7% upper middle to higher-income) followed from grades 4 to 5. The assumption that social withdrawal instigates a cascade of within-person changes in the quality of peer relationships, sense of loneliness and social dissatisfaction, and depression was evaluated using Boivin et al.'s (1995) original regression strategy plus two variants of cross-lagged panel models (classical CLPM; Latent Curve Model with Structured Residuals [LCM-SR]). Unlike classical CLPM, LCM-SR allowed for isolating within-person changes and testing hypothesized predictors of within-person increases and decreases. Results differed by type of analysis. Regression and classical CLPM yielded greater substantiation for some of the processes stipulated by Boivin et al. (1995). LCM-SR results, however, called into question the assumption of a cascade effect of early social withdrawal and the reliance on traditional regression and CLPM analyses to test for presumed predictors of within person change. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


[Bladder leiomyoma in a male patient].
Bladder leiomyoma is an uncommon mesenchymal benign tumor. It is generally asymptomatic and incidentally detected. We report a new case managed with transurethral resection without evidence of relapse. A bibliographic search was performed to evaluate the diagnostic techniques, clinical features and treatment options of this rare disease. Bladder leiomyoma is a benign mesenchymal tumor originating from smooth muscle. Biopsy and histological study are required for definitive diagnosis. Surgery is the treatment of choice, and it has an excellent prognosis if resection is complete.


Creatine supplementation does not enhance submaximal aerobic training adaptations in healthy young men and women.
The benefits of dietary creatine supplementation on muscle performance are generally related to an increase in muscle phosphocreatine content. However, creatine supplementation may benefit endurance sports through increased glycogen re-synthesis following exercise. This study investigated the effect of creatine supplementation on muscle glycogen content, submaximal exercise fuel utilisation and endurance performance following 4 weeks of endurance training. Thirteen healthy, physically active, non-vegetarian subjects volunteered to take part and completed the study. Subjects were supplemented with either creatine monohydrate (CREAT, n = 7) or placebo-maltodextrin (CON, n = 6). Submaximal fuel utilisation and endurance performance were assessed before and after a 4 week endurance training program. Muscle biopsies were also collected before and following training for assessment of muscle creatine and glycogen content. Training increased quadriceps glycogen content to the same degree (approximately 20%) in both groups (P = 0.04). There was a significant training effect on submaximal fuel utilisation and improved endurance performance. However, there was no significant treatment effect of creatine supplementation. Creatine supplementation does not effect metabolic adaptations to endurance training.


Surgical management of Encapsulating Peritoneal Sclerosis (EPS) in children: international case series and literature review.
Encapsulating Peritoneal Sclerosis (EPS) is a rare phenomenon in paediatric patients with kidney failure treated with peritoneal dialysis (PD). This study highlights clinical challenges in the management of EPS, with particular emphasis on peri-operative considerations and surgical technique. Retrospective analysis of all paediatric patients with EPS treated at the Manchester Centre for Transplantation. Four patients were included with a median duration of 78 months on PD. All patients had recurrent peritonitis (> 3 episodes), and all had symptoms within three months of a change of dialysis modality from PD to haemodialysis or transplant. In Manchester, care was delivered by a multi-disciplinary team, including surgeons delivering the adult EPS surgical service with a particular focus on nutritional optimisation, sepsis control, and wound management. The surgery involved laparotomy, lavage, and enterolysis of the small bowel + / - stoma formation, depending on intra-abdominal contamination. Two patients had a formal stoma, which were reversed at three and six months, respectively. Two patients underwent primary closure of the abdomen, whereas two patients had re-look procedures at 48 h with secondary closure. One patient had a post-operative wound infection, which was managed medically. One patient's stoma became detached, leading to an intra-abdominal collection requiring re-laparotomy. The median length of stay was 25 days, and patients were discharged once enteral feeding was established. All patients remained free of recurrence with normal gut function and currently two out of four have functioning transplants. This series demonstrates 100% survival and parenteral feed independence following EPS surgery. Post-operative morbidity was common; however, with individualised experience-based decision-making and relevant additional interventions, patients made full recoveries. Health and development post-surgery continued, allowing the potential for transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.


Magnetic order and disorder in nanomagnets probed by superconducting vortices.
We have studied two nanomagnet systems with strong (Co/Pd multilayers) and weak (NdCo alloy films) stray magnetic fields by probing the out-of-plane magnetic states with superconducting vortices. The hybrid samples are made of array of nanomagnets embedded in superconducting Nb thin films. The vortex motion detects relevant magnetic state features, since superconducting vortices are able to discriminate between different magnetic stray field strengths and directions. The usual matching effect between the superconducting vortex lattice and the periodic pinning array can be quenched by means of disorder magnetic potentials with strong stray fields at random. Ordered stray fields retrieve the matching effect and yield asymmetry and shift in the vortex dissipation signal. Furthermore vortices can discriminate the sizes of the nanomagnet magnetic domains, detecting magnetic domain sizes as small as 70 nm. In addition, we observe that the vortex cores play the crucial role instead of the supercurrents around the vortex.


Whole-body vibration exposure in metropolitan bus drivers.
Back injuries are common in transit drivers, and can result in substantial direct and indirect cost to the employer and employee. Whole-body vibration (WBV) is one risk factor for drivers. Standards have been adopted (ISO 2631-1) to guide researchers in measuring and analysing WBV levels. Lately, a new standard has been added (ISO 2631-5) that takes impulsive exposures into account. The aims of this study were to determine the levels of vibration for bus drivers using both ISO 2631-1 and 2631-5 standards, and whether there are differences in vibration levels and seat transmissibility between different road types. Thirteen bus drivers drove a 7-year-old bus, instrumented to measure WBV in the seat and floor. The 52 km long test route included freeway, city streets and speed humps. Additionally, for comparison, a subset of five drivers also drove a car over the same route. Road type had a significant effect on all the vibration parameters. Based on exposure limit values in the standards, the continuous z-A (w)(8) exposures exceeded the limit value on freeways, and the impulsive z-VDV(8) and S (ed) exposures were above limit values in city streets and speed humps. Bus WBV exposures were about twice as high relative to the car and the bus seat amplified rather than attenuated WBV exposures. Bus drivers are potentially being exposed to daily vibration levels higher than recommended especially on certain road types. The current seat in this study does not attenuate the vibration.


Estimation of centroid positions with a matched-filter algorithm: relevance for aberrometry of the eye.
Most Shack-Hartmann based aberrometers use infrared light, for the comfort of the patients. A large amount of the light that is scattered from the retinal layers is recorded by the detector as background, from which it is not trivial to estimate the centroid of the Shack-Hartmann spot. For a centroiding algorithm, background light can lead to a systematic bias of the centroid positions towards the centre of the software window. We implement a matched filter algorithm for the estimation of the centroid positions of the Shack-Hartmann spots recorded by our aberrometer. We briefly present the performance of our algorithm, and recall the well-known robustness of the matched filter algorithm to background light. Using data collected on 5 human eyes, we parameterise a simple and fast centroiding algorithm and reduce the difference between the two algorithms down to a mean residual wavefront of 0.02 microm rms.


Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation.
Systemic lupus erythematosus (SLE) is the most common disease associated with antiphospholipid syndrome (APS). We, therefore, evaluated 46 patients with refractory SLE treated by autologous hematopoietic stem cell transplantation (HSCT) for a history of APS prior to transplantation. The prevalence of SLE-related APS in our patient population was 61% (28 of 46 patients with refractory SLE). Nineteen of 28 patients with APS had lupus anticoagulant (LA) or high titers of anticardiolipin antibodies (ACLAs), either immunoglobulin (Ig)G or IgM, when evaluated at study entry. Six of 8 evaluable LA+ patients became and remained LA-; 5 of 7 initially ACLA IgG+ patients and 9 of 11 ACLA IgM+ patients demonstrated normalization of ACLA titers when followed after HSCT. Eighteen of 22 patients refractory to chronic anticoagulation discontinued anticoagulation therapy a median of 4 months after transplantation; 78% of them remained free of thrombotic events and in complete SLE remission for up to 78 months (median, 15 months) after HSCT. There was no treatment-related mortality. Autologous HSCT may be performed safely in patients with APS and appears to be effective therapy for eliminating ALPAs and preventing thrombotic complications in patients with SLE.


[14C]iodoantipyrine and microsphere blood flow estimates in cat brain.
A comparison of local cerebral blood flow estimates with the microsphere and the 4-[N-methyl-14C]iodoantipyrine ([14C]IAP) techniques has been performed in cats. Good correlation of [14C]IAP with microsphere flow estimates in the gray matter was found. In the white matter, however, [14C]IAP flow estimates were consistently lower than microsphere flow estimates. Error analysis of both techniques and comparison with previous studies suggest that peculiarities of white matter arterial vasculature with preferential microsphere accumulation may lead to this discrepancy. Microspheres did not interfere with flow as shown by the normal appearance of subsequent [14C]IAP autoradiograms. The number of microspheres seen on autoradiograms was used for an estimate of microvessels blocked by spheres and found to be negligible. The study also demonstrates that [14C]IAP is not diffusion limited up to the observed flow values of 2 ml.g-1.min-1. Both techniques might be used together for a combination of their respective advantages, which are temporal and spatial resolution for microsphere and [14C]IAP, respectively.


Focal adhesion kinase knockdown modulates the response of human corneal epithelial cells to topographic cues.
A rapidly expanding literature broadly documents the impact of biophysical cues on cellular behaviors. In spite of increasing research efforts in this field, the underlying signaling processes are poorly understood. One of the candidate molecules for being involved in mechanotransduction is focal adhesion kinase (FAK). To examine the role of FAK in the response of immortalized human corneal epithelial (hTCEpi) cells to topographic cues, FAK was depleted by siRNA transfection. Contrary to expectations, FAK knockdown resulted in an enhanced response with a greater number of hTCEpi cells aligned to the long axis of anisotropically ordered surface ridges and grooves. Both underlying topographic features and FAK depletion modulated the migration of corneal epithelial cells. The impact of FAK knockdown on both migration and alignment varied depending on the topographic cues to which the cells were exposed, with the most significant change observed on the biologically relevant size scale (400nm). Additionally, a change in expression of genes encoding perinuclear Nesprins 1 and 2 (SYNE1, 2) was observed in response to topographic cues. SYNE1/2 expression was also altered by FAK depletion, suggesting that these proteins might represent a link between cytosolic and nuclear signaling processes. The data presented here have relevance to our understanding of the fundamental processes involved in corneal cell behavior to topographic cues. These results highlight the importance of incorporating biophysical cues in the conduction of in vitro studies and into the design and fabrication of implantable prosthetics.


Derivation of a clinical prediction rule for the noninvasive diagnosis of varices in children.
Identification of children who are at high risk for having varices using noninvasive tests would enable the selection of children for future studies of primary prophylaxis of variceal hemorrhage, but this has been inadequately studied. The objective of the study was to derive a noninvasive clinical prediction rule that is able to identify children with esophageal varices. Fifty-one consecutive children with liver disease or portal hypertension who underwent endoscopy were included in the present retrospective study. At endoscopy, variceal size was graded on a 4-point Likert scale. Results of physical examination, blood tests, and abdominal ultrasound scan (USS) were recorded. Spleen length on USS was expressed as a standard deviation score (z score). A descriptive univariate analysis was performed on variables that were potentially associated with esophageal varices and multivariate logistic regression was then modeled to derive a clinical prediction rule. Esophageal varices were found in 17 of the 51 children (33%). Variables found to differ significantly between children with and without varices included platelet/spleen-length z score ratio (P < 0.001), platelet count (P < 0.001), international normalized ratio (P = 0.001), aspartate aminotransferase/alanine aminotransferase ratio (P = 0.002), and albumin (P = 0.003). Using multivariate logistic regression, a model with platelet count, spleen length z score, and albumin as the independent variables had the best fit. Area under the receiver operating characteristic curve for this clinical prediction rule was 0.93 (95% confidence interval 0.85-0.99), sensitivity 94%, specificity 81%, positive predictive value 0.83, negative predictive value 0.94, positive likelihood ratio 5, and negative likelihood ratio 0.06. This clinical prediction rule is a simple noninvasive measure that may identify children at high risk for esophageal varices. A prospective validation study is in progress.


Organic matter fluorescence in municipal water recycling schemes: toward a unified PARAFAC model.
Organic matter (OM) is a ubiquitous constituent of natural waters quantifiable at very low levels using fluorescence spectroscopy. This technique has recognized potential in a range of applications where the ability to monitor water quality in real time is desirable, such as in water treatment systems. This study used PARAFAC to characterize a large (n=1479) and diverse excitation emission matrix (EEM) data set from six recycled water treatment plants in Australia, for which sources of variability included geography, season, treatment processes, pH and fluorometer settings. Five components were identified independently in four or more plants, none of which were generated during the treatment process nor were typically entirely removed. PARAFAC scores could be obtained from EEMs by simple regression. The results have important implications for online monitoring of OM fluorescence in treatment plants, affecting choices regarding experimental design, instrumentation and the optimal wavelengths for tracking fluorescent organic matter through the treatment process. While the multimodel comparisons provide a compelling demonstration of PARAFAC's ability to distill chemical information from EEMs, deficiencies identified through this process have broad implications for interpreting and reusing (D)OM-PARAFAC models.


Comparison of multimodal intra-arterial treatment versus intravenous thrombolysis for hypertensive patients with severe large vessel cerebral infarction.
Since intravenous thrombolysis (IVT) is often associated with poor outcomes in hypertensive patients with severe acute cerebral infarction (ACI) due to occlusions of the internal carotid, basilar, or proximal middle cerebral artery, we evaluated whether multimodal intra-arterial treatment (IAT) might improve functional outcomes in this patient population. We retrospectively reviewed the charts of eligible patients who underwent multimodal IAT including intra-arterial thrombolysis, mechanical thrombectomy, balloon and/or stent angioplasty (IAT group) or IVT alone (IVT group). Outcomes included the revascularization rate 24 hours postprocedure, the frequency of survival at 7, 90, and 180 days postonset, and a measure of functional outcomes using the modified Rankin Scale (mRS). The IAT group included 62 patients and the IVT group included 31 patients. Multimodal IAT increased the revascularization rate at 24 hours (p<0.001) and the frequency of survival and functional independence (mRS ≤2) at 7 days (p<0.001 and p=0.018, respectively), 90 days (both p<0.001), and 180 days (both p<0.001). Independent predictors of longer survival were treatment with multimodal IAT (HR 0.1; 95% CI 0.0 to 0.4; p<0.001) and revascularization (HR 0.1; 95% CI 0.0 to 0.4; p<0.001), whereas a longer duration from onset to treatment was a risk factor for death (HR 1.4; 95% CI 1.2 to 1.8; p<0.001). There was no significant between-group difference for symptomatic hemorrhagic transformation. This study found that for patients with severe hypertensive ACI with large vessel occlusions, multimodal IAT improved the outcomes, including early revascularization, survival, and functional outcome.


The cognitive and neural expression of semantic memory impairment in mild cognitive impairment and early Alzheimer's disease.
Semantic deficits in Alzheimer's disease have been widely documented, but little is known about the integrity of semantic memory in the prodromal stage of the illness. The aims of the present study were to: (i) investigate naming abilities and semantic memory in amnestic mild cognitive impairment (aMCI), early Alzheimer's disease (AD) compared to healthy older subjects; (ii) investigate the association between naming and semantic knowledge in aMCI and AD; (iii) examine if the semantic impairment was present in different modalities; and (iv) study the relationship between semantic performance and grey matter volume using voxel-based morphometry. Results indicate that both naming and semantic knowledge of objects and famous people were impaired in aMCI and early AD groups, when compared to healthy age- and education-matched controls. Item-by-item analyses showed that anomia in aMCI and early AD was significantly associated with underlying semantic knowledge of famous people but not with semantic knowledge of objects. Moreover, semantic knowledge of the same concepts was impaired in both the visual and the verbal modalities. Finally, voxel-based morphometry analyses revealed that semantic impairment in aMCI and AD was associated with cortical atrophy in the anterior temporal lobe (ATL) region as well as in the inferior prefrontal cortex (IPC), some of the key regions of the semantic cognition network. These findings suggest that the semantic impairment in aMCI may result from a breakdown of semantic knowledge of famous people and objects, combined with difficulties in the selection, manipulation and retrieval of this knowledge.


Emissions of decamethylcyclopentasiloxane from Chicago.
Decamethylcyclopentasiloxane (D5) is a high-production-volume chemical that is emitted to air in tens of thousands of tonnes each year globally. However, specific information about emission rates to air is still limited. Here we present an estimate of D5 emissions from the city of Chicago based on measurements that have recently been published. We used a multimedia environmental fate model parameterized for Chicago to back-calculate the emission rate of D5 from the measurements. Our estimated average emission rate for D5 is 500 (2.5-to-97.5-percentile interval: 260-1100) kg d(-1). The corresponding per-capita emissions of 190 (100-420) mg capita(-1)d(-1) agree well with previous estimates for Europe and North America.


miR-29a Is Repressed by MYC in Pancreatic Cancer and Its Restoration Drives Tumor-Suppressive Effects via Downregulation of LOXL2.
Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer with a dismal prognosis. miR-29a is commonly downregulated in PDAC; however, mechanisms for its loss and role still remain unclear. Here, we show that in PDAC, repression of miR-29a is directly mediated by MYC via promoter activity. RNA sequencing analysis, integrated with miRNA target prediction, identified global miR-29a downstream targets in PDAC. Target enrichment coupled with gene ontology and survival correlation analyses identified the top five miR-29a-downregulated target genes (LOXL2, MYBL2, CLDN1, HGK, and NRAS) that are known to promote tumorigenic mechanisms. Functional validation confirmed that upregulation of miR-29a is sufficient to ablate translational expression of these five genes in PDAC. We show that the most promising target among the identified genes, LOXL2, is repressed by miR-29a via 3'-untranslated region binding. Pancreatic tissues from a PDAC murine model and patient biopsies showed overall high LOXL2 expression with inverse correlations with miR-29a levels. Collectively, our data delineate an antitumorigenic, regulatory role of miR-29a and a novel MYC-miR-29a-LOXL2 regulatory axis in PDAC pathogenesis, indicating the potential of the molecule in therapeutic opportunities. IMPLICATIONS: This study unravels a novel functional role of miR-29a in PDAC pathogenesis and identifies an MYC-miR-29a-LOXL2 axis in regulation of the disease progression, implicating miR-29a as a potential therapeutic target for PDAC. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/2/311/F1.large.jpg.


Localized content-based image retrieval.
We define localized content-based image retrieval as a CBIR task where the user is only interested in a portion of the image, and the rest of the image is irrelevant. In this paper we present a localized CBIR system, Accio, that uses labeled images in conjunction with a multiple-instance learning algorithm to first identify the desired object and weight the features accordingly, and then to rank images in the database using a similarity measure that is based upon only the relevant portions of the image. A challenge for localized CBIR is how to represent the image to capture the content. We present and compare two novel image representations, which extend traditional segmentation-based and salient point-based techniques respectively, to capture content in a localized CBIR setting.


Metal ions based dynamic nuclear polarization: MI-DNP.
Over the last two decades magic angle spinning dynamic nuclear polarization (MAS DNP) has revolutionized NMR for materials characterization, tackling its main limitation of intrinsically low sensitivity. Progress in theoretical understanding, instrumentation, and sample formulation expanded the range of materials applications and research questions that can benefit from MAS DNP. Currently the most common approach for hyperpolarization under MAS consists in impregnating the sample of interest with a solution containing nitroxide radicals, which upon microwave irradiation serve as exogenous polarizing agents. On the other hand, in metal ion based (MI)-DNP, inorganic materials are doped with paramagnetic metal centres, which then can be used as endogenous polarizing agents. In this work we give an overview of the electron paramagnetic resonance (EPR) concepts required to characterize the metal ions and discuss the expected changes in the NMR response due to the presence of paramagnetic species. We highlight which properties of the electron spins are beneficial for applications as polarizing agents in DNP and how to recognize them, both from the EPR and NMR data. A theoretical description of the main DNP mechanisms is given, employing a quantum mechanical formalism, and these concepts are used to explain the spin dynamics observed in the DNP experiment. In addition, we highlight the main differences between MI-DNP and the more common approaches in MAS DNP, which use organic radicals as exogenous polarizing source. Finally, we review some applications of metal ions as polarizing agents in general and then focus particularly on research questions in materials science that can benefit from MI-DNP.


Cork-in-bottle mechanism of inhibitor binding to mammalian complex I.
Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia-reperfusion injury, metabolic disorders, and various cancers. Several pharmacologically relevant but structurally unrelated small molecules have been identified as specific complex I inhibitors, but their modes of action remain unclear. Here, we present a 3.0-Å resolution cryo-electron microscopy structure of mammalian complex I inhibited by a derivative of IACS-010759, which is currently in clinical development against cancers reliant on oxidative phosphorylation, revealing its unique cork-in-bottle mechanism of inhibition. We combine structural and kinetic analyses to deconvolute cross-species differences in inhibition and identify the structural motif of a "chain" of aromatic rings as a characteristic that promotes inhibition. Our findings provide insights into the importance of π-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design.


Initial emergency department systolic blood pressure predicts left ventricular systolic function in acute decompensated heart failure.
Ejection fraction (EF) is often unknown in patients who present with acute decompensated heart failure (ADHF). The objective of this study was to determine whether a patient's systolic blood pressure is associated with their left ventricular EF. This study was a retrospective chart review of all patients admitted to an emergency department (ED) observation unit from January 2002 to December 2004. A low EF was defined as <40%. Among 475 patients, the median age was 72 years, 53% were men, 40% were white, 59% were black, and 59% had a low EF. Patients with low EFs were more likely male ( P<.0001), with prior congestive heart disease ( P<.0001), longer QRS duration ( P<.0001), left bundle branch block ( P<.0001), and higher B-type natriuretic peptide ( P<.0001). The low EF group was less likely to have diabetes ( P<.0001). Adjusted odds ratios for an EF >or=40% were significant at all systolic blood pressure readings >120 mm Hg. Having an ED systolic BP >120 mm Hg is associated with significantly higher rates of preserved left ventricular systolic function in patients with ADHF.


The dynamics of disruption from altered auditory feedback: Further evidence for a dissociation of sequencing and timing.
Three experiments were designed to test whether perception and action are coordinated in a way that distinguishes sequencing from timing (Pfordresher, 2003). Each experiment incorporated a trial design in which altered auditory feedback (AAF) was presented for varying lengths of time and then withdrawn. Experiments 1 and 2 included AAF that resulted in action-effect asynchronies (delayed auditory feedback) during simple tapping (Experiment 1) and melody production (Experiment 2). Asynchronous AAF immediately slowed production; this effect then diminished rapidly after removal of AAF. By contrast, sequential alterations of feedback pitch during melody production (Experiment 3) had an effect that varied over successive presentations of AAF (by increasing error rates) that lasted after its withdrawal. The presence of auditory feedback after withdrawal of asynchronous AAF (Experiments 1 and 2) led to overcompensation of timing, whereas the presence of auditory feedback did not influence performance after withdrawal of AAF in Experiment 3. Based on these results, we suggest that asynchronous AAF perturbs the phase of an internal timekeeper, whereas alterations to feedback pitch over time degrade the internal representation of sequence structure.


The influence of increased fluid intake in the prevention of urinary stone formation: a systematic review.
to assess whether the volume of fluid intake influence the prevention of urinary stone formation. a systematic review from MEDLINE Electronic database was conducted. All of the controlled trial (RCT), case-control, and cohort studies written in English language were included in the study. Data analysis was performed to the design of the study, volume of fluid intake (higher volume as experimental group and lower volume as control group), and risk of stone formation. All of the included studies were appraised using the Oxford Center for Evidence-based Medicine appraisal tool for therapy (Randomized Controlled Trial) and level of evidence. our systematic review included five studies (1 RCT and case-control study in patients with history of urolithiasis, and 3 prospective cohorts in patients without history of urolithiasis). Three studies increased fluid intake to 2.5 Liters/day and one study to 2 Liters/day, while one other study used the urine production target of 2 Liters/day. All of these studies showed that increased fluid intake per day could decrease the risk of both primary and secondary stone formation. stronger evidence are still needed to conclude that increasing fluid intake could be utilized as a strategy to prevent primary urolithiasis because of the lack of data from the clinical trials supporting it. However, to prevent the recurrence of urolithiasis, increasing fluid intake could be recommended with the urine volume target of more than 2,000 mL/day.


Sequence selective binding of bis-daunorubicin WP631 to DNA.
We have used footprinting techniques on a wide range of natural and synthetic footprinting substrates to examine the sequence-selective interaction of the bis-daunorubicin antibiotic WP631 with DNA. The ligand produces clear DNase I footprints that are very different from those seen with other anthracycline antibiotics such as daunorubicin and nogalamycin. Footprints are found in a diverse range of sequences, many of which are rich in GT (AC) or GA (TC) residues. As expected, the ligand binds well to the sequences CGTACG and CGATCG, but clear footprints are also found at hexanucleotide sequences such GCATGC and GCTAGC. The various footprints do not contain any particular unique di-, tri- or tetranucleotide sequences, but are frequently contain the sequence (G/C)(A/T)(A/T)(G/C). All sequences with this composition are protected by the ligand, though it can also bind to some sites that differ from this consensus by one base pair.