Prevalence and patterns of nitrosatable drug use among U.S. women during early pregnancy.
Experimental evidence indicates that certain drugs, that are secondary or tertiary amines or amides, form N-nitroso compounds in the presence of nitrite in an acidic environment. Nitrosatable drugs have been associated with birth defects in a few epidemiologic studies. This study describes the prevalence and patterns of nitrosatable drug use among U.S. women during early pregnancy and examines maternal factors associated with such use. Data were analyzed from the National Birth Defects Prevention Study and included 6807 mothers who gave birth to babies without major congenital malformations during 1997 to 2005. Information was collected by telephone interview about medication use, demographic factors, and maternal health. Drugs taken during the first trimester were classified according to nitrosatability, amine and amide functional groups, and primary indication of use. Approximately 24% of the women took one or more nitrosatable drugs during the first trimester, including 12.4%, 12.2%, and 7.6% who respectively took secondary amines, tertiary amines, or amides. Five of the ten most commonly taken drugs were available over the counter. Women who were non-Hispanic white (29.5%), with 1 year or more college education (27.3%) or 40 years or older (28.8%) had the highest prevalence of use. Supplemental vitamin C, an inhibitor of nitrosation, was not taken by 41.6% and 19.3% of nitrosatable drug users during the first and second months of pregnancy, respectively. In this U.S. population, ingestion of drugs classified as nitrosatable was common during the first trimester of pregnancy, especially among non-Hispanic white, more educated, and older mothers.


Computational and Synthetic Investigation of Cationic Rearrangement in the Putative Biosynthesis of Justicane Triterpenoids.
A biomimetic cationic structural rearrangement of the oleanolic acid framework is reported for the gram-scale synthesis and structural reassignment of justicioside E aglycone. The mechanism of the putative biosynthetic rearrangement is investigated with kinetic, computational, and synthetic approaches. The precursor to rearrangement was accessed through two strategic advancements: (1) synthesis of a 1,3-diketone via oxidation of a β-silyl enone, and (2) diastereoselective 1,3-diketone reduction to form a syn-1,3-diol using SmI2 with PhSH as a key additive.


Estimating the rate of plasmid transfer: an end-point method.
We describe a method for determining the rate parameter of conjugative plasmid transfer that is based on single estimates of donor, recipient and transconjugant densities and the growth rate in exponential phase of the mating culture. The formula for estimating the plasmid transfer rate, gamma, was derived from a mathematical model describing cell growth and plasmid transfer in batch culture. Computer simulations were used to explore the sensitivity of this method to the realities of bacterial life, such as growth rate differences, plasmid segregation and transitory derepression of pilus synthesis. As predicted by the theory, mating experiments with the plasmid R1 in Escherichia coli K12 demonstrated that the estimate gamma is unaffected by cell density, donor:recipient ratio and mating time. Unlike previous techniques, our method allows us to investigate the effect of environmental factors on plasmid transfer rates when these factors also influence population growth rates. To illustrate this, we examined the effect of temperature on the rate of plasmid transfer.


The design of patient decision support interventions: addressing the theory-practice gap.
Although an increasing number of decision support interventions for patients (including decision aids) are produced, few make explicit use of theory. We argue the importance of using theory to guide design. The aim of this work was to address this theory-practice gap and to examine how a range of selected decision-making theories could inform the design and evaluation of decision support interventions. We reviewed the decision-making literature and selected relevant theories. We assessed their key principles, theoretical pathways and predictions in order to determine how they could inform the design of two core components of decision support interventions, namely, information and deliberation components and to specify theory-based outcome measures. Eight theories were selected: (1) the expected utility theory; (2) the conflict model of decision making; (3) prospect theory; (4) fuzzy-trace theory; (5) the differentiation and consolidation theory; (6) the ecological rationality theory; (7) the rational-emotional model of decision avoidance; and finally, (8) the Attend, React, Explain, Adapt model of affective forecasting. Some theories have strong relevance to the information design (e.g. prospect theory); some are more relevant to deliberation processes (conflict theory, differentiation theory and ecological validity). None of the theories in isolation was sufficient to inform the design of all the necessary components of decision support interventions. It was also clear that most work in theory-building has focused on explaining or describing how humans think rather than on how tools could be designed to help humans make good decisions. It is not surprising therefore that a large theory-practice gap exists as we consider decision support for patients. There was no relevant theory that integrated all the necessary contributions to the task of making good decisions in collaborative interactions. Initiatives such as the International Patient Decision Aids Standards Collaboration influence standards for the design of decision support interventions. However, this analysis points to the need to undertake more work in providing theoretical foundations for these interventions.


Neuropeptide Y blocks GABAB-induced phase-shifts of the suprachiasmatic circadian clock in vitro.
The mammalian circadian clock in the suprachiasmatic nucleus (SCN) generates 24-h rhythms of neuronal activity in vitro. We have previously shown that the GABAB agonist baclofen resets the SCN pacemaker in vitro in a phase-dependent manner: advances are induced at zeitgeber time (ZT) 6 and delays are induced at ZT 22. We have also previously shown that neuropeptide Y (NPY) phase-shifts the SCN clock when applied at ZT 10 but not at other times. Here, we show that NPY blocks the baclofen-induced phase-shifts at ZT 6 and ZT 22. The inhibition by NPY appears dose-dependent, and a higher concentration of NPY is required for complete inhibition of the baclofen-induced phase-advances than the phase-delays. Conversely, NPY-induced phase-shifts at ZT 10 are unaffected by co-application of baclofen. These results are consistent with previous findings showing that NPY blocks in vitro phase-shifts induced by a variety of neuromodulators during both the daytime and nighttime.


Depth-first picture expression viewed from digital picture processing.
A picture coding strategy titled DF-expression (Depth-First picture expression) is now studied from another point of view. The basic idea of DF-expression is briefly reviewed at first. Its capability in data compression is demonstrated using 1024 × 1024 binary pictures. Then the new aspects of DF-expression are studied in reference to picture processing algorithm on the coded form. They include circular shiftings, spectrum of primitives, logical operations, etc. Application of DF-expression to gray images (or multivalued pictures) is the next topics of the paper. DF-expression is applicable to bit-plane coding of any binary image data. Our conclusion with this point is that the gray code is the best binary code system for DF-expression in information preserving sense. Information-lossy type data reduction is another topics in this paper. The authors propose a new data reduction technique in terms of uniformalization of excessively complicated regions in bit-planes. Experimental study follows using a 256 × 256 sized fourbit test picture. Finally, conclusions and other possibility of the applications are remarked.


Genome organization in dicots: genome duplication in Arabidopsis and synteny between soybean and Arabidopsis.
Synteny between soybean and Arabidopsis was studied by using conceptual translations of DNA sequences from loci that map to soybean linkage groups A2, J, and L. Synteny was found between these linkage groups and all four of the Arabidopsis chromosomes, where GenBank contained enough sequence for synteny to be identified confidently. Soybean linkage group A2 (soyA2) and Arabidopsis chromosome I showed significant synteny over almost their entire lengths, with only 2-3 chromosomal rearrangements required to bring the maps into substantial agreement. Smaller blocks of synteny were identified between soyA2 and Arabidopsis chromosomes IV and V (near the RPP5 and RPP8 genes) and between soyA2 and Arabidopsis chromosomes I and V (near the PhyA and PhyC genes). These subchromosomal syntenic regions were themselves homeologous, suggesting that Arabidopsis has undergone a number of segmental duplications or possibly a complete genome duplication during its evolution. Homologies between the homeologous soybean linkage groups J and L and Arabidopsis chromosomes II and IV also revealed evidence of segmental duplication in Arabidopsis. Further support for this hypothesis was provided by the observation of very close linkage in Arabidopsis of homologs of soybean Vsp27 and Bng181 (three locations) and purple acid phosphatase-like sequences and homologs of soybean A256 (five locations). Simulations show that the synteny and duplications we report are unlikely to have arisen by chance during our analysis of the homology reports.


The effects of viscoelastic fluid on kinesin transport.
Kinesins are molecular motors which transport various cargoes in the cytoplasm of cells and are involved in cell division. Previous models for kinesins have only targeted their in vitro motion. Thus, their applicability is limited to kinesin moving in a fluid with low viscosity. However, highly viscoelastic fluids have considerable effects on the movement of kinesin. For example, the high viscosity modifies the relation between the load and the speed of kinesin. While the velocity of kinesin has a nonlinear dependence with respect to the load in environments with low viscosity, highly viscous forces change that behavior. Also, the elastic nature of the fluid changes the velocity of kinesin. The new mechanistic model described in this paper considers the viscoelasticity of the fluid using subdiffusion. The approach is based on a generalized Langevin equation and fractional Brownian motion. Results show that a single kinesin has a maximum velocity when the ratio between the viscosity and elasticity is about 0.5. Additionally, the new model is able to capture the transient dynamics, which allows the prediction of the motion of kinesin under time varying loads.


Mercury bioaccumulation and biomagnification in a small Arctic polynya ecosystem.
Recurring polynyas are important areas of biological productivity and feeding grounds for seabirds and mammals in the Arctic marine environment. In this study, we examined food web structure (using carbon and nitrogen isotopes, δ(13)C and δ(15)N) and mercury (Hg) bioaccumulation and biomagnification in a small recurring polynya ecosystem near Nasaruvaalik Island (Nunavut, Canada). Methyl Hg (MeHg) concentrations increased by more than 50-fold from copepods (Calanus hyperboreus) to Arctic terns (Sterna paradisaea), the abundant predators at this site. The biomagnification of MeHg through members of the food web - using the slope of log MeHg versus δ(15)N - was 0.157 from copepods (C. hyperboreus) to fish. This slope was higher (0.267) when seabird chicks were included in the analyses. Collectively, our results indicate that MeHg biomagnification is occurring in this small polynya and that its trophic transfer is at the lower end of the range of estimates from other Arctic marine ecosystems. In addition, we measured Hg concentrations in some poorly studied members of Arctic marine food webs [e.g. Arctic alligatorfish (Ulcina olrikii) and jellyfish, Medusozoa], and found that MeHg concentrations in jellyfish were lower than expected given their trophic position. Overall, these findings provide fundamental information about food web structure and mercury contamination in a small Arctic polynya, which will inform future research in such ecosystems and provide a baseline against which to assess changes over time resulting from environmental disturbance.


Germplasm of Ozark chinquapin (Castanea ozarkensis Ashe) can be cryopreserved by dormant winter buds.
Ozark chinquapin (Castanea ozarkensis Ashe) is a forest tree, endemic to the Ozark Mountain region in Eastern United States. Its nutritious nuts were consumed by Native Americans, European settlers, livestock, and wild animals and its wood was an important rot-resistant construction material. Once a significant tree in regional forest communities, the species was nearly eradicated by a chestnut blight caused by Cryphonectria parasitca (Murill) Barr fungus. Some individuals have survived as sprouts from adventitious root buds, but they rarely reach reproductive maturity. While some in situ restoration efforts are underway, the development of a viable ex situ germplasm preservation method is critical to the conservation of this important food-bearing species. Our experiment aimed to develop a cryopreservation method for C. ozarkensis dormant winter buds subjected to eight experimental treatments before desiccation, slow cooling, and storage in liquid nitrogen vapor. The highest post cryogenic viability was 91.2 % for dormant buds pretreated with 0.3 M sucrose for 16 h followed by 0.75 M sucrose for 3 h; this treatment is suggested for cryopreservation of dormant winter buds of Ozark chinquapin germplasm.


A bibliometric of publication trends in medical image segmentation: Quantitative and qualitative analysis.
Medical images are important in diagnosing disease and treatment planning. Computer algorithms that describe anatomical structures that highlight regions of interest and remove unnecessary information are collectively known as medical image segmentation algorithms. The quality of these algorithms will directly affect the performance of the following processing steps. There are many studies about the algorithms of medical image segmentation and their applications, but none involved a bibliometric of medical image segmentation. This bibliometric work investigated the academic publication trends in medical image segmentation technology. These data were collected from the Web of Science (WoS) Core Collection and the Scopus. In the quantitative analysis stage, important visual maps were produced to show publication trends from five different perspectives including annual publications, countries, top authors, publication sources, and keywords. In the qualitative analysis stage, the frequently used methods and research trends in the medical image segmentation field were analyzed from 49 publications with the top annual citation rates. The analysis results showed that the number of publications had increased rapidly by year. The top related countries include the Chinese mainland, the United States, and India. Most of these publications were conference papers, besides there are also some top journals. The research hotspot in this field was deep learning-based medical image segmentation algorithms based on keyword analysis. These publications were divided into three categories: reviews, segmentation algorithm publications, and other relevant publications. Among these three categories, segmentation algorithm publications occupied the vast majority, and deep learning neural network-based algorithm was the research hotspots and frontiers. Through this bibliometric research work, the research hotspot in the medical image segmentation field is uncovered and can point to future research in the field. It can be expected that more researchers will focus their work on deep learning neural network-based medical image segmentation.


Spatial clusters of nontuberculous mycobacterial lung disease in the United States.
Prevalence of pulmonary nontuberculous mycobacterial (PNTM) disease varies by geographic region, yet the factors driving these differences remain largely unknown. To identify spatial clusters of PNTM disease at the county level and to describe environmental and sociodemographic factors predictive of disease. PNTM cases identified from a nationally representative sample of Medicare Part B beneficiaries from 1997 to 2007 were geocoded by county and state of residence. County-level PNTM case counts and Medicare population data were then uploaded into SaTScan to identify significant spatial clusters and low-risk areas of disease. High-risk and low-risk counties were then compared to identify significant sociodemographic and environmental differences. We identified seven significant (P < 0.05) clusters of PNTM cases. These high-risk areas encompassed 55 counties in 8 states, including parts of California, Florida, Hawaii, Louisiana, New York, Oklahoma, Pennsylvania, and Wisconsin. Five low-risk areas were also identified, which encompassed 746 counties in 23 states, mostly in the Midwest. Counties in high-risk areas were significantly larger, had greater population densities, and higher education and income levels than low-risk counties. High-risk counties also had higher mean daily potential evapotranspiration levels and percentages covered by surface water, and were more likely to have greater copper and sodium levels in the soil, although lower manganese levels. Specific environmental factors related to soil and water exposure appear to increase the risk of PNTM infection. Still, given that environmental sources of NTM are ubiquitous and PNTM disease is rare, both host susceptibility and environmental factors must be considered in explaining disease development.


CYP2C9*3 polymorphism presenting as lethal subdural hematoma with low-dose warfarin.
Warfarin is the most common and cheap oral anticoagulant currently used in clinical practice. A high inter-individual variation is seen in the response to warfarin. Recently, pharmacogenetics has gained importance in managing patients on warfarin, both in predicting the optimum required dose as well as in decreasing the risk of bleeding. This case report is a description of a 49-year-old patient who had a lethal subdural hematoma with low-dose warfarin. He was subsequently found to have CYP2C9 gene polymorphism (*1/*3). This case report stresses the importance of pre-prescription assessment of genetic analysis for those initiated on warfarin.


[Diagnosis and therapy in acute stroke: a rehabilitation center viewpoint].
The extent of the diagnostic work-up of patients with acute stroke was evaluated in 101 patients admitted for rehabilitation during a 4-month period in 1997. This included specific blood tests and neuro- and cardiac imaging, and compared the extent of work-up in a community hospital versus a rehabilitation center. Comparisons were also made with similar investigations 10 and 20 years earlier. Results demonstrated that the trend to admit younger stroke patients (< 50 years) to neurological (as opposed to medical) departments observed between 1977-1987 persisted in 1997. The use of CT scan increased dramatically from 1977 to 1987 (19% vs 78%), and in 1997 was actually 100%. The use of carotid duplex and echocardiography increased steadily during the 3 decades reaching 26% and 28% respectively. Tests for thrombophilia were seldom done. However, in neurological departments it was done in about 50% of the younger stroke patients. In neurology departments carotid duplex was done 2 to 3 times more often than in medical departments. During rehabilitation imaging tests were done once or more in almost half the patients. The results and those of additional blood tests, have led to modification of antithrombotic treatment in 14% of the younger group and 4% of the older group. We have clearly shown that while stroke work-up has become more comprehensive in recent years, there is still much to do in this field. Stroke units or teams in our general hospitals will increase stroke awareness, improve work-up and hasten definitive treatment.


The effect of a body burden of methylmercury on hepatic regeneration.
The model of hepatic regeneration is chosen to study the effect of methylmercury burden on cell proliferation. The results show that chronic methylmercury burden impedes the rate of thymidine incorporation during the process of DNA synthesis. At 24 hours after partial hepatectomy, thymidine incorporation in the mercury exposed rats is 53% of the controls. Counts of labeled hepatocytes in radioautographic preparations also support this observation. This remarkable difference in DNA synthetic activity at 24 hours also reflects in the DNA content and liver, weights at 72 hours after partial hepatectomy (Liver weights 2.36 +/- 0.21 gm/100 gm B. W. vs. 2.67 +/- 0.31 gm/100 B. W., P < 0,05; DNA contents 160.78 +/- 36.76 microgram/gm vs. 214.80 +/- 37.908 microgram/gm, P < 0.05). After two weeks, no significant difference is noted in liver weight, DNA content and synthetic activity. On the other hand, protein content and biosynthesis in the liver of methylmercury burdened rats shows no significant difference from the controls in all the periods studied. From these data it is concluded that the dividing fraction of hepatocytes is reduced in methylmercury-treated group at an early stage of regeneration when cell proliferation is most active.


University Hospitals: creating the infrastructure for quality and value through accountable care.
University Hospitals Health System Inc. (UH), in Cleveland, Ohio, like many hospitals and healthcare systems, sought to anticipate the dramatic changes of healthcare reform, including its increased focus on quality and outcomes. UH evaluated incentives to keep patients out of hospital and to ease mounting pressures on reimbursement and costs. During UH's strategic planning sessions in 2009 and 2010, we identified value--the combination of quality and efficiency--to be a key driver of our future success. Ahead of the enactment of the Affordable Care Act, in early 2010 we chose to proceed with the formation of an accountable care organization (ACO). We believed the ACO was a novel vehicle by which to improve the efficient delivery of our high-quality healthcare to maximize the value of the services we provide. We also believed that the most successful strategy, if it can be achieved, is to build on success. A major success, or a series of smaller successes, will go a long way toward achieving operational buy-in, enhancing respect for strategic initiatives, and convincing physicians of the need for change. Through thoughtful governance, effective plan design, customized data analytics, physician networks and incentives, innovative patient engagement, and supplemental coordination resources, our ACOs have succeeded in improving population health and delivering value.


Long-term survival after orthotopic and heterotopic cardiac transplantation.
Five long-term survivors of heart transplantation were reinvestigated. Two patients had undergone orthotopic heart transplantation over 11 and 9 years earlier and constitute two of the world's longest-surviving patients after this procedure. Three patients had undergone heterotopic heart transplantation (one left heart bypass alone and two biventricular bypass) four to six years earlier. Four of the five patients had had only one or no documented acute rejection episodes. Three had been given blood transfusions. None had had particularly good tissue matching in relation to the donor on HLA typing. All five patients were leading full and active lives. At review two patients had significant coronary artery disease, one severe, presumably due to chronic immune-complex deposition. Heart transplantation remains a major undertaking, but it can offer the patient many years of good-quality life.


The impact of university provided nurse electronic medical record training on health care organizations: an exploratory simulation approach.
Training providers appropriately, particularly early in their caregiving careers, is an important aspect of electronic medical record (EMR) implementation. Considerable time and resources are needed to bring the newly hired providers 'up to speed' with the actual use practices of the organization. Similarly, universities lose valuable clinical training hours when students are required to spend those hours learning organization-specific EMR systems in order to participate in care during clinical rotations. Although there are multiple real-world barriers to university/health care organization training partnerships, the investment these entities share in training care providers, specifically nurses, to use and understand EMR technology encourages a question: What would be the cumulative effect of integrating a mutually agreed upon EMR system training program in to nursing classroom training on downstream hospital costs in terms of hours of direct caregiving lost, and benefits in terms of number of overall EMR trained nurses hired? In order to inform the development of a large scale study, we employed a dynamic systems modeling approach to simulate the theoretical relationships between key model variables and determine the possible effect of integrating EMR training into nursing classrooms on hospital outcomes. The analysis indicated that integrating EMR training into the nursing classroom curriculum results in more available time for nurse bedside care. Also, the simulation suggests that efficiency of clinical training can be potentially improved by centralizing EMR training within the nursing curriculum.


Association of Skin Microbiome with the Onset and Recurrence of Pressure Injury in Bedridden Elderly People.
Pressure injuries have been identified as one of the main health hazards among bedridden elderly people. Bedridden elderly people often stay in the same position for a long time, because they cannot switch positions; thus, the blood flow in the part of the body that is being compressed between the bed and their own weight is continuously blocked. As a result, redness and ulcers occur due to lacking oxygen and nutrients in the skin tissues, and these sites are often infected with microorganisms and, thus, become suppurative wounds, a condition commonly determined as pressure injuries. If left untreated, the pressure injury will recur with microbial infections, often resulting in cellulitis, osteomyelitis, and sepsis. The skin microbiome, in which many types of bacteria coexist, is formed on the skin surface. However, it remains unclear what characteristic of the skin microbiome among the bedridden elderly constitutes the development and severity of pressure injuries and the development of post-pressure injury infections. Thus, in this review article, we outlined the changes in the skin microbiome among the bedridden elderly people and their potential involvement in the onset and recurrence of pressure injuries.


Studies on the technique of vitreous fluorophotometry.
We examined the sources of artifacts of vitreous fluorophotometry (VF), a technique used to assess the permeability of the blood-retinal barrier. By performing in vitro measurements in a model eye and in vivo readings in humans, we investigated the influence of various concentrations of fluorescein in the anterior chamber and in the retina on the measurements performed in the vitreous. Upper limits for the artifactual effects are set under clinical conditions, and a way to account for them is proposed. Special attention is given to depth resolution, which was investigated as a function of the region being scanned, the beam width, and the probe size. Further, preliminary results indicate that a procedure to account for light attenuation by the lens is feasible. It appears that reliable quantitative results can be obtained by VF, provided that the artifacts are acknowledged, minimized, and corrected.


Pipeline embolization device treatment of internal carotid artery terminus aneurysms.
The pipeline embolization device (PED) is approved for the treatment of large aneurysms of the proximal internal carotid artery (ICA). Its off-label application in treating aneurysms located specifically at the ICA terminus (ICA-T) has not been studied. We conducted a retrospective chart review of patients from 2011 to 7 treated with PEDs. Out of 365 patients, 10 patients with ICA-T aneurysms were included. Patient demographics, procedural information, follow-up imaging, and clinical assessments were recorded. Mean age was 46.9 years (± 8.8), and 6 (60%) patients were women. The mean maximum diameter of the aneurysms treated was 14.7 mm (± 10.7) and the mean neck diameter was 9.3 mm (± 6.6). Reasons for presentation included six incidental findings, one acute subarachnoid hemorrhage (SAH), and three patients with prior SAH. Kamran-Byrne Occlusion Scale scores for the treated aneurysms were as follows: three class IV (complete obliteration), four class III (<50% filling in both height and width for fusiform aneurysms or residual neck for saccular aneurysms), one class II fusiform aneurysm, 1 class 0 saccular aneurysm (residual aneurysm body), and one not classified due to pipeline thrombosis. Two clinically asymptomatic complications were noted: one patient who had a small distal cortical SAH post PED and one patient whose stent was found to be thrombosed on follow-up angiogram. All patients were seen in follow-up, and no patients were found to have worsening of their pre-procedure modified Rankin Scale score. The PED has potential for treating ICA-T aneurysms not amenable to conventional treatment strategies. Further studies are warranted to confirm the long term outcomes.


Role of glutathione S-transferases in the resistance of human colon cancer cell lines to doxorubicin.
The anthracycline doxorubicin has little activity against colorectal cancers. It is hypothesized that this is attributable to a multifactorial resistance mechanism in which the glutathione S-transferases (GST) may play a role. We studied the relationship between GST expression and doxorubicin resistance in four human colon adenocarcinoma cell lines (HT-29, LoVo, SW620, and Caco-2), with the goal of modulating GST activity to overcome resistance. Caco-2 cells were the most resistant to doxorubicin, showing an IC50 value approximately 80- to 90-fold higher than HT-29 or LoVo and 600-fold higher than SW620. Total GST catalytic activity was significantly higher in Caco-2 cells compared with the other lines. All four cell lines expressed GST-pi at the catalytic activity, protein, and mRNA levels; however, no significant differences were observed among the cell lines. GST-mu expression was not detectable at the protein and mRNA levels, and the four cell lines displayed very low catalytic activity toward a GST-mu-selective substrate. Caco-2 cells showed a unique, highly expressed GST-alpha-immunoreactive band that was not detected in the other lines; however, the glutathione peroxidase activity of Caco-2 cells was the lowest among the four cell lines. Neither ethacrynic acid nor glutathione analogues that function as GST class-selective inhibitors were able to potentiate the cytotoxic effects of doxorubicin in these colon cancer cell lines, as demonstrated in both microplate colorimetric and clonogenic assays. The multidrug resistance-associated protein and P-glycoprotein were either not detectable or expressed at such low levels that they are not likely to contribute to the differences in doxorubicin sensitivity observed among these cell lines.


Route of placebo administration: Robust placebo effects in laboratory and clinical settings.
Recent advances in laboratory and clinical research have greatly enhanced our understanding of placebo effects. However, little progress has been made in translational research that can well integrate these findings. This article examines pivotal role of placebo administration in subsequent placebo responses, providing a unified framework that accounts for robust placebo effects in both laboratory and clinical settings.


Endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (FNA) of liver lesions.
Endoscopic ultrasonography (EUS) is not traditionally thought to be clinically applicable in liver imaging. EUS-guided fine-needle aspiration of the liver has not been well described. A prospective study was conducted in which 574 consecutive patients with a history or suspicion of gastrointestinal or pulmonary malignant tumor undergoing upper EUS examinations underwent EUS evaluation of the liver. Fourteen (2.4%) patients were found to have focal liver lesions and underwent EUS-guided fine-needle aspiration. The median largest diameter of the liver lesions was 1.1 cm (range 0.8 to 5.2 cm). The mean number of passes was 2.0 (range 1 to 5 passes). All fine-needle passes yielded an adequate specimen. One of the 14 patients underwent EUS-guided fine-needle aspiration of 2 liver lesions. Fourteen of the 15 liver lesions sampled by means of EUS-guided fine-needle aspiration were malignant and one was benign. Before EUS, computed tomography (CT) depicted liver lesions in only 3 of 14 (21%) patients. Seven of 14 patients had a known cancer diagnosis. For the other 7, the initial diagnosis of cancer was made by means of EUS-guided fine-needle aspiration of the liver. There were no immediate or late complications. EUS can detect small focal liver lesions that are not detected at CT. Findings of EUS-guided fine-needle aspiration can confirm a cytologic diagnosis of liver metastasis and establish a definitive M stage that may change clinical management.


Field trials of blood culture identification FilmArray in regional Australian hospitals.
Purpose. In this field trial of rapid blood culture identification (BCID), we aimed to determine whether the improved speed and accuracy of specific BCID predicted in our earlier pilot study could be obtained in regional hospitals by deploying a multiplex PCR FilmArray (Biomerieux, France) capability in their laboratories.Methods. We trained local hospital laboratory staff to operate the FilmArray equipment and act on the results. To do this, we integrated the multiplex PCR into the standard laboratory blood culture workflow and reporting procedure.Results. Of 100 positive blood culture episodes, BCID FilmArray results were correct in all 42 significant monobacterial cultures, with a fully predictive identity in 38 (90.5 %) and a partial identity in another four (9.5 %). There was one major error; a false positive Pseudomonas aeruginosa. The minor errors were the detection of one methicillin-resistant Staphylococcus aureus, which proved to be a methicillin-sensitive S. aureus mixed with a methicillin-resistant coagulase-negative staphylococcus, five false negative coagulase-negative staphylococci and one false negative streptococcus species. We found that 41/49 (84 %) clinically significant mono- and polymicrobial culture results were fully predictive of culture-based identification to bacterial species level at a mean of 1.15 days after specimen collection.Conclusions. There was a reduction of 1.21 days in the time taken to produce a definitive BCID compared to the previous year, translating into earlier communication of more specific blood culture results to the treating physician. Reduced time to definitive blood culture results has a direct benefit for isolated Australian communities at great distances from specialist hospital services.


Simple technique to evaluate thorax asymmetry in scoliosis: clinical usefulness to assess deformity and mobility.
In subjects with scoliosis the thoracic cage deformity is a complex 3D phenomenon. There is a deficiency of simple clinical methods of thorax shape evaluation. The study aimed to introduce and assess an anthropometric technique measuring transverse plane deformity of the thorax in patients with idiopathic scoliosis. Thirty scoliotic girls, aged 14.4+/-1.5 years, thoracic scoliosis type Lenke 1, mean Cobb 54.1+/-24.7 degrees, and 30 healthy volunteers matched for sex and age were examined. Using a Martin anthropometric caliper the length of the long and the short horizontal axes of the thorax were measured at the level of the xiphoid process (upper index) and of the costal arch (lower index), both on maximum inspiration and expiration. Asymmetry index, defined as difference of the length of the long and the short axes expressed as the percentage of the short one, was calculated. The upper asymmetry index in the study group was 35.2+/-18.6 (inspiration) while in the control group it was 13.6+/-13.6, difference significant, p<0.001. The lower asymmetry index in the study group was 26.2+/-12.9 (inspiration) while in the control group it was 12.5+/-11.7, difference significant, p<0.001. In conclusion, thorax asymmetry index revealed significantly higher values in scoliotic patients. Asymmetry of respiratory movements could be measured. This simple technique may be used as a helpful tool for clinicians.


Polymicrogyria with dysmorphic basal ganglia? Think tubulin!
Dominant mutations in TUBB2B have been reported in patients with polymicrogyria. We further explore the phenotype associated with mutations in TUBB2B. Twenty patients with polymicrogyria (five unilateral) were tested for mutations in TUBB2B by Sanger sequencing. We identified two novel de novo mutations, c.743C>T (p.Ala248Val) and c.1139G>T (p.Arg380Leu) in exon 4 of TUBB2B in three unrelated families. Brain magnetic resonance images showed polymicrogyria involving predominantly the perisylvian regions. In addition, there was a dysmorphic appearance of the basal ganglia, thin corpus callosum, enlargement of the ventricles, thinning of the white matter and hypoplasia of pons and cerebellar vermis. This combination of associated features was absent in all 17 patients with polymicrogyria in whom no mutation was identified. This report underlines that the association of polymicrogyria with thin or absent corpus callosum, dysmorphic basal ganglia, brainstem and vermis hypoplasia is highly likely to result from mutations in TUBB2B and provides further insight in how mutations in TUBB2B affect protein function.


Immediate orthostatic hypotension: diagnostic value in acutely ill patients.
Hypotension (systolic blood pressure less than 90 mm Hg) was induced immediately in 21 acutely ill normotensive patients when they were raised from a supine to an upright position. Systolic blood pressure declined to 80 mm Hg or lower in all patients and to 65 mm Hg or lower in 10 patients when they assumed an upright posture. Immediate orthostatic hypotension observed in 9 patients suggested hypovolemia, which was promptly corrected by rapid infusion of large volumes of normal saline and/or albumin. Orthostatic hypotension was of diagnostic aid in 16 patients, including 4 with infections (pelvic inflammatory disease, occult septic shock, legionnaires' disease, Rocky Mountain spotted fever), 3 with adrenal insufficiency, 2 with acute myocardial infarction, 1 with hypoglycemia, 2 with severe cardiac valvular obstruction, and 4 with inappropriate drug use (enalapril or trazodone). These findings suggest that immediate orthostatic hypotension in acutely ill patients is a physical sign that might have valuable diagnostic and therapeutic implications.


Digital dentistry and implant dentistry--a case study.
In the area of fixed prosthodontics, implants have evolved to become the gold standard in terms of longevity and esthetic outcome (1). As in all of dentistry, careful diagnosis and treatment planning is a must to achieve an optimum result. When evaluating the recipient site, one must determine if any type of defect (hard or soft tissue) exists which would require augmentation. The existing occlusion must also be evaluated to ensure the dentist is aware of possible prosthetic complications. In straightforward cases, such as those without the need for augmentation, the conventional timeline requires a waiting period of 3 months following surgical placement to begin the restorative procedures. Factoring in the restorative time frame, the patient may wait up to approximately 4 months for the final implant prosthesis. Various advancements in dentistry are changing the way dentists approach implant dentistry--from diagnosis and treatment planning to final restorations. This article illustrates these advances through a case study.


Translation and Validation of the Turkish Version of Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ).
Poor adherence is widely observed in MS as in other chronic diseases; therefore, improving adherence should be a significant treatment objective. Therefore, it is important to determine the causes of nonadherence and to make improvement plans by establishing a special measurement tool for MS patients. The aim of this study is to investigate validity and Turkish equivalence of The Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ) that developed by Paul Wicks and Michael Massagli in 2009. The sample of the methodological study comprised 198 MS patients who stayed in University Faculty of Medicine, Department of Neurology, MS clinic between July 2016 and February 2017. In the research, "Data Collection Form" and "MS-TAQ" was used. To conduct this study, permission was obtained from the university ethics committee and the hospital administration. All participants in the study were informed of the study's purpose and their role. Translation procedure (forward and backward) and pre-test were performed for translation equivalence and linguistic adaptation. MS-TAQ's Cronbach alfa coefficient 0.83 were calculated. According to expert's suggestion modifications was made and content validity index was calculated with Davis technic between 1.0-1.4. As a result, "MS-TAQ" has been found a sufficiently valid and reliable tool in Turkey.


Comparison of two soft tissue substitutes for the treatment of gingival recession defects: an animal histological study.
This study aimed to compare two different soft tissue replacement grafts in their ability to treat gingival recession defects and successfully integrate with the surrounding tissues. Nine beagle dogs were included and followed up to 10 weeks. Sites for intervention were allocated to one of the grafting materials investigated. Treatment consisted of coronally advanced flap combined with one of the two soft tissue substitutes on a previous surgically created defect. Materials employed were porcine-derived acellular dermal matrix (ADM) [Novomatrix™ (Test)] and collagen-based matrix (CBM) [Mucograft® (Control)]. Animals were sacrificed at 2, 6, and 10 weeks postoperatively and compared using descriptive histology and histomorphometric outcomes. Macroscopic findings were similar between test and control groups at all intervals. After 10 weeks, both groups demonstrated successful incorporation of the grafting materials without signs of rejection and with comparable tissue integration. The histomorphometric data were similar between groups at 2 weeks; however, the test group provided greater root coverage and increase in tissue thickness than the control at 6- and 10-weeks post surgically. Both porcine-derived ADM and CBM revealed similar histological outcomes with successful integration and absence of adverse events. Test group provided superior outcomes regarding root coverage and increase in tissue thickness.


Levosulpiride, (S)-(-)-5-Aminosulfonyl-N-[(1-ethyl-2-pyrrolidinyl) methyl]-2-methoxybenzamide, enhances the transduction efficiency of PEP-1-ribosomal protein S3 in vitro and in vivo.
Many proteins with poor transduction efficiency were reported to be delivered to cells by fusion with protein transduction domains (PTDs). In this study, we investigated the effect of levosulpiride on the transduction of PEP-1 ribosomal protein S3 (PEP-1-rpS3), and examined its influence on the stimulation of the therapeutic properties of PEP-1-rpS3. PEP-1-rpS3 transduction into HaCaT human keratinocytes and mouse skin was stimulated by levosulpiride in a manner that did not directly affect the cell viability. Following 12-O-tetradecanoylphorbol- 13-acetate (TPA)-induced inflammation in mice, levosulpiride alone was ineffective in reducing TPA-induced edema and in inhibiting the elevated productions of inflammatory mediators and cytokines, such as cyclooxygenase-2, inducible nitric oxide synthase, interleukin-6 and -1β, and tumor necrosis factor- α. Anti-inflammatory activity by PEP-1-rpS3 + levosulpiride was significantly more potent than by PEP-1-rpS3 alone. These results suggest that levosulpiride may be useful for enhancing the therapeutic effect of PEP-1-rpS3 against various inflammatory diseases. [BMB reports 2011; 44(5): 329-334].


[Genetic engineering approaches to the study of insulin-dependent diabetes mellitus markers].
In the present study, gene-engineering producers for proinsulin and peptide fragments of glutamic acid decarboxylase (GAD), the main autoantigens of islet cells responsible for development of insulin-dependent diabetes mellitus (IDDM), were prepared. Basing on the obtained antigens. ELISA was developed to determine the autoantibodies in sera of patients. Sera from the following two groups of IDDM patients were studied: 1) adult patients with recently developed IDDM before insulinotherapy, and 2) adult patients with long-lasting IDDM with associated complications. Insulin/proinsulin antibodies were detected in 20% patients of group 1 and 41.7% patients of group 2. In sera from IDDM patients, antibodies to two GAD fragments containing amino acid sequences 1-80 and 151-585 were also detected. 16% of sera from patients with recently developed IDDM and 37.5% of sera from patients with long-lasting IDDM reacted with N-terminal GAD fragment. 12% of sera from group 1 and 45.8% of sera from group 2 reacted with central-C-terminal GAD fragment. The rate of sera of IDDM patients with detected antibodies in this study was some lower than that described in the literature.


Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1alpha-hydroxyvitamin D3-26,23-lactone.
TEI-9647 antagonizes vitamin D receptor (VDR) mediated genomic actions of 1alpha,25(OH)2D3 in human cells but is agonistic in rodent cells. The presence of Cys403, Cys410 or of both residues in the C-terminal region of human VDR (hVDR) results in antagonistic action of this compound. In the complexes of TEI-9647 with wild-type hVDR (hVDRwt) and H397F hVDR, TEI-9647 functions as an antagonist and forms a covalent adduct with hVDR according to MALDI-TOF MS. The crystal structures of complexes of TEI-9647 with rat VDR (rVDR), H305F hVDR and H305F/H397F hVDR showed that the agonistic activity of TEI-9647 is caused by a hydrogen-bond interaction with His397 or Phe397 located in helix 11. Both biological activity assays and the crystal structure of H305F hVDR complexed with TEI-9647 showed that the interaction between His305 and TEI-9647 is crucial for antagonist activity. This study indicates the following stepwise mechanism for TEI-9647 antagonism. Firstly, TEI-9647 forms hydrogen bonds to His305, which promote conformational changes in hVDR and draw Cys403 or Cys410 towards the ligand. This is followed by the formation of a 1,4-Michael addition adduct between the thiol (-SH) group of Cys403 or Cys410 and the exo-methylene group of TEI-9647.


Is maternal periconceptional smoking associated with 2D:4D digit ratio in their children?
The 2nd--4th finger ratio (2D:4D) has been proposed as a potential indicator of greater androgen exposure during fetal development. Maternal periconceptional smoking may alter the homeostasis of fetal androgens, which could in turn result in differential development of 2D:4Ds in utero. The aim of the present study was to assess the effect of maternal periconceptional smoking (i.e. 1 year before through the first trimester of pregnancy) on the 2D:4D of children within The Maternal-Infant Research on Environmental Chemicals (MIREC) study. Maternal smoking history was obtained through questionnaires during the first trimester of pregnancy in 2001 women from 10 cities across Canada. The periconceptional smoking prevalence was 12%. A follow-up study was conducted to measure growth and development up to 5 years of age in a subsample of some 800 MIREC children (MIREC-CD Plus), and digital pictures of the ventral surface of both hands were obtained in mothers and children (2-5 years). The 2D:4D was calculated as the ratio of the 2nd and 4th fingers of each hand. Boys had lower mean 2D:4Ds compared with girls in both hands. Age and maternal 2D:4D were strong determinants of the children's 2D:4D, however, the mean 2D:4D did not differ among children whose mothers had smoked during the periconceptional period compared with those who had not, irrespective of sex. In conclusion, we did not find an association between maternal periconceptional smoking and children's 2D:4D, although the smoking prevalence was low.


Bladder Rupture During ECT.
We report a case of intraperitoneal bladder rupture during electroconvulsivee therapy. We consider that the likely cause of this complication was powerful abdominal muscle contraction, during an unmodified seizure, on a bladder distended by failure to void urine before treatment and the anticholinergic effects of medication. The literature is reviewed, a similar case is discussed, and we make recommendations for the prevention of this complication.


The pseudorabies virus UL28 protein enters the nucleus after coexpression with the herpes simplex virus UL15 protein.
Herpesvirus DNA is packaged into capsids in the nuclei of infected cells in a process requiring at least six viral proteins. Of the proteins required for encapsidation of viral DNA, UL15 and UL28 are the most conserved among herpes simplex virus type 1 (HSV), varicella-zoster virus, and equine herpesvirus 1. The subcellular distribution of the pseudorabies virus (PRV) UL28 protein was examined by in situ immunofluorescence. UL28 was present in the nuclei of infected cells; however, UL28 was limited to the cytoplasm in the absence of other viral proteins. When cells expressing variant forms of UL28 were infected with a PRV UL28-null mutant, UL28 entered the nucleus, provided the carboxyl-terminal 155 amino acids were present. Additionally, PRV UL28 entered the nucleus in cells infected with HSV. Two HSV packaging proteins were tested for the ability to affect the subcellular distribution of UL28. Coexpression of HSV UL15 enabled PRV UL28 to enter the nucleus in a manner that required the carboxyl-terminal 155 amino acids of UL28. Coexpression of HSV UL25 did not affect the distribution of UL28. We propose that an interaction between UL15 and UL28 facilitates the transport of a UL15-UL28 complex to the infected-cell nucleus.


Hematopoietic stem cell graft manipulation as a mechanism of immunotherapy.
Hematopoietic stem cell transplants (SCT) are used in the treatment of neoplastic diseases, in addition to congenital, autoimmune, and inflammatory disorders. Both autologous and allogeneic SCT are used, depending on donor availability and the type of disease being treated, resulting in different morbidity and outcomes. In both types of SCT, immune regulation via graft manipulation is being studied, although with highly different targeted outcomes. In general, autologous SCT have lower treatment-related morbidity and mortality, but a higher incidence of tumor relapse, and graft manipulation targets immune augmentation and/or the reduction of immune tolerance. In contrast, allogeneic SCT have a higher incidence of treatment-related morbidity and mortality and a significantly longer time of disease progression, and the targeted outcomes or graft manipulation focus on a reduction in graft versus host disease (GVHD). One source of the increased relapse rate and shorter overall survival (OS) following high dose chemotherapy (HDT) and autologous SCT is the immune tolerance that limits host response, both innate and antigen (Ag) specific, against the tumor. The immune tolerance that is observed is due in part to the tumor burden and prior cytotoxic therapy. Therefore, graft manipulation, as an adjuvant therapeutic approach in autologous SCT, is primarily focused on non-specific or specific immune augmentation using cytokines and vaccines. Recently, manipulation of the infused product as a form of cellular therapy has begun to also focus on approaches to reduce immune tolerance found in transplant patients, both prior to and following HDT and SCT. To this end, graft manipulation to reduce the presence of Fas Ligand (FasL)-expressing cells or interleukin (IL)10 and tumor growth factor (TGF)beta production has been proposed. In contrast to autologous transplantation, graft manipulation during allogeneic transplantation is used extensively. This includes limiting the infusion of T cells within the product or as a donor leukocyte infusion (DLI), resulting in a reduction in GVHD and the induction of long-term survivors. Indeed, allogeneic SCT provide the only curative therapy for patients with chronic myelogenous leukemia (CML), refractory acute leukemia, and myelodysplasia. The curative potential of allogeneic SCT is reduced, however, by the development of GVHD, a potentially lethal T-cell-mediated immune response targeting host tissues [Int. Arch. Allergy Immunol. 102 (1993) 309, J. Exp. Med. 183 (1996) 589]. The morbidity and mortality associated with GVHD limit this technology, resulting focus on those patients who have no alternative therapeutic options or who have advanced disease. Thus, allogeneic SCT provide one of the few statistically supported demonstrations of therapeutic efficacy by T cells (comparison of allogeneic to autologous transplantation). In contrast to autologous transplantation, control of GVHD following allogeneic SCT focuses on immune suppression and the induction of tolerance. Here too, graft manipulation is appropriate, and there are numerous studies of T-cell depletion to reduce GVHD, with or without the isolation and infusion of T cells as DLI. Additional strategies are examining the isolation and infusion of T cells with graft versus leukemia (GVL) activity to reduce GVHD and/or the infusion of genetically manipulated and/or selected cellular populations (monocytes or dendritic cells (DC)) to induce tolerance. Therefore, depending upon the type of transplant, the goals associated with graft manipulation can be radically different. In this review, we emphasize using graft manipulation to regulate immune tolerance and anergy in association with SCT. Although this paper focuses on hematopoietic SCT, it should be noted that these strategies are relevant to conditions other than neoplastic and congenital diseases, including solid organ transplants, and autoimmune and inflammatory diseases.


Abnormal lipid composition of the red cell membrane in congenital dyserythropoietic anemia type II (HEMPAS).
The lipids derived from the erythrocytes of two siblings with clinical congenital dyserythropietic anemia Type II (CDA-II) and one sibling without clinical evidence of CDA-II underwent a detailed analysis. The total phospholipids, total cholesterol, and cholesterol: phosphate ratio were normal in all siblings. In the two clinically affected siblings there was a significant increase in the phosphatidyl choline with a concomitant decrease in the other phospholipids. The fatty acids of phosphatidyl choline from the CDA-II erythrocytes were normal. The total gylcosphingolipids were increased in all siblings. The glycosphingolipids, di- , tri-, and tetrahexosyl ceramides were increased 1.5- to 10-fold over controls in the clinically affected siblings. The increases were present but less striking in the clinically unaffected sibling. Gluococerebroside was not significantly increased in any of the siblings. The possible causes and significance of the lipid changes are discussed.


A double-blind crossover study of cinromide versus placebo in epileptic outpatients with partial seizures.
Cinromide was evaluated versus placebo as add-on therapy in a double-blind crossover study in epileptic outpatients with partial seizures at three sites. Four-week base lines were used before, between, and after the two 12-week treatment periods of the crossover. An operational definition was used to classify each partial seizure as Type A, B, or C. Doses of concurrent antiepileptic drugs were adjusted to maintain pretreatment therapeutic plasma levels. Doses of cinromide ranged from 1,200 to 4,800 mg/day, depending on patient response. Seven patients were withdrawn from the study because of adverse experiences (two receiving placebo and five receiving cinromide). Twenty-eight patients completed the entire 36-week study. A decrease in the average frequency of seizures/week was observed in 12 patients receiving cinromide and in 16 patients receiving placebo. The median frequencies with cinromide and placebo were 3.3 and 2.9 seizures/week, respectively (median initial base-line frequency 3.5 seizures/week for all 28 patients). Although patients were randomly assigned to receive either cinromide or placebo first, the median base-line seizure frequency was greater at the start of the first treatment period in the cinromide group (4.3 versus 2.5 seizures/week) and greater at the start of the second treatment period in the placebo group (3.8 versus 1.4). The median seizure frequency in each higher group decreased with treatment, whereas it increased in each of the lower groups. This study did not demonstrate a beneficial effect of cinromide over placebo for Type A, B, or C partial seizures. The data suggested the presence of an oscillation of seizure frequency in our population of epileptic patients having partial seizures, as well as a placebo effect. No significant carry-over effects were observed. Cinromide has previously been shown to have significant antiepileptic activity in various animal models of epilepsy. The lack of an antiepileptic response to cinromide in humans may have been due to factors other than species differences but indicates that a positive results of a drug in animal models is not the sole factor necessary to predict beneficial antiepileptic activity in humans.


Adenotonsillectomy improves slow-wave activity in children with obstructive sleep apnoea.
The aim of the present study was to estimate slow-wave activity (SWA), a marker of sleep homeostasis, in children with obstructive sleep apnoea (OSA) before and after adenotonsillectomy (AT) compared with untreated OSA children (comparison group). 14 children with OSA (mean ± sd age 6.4 ± 2.5 yrs; apnoea-hypopnoea index (AHI) 10.0 ± 10.3 events·h⁻¹) who underwent AT were consecutively recruited to the study. The comparison group comprised six retrospectively recruited children (age 5.4 ± 2.2 yrs; AHI 9.4 ± 7.6 events·h⁻¹) with OSA that did not undergo treatment. Electroencephalogram (derivation C3/A2) was analysed using spectral and waveform analysis to determine SWA energy and slow-wave slope. The same procedure was repeated 5.4 and 19 months later for the AT and comparison groups, respectively. AT improved respiration without a change in duration of sleep stages. Following AT, >50% elevation of SWA during the first two sleep cycles (p<0.01) and a more physiological decay of SWA across the night (p<0.0001) were noted. The slow-wave slope increased by >30% following AT (p<0.03). No significant changes were found in SWA in the comparison group. Sleep homeostasis is considerably impaired in pre-pubescent children with OSA. AT restores more physiological sleep homeostasis in children with OSA. SWA analysis may provide a useful addition to standard sleep-stage analyses in children with OSA.


Hepatitis C virus interacts with human platelet glycoprotein VI.
Hepatitis C virus (HCV) interacts with human platelets in vivo as a potential transport of infectious virions to the target liver. The binding of native viral particles with the platelet membrane glycoprotein VI (GPVI) was analysed. A consistent interaction between HCV from plasma or after purification by two different methods and the recombinant extracellular immunoglobulin (Ig)-like domains of human GPVI (hD1D2) was observed with two independent experimental approaches: pull-down and ELISA assays. Between 2 and 7 % of HCV particles were specifically bound to hD1D2. The binding was inhibited by an anti-hD1D2 in a dose-dependent manner. Human D1D2 interaction with HCV was significantly higher than the murine D1D2, supporting the specificity of the interaction and to the single human domains (D1 and D2), suggesting that both Ig-like domains of the molecule are required for efficient binding. GPVI may be a platelet surface ligand for HCV playing a role in viral transport and persistence.


Experimental and numerical investigation on soft tissue dynamic response due to turbulence-induced arterial vibration.
Peripheral arterial occlusive disease is a serious cardiovascular disorder. The arterial occlusion leads to turbulent flow and arterial sound generation on the inner vessel wall. Stenosis-induced vibro-acoustic waves propagate through the surrounding soft tissues and reach the skin surface. In this study, the feasibility of noninvasive acoustic detection of the peripheral arterial stenosis is investigated using the vibration responses by means of experimental and computational models. Latex rubber tube is used to model the artery, and it is surrounded by a tissue mimicking phantom made of bovine gelatin. Vibration responses on phantom surface are measured using laser Doppler vibrometer, and computational results are obtained performing modal analysis. Experimental findings and computational results showed well agreement in terms of spectral content and vibration amplitudes. The effects of various stenosis severities, flow rates, and phantom thicknesses on the vibration responses are investigated from diagnostic perspective. Stenosis severities greater than 70% resulted in a considerable increase in vibration amplitudes. The structural mode shapes of the tissue phantom are dominant between 0 and 100 Hz, suppressing the signals generated by the stenosis. The optimum range of frequency for acoustic stenosis detection is concluded to be between 200 and 500 Hz, particularly around 300 Hz. Graphical abstract .


Job preferences for medical students in China: A discrete choice experiment.
Although the number of medical workers has increased rapidly, its scarcity in rural areas remains a serious problem in China. This study aimed to investigate medical students' stated preferences when choosing a job, so as to assist policy makers with designing alternative interventions to address the unbalanced distribution of the health workforce in China.A discrete choice experiment (DCE) was conducted to elicit the job preferences of final year medical students. Attributes include work location, hospital type, monthly income, bianzhi (which can be loosely regarded as state administrative staffing), work environment, Training and career development opportunity. This study was carried out during April to June 2017 in 4 medical universities in Shandong Province, China. Mixed logit models were used to analyze the relative importance of job attributes.A total of 519 medical students participated in the survey. All 6 attributes were statistically significant with the expected sign and demonstrated the existence of preference heterogeneity. In the main effects mixed logit model, working in the city and a superior working environment were most strongly associated with job preference. A relatively unexpected finding was the relatively lower utility of offering bianzhi in job preferences. Subgroup analysis showed that females and those who have an urban background were significantly willing to pay more for working in the city. The most preferred scenario for medical students was to select a better work environment job in a tertiary hospital in the city, which could offer 9000 CNY monthly, with sufficient training and career development opportunities and bianzhi.Both monetary and nonmonetary intervention could be considered by policy makers to attract medical students to work in rural areas in China. There exists preference heterogeneity on medical students' job preferences, which should also be taken into account in developing more effective policy incentive packages.


Differential regulation of extracellular signal-regulated protein kinases (ERKs) 1 and 2 by cAMP and dissociation of ERK inhibition from anti-mitogenic effects in rabbit vascular smooth muscle cells.
The inhibition of extracellular signal-regulated protein kinases (ERKs) is implicated in the negative regulation of vascular smooth muscle cell (VSMC) mitogenesis by cAMP-elevating agents and transforming growth factor beta(1) (TGF-beta(1)). These factors inhibited rabbit aortic VSMC mitogenesis induced by platelet-derived growth factor (PDGF)-BB by preventing the entry of cells into S-phase. cAMP-elevating agents partly inhibited the late phase (1-4 h) of activation of ERKs 1 and 2 induced by PDGF-BB without inhibiting the early phase of activity (5-15 min) and had no effect on activity induced by basic fibroblast growth factor (bFGF). In contrast, cAMP elevation caused a marked inhibition of early ERK activation induced by angiotensin II and thrombin. TGF-beta(1) had no inhibitory effect on ERK activation induced by PDGF-BB or bFGF. The inhibition of PDGF-BB-stimulated DNA synthesis by either forskolin/3-isobutyl-1-methylxanthine (IBMX) or TGF-beta(1) was not decreased when the agents were added up to 8 h after growth factor. In contrast, the selective ERK kinase inhibitor PD98059 was a weak inhibitor of DNA synthesis; a combination of PD98059 and forskolin/IBMX had an additive inhibitory effect on DNA synthesis. Forskolin/IBMX inhibited the growth factor-induced expression of c-myc mRNA and cyclin D(1) protein, and enhanced the protein expression of p27(kip1). TGF-beta(1) had no effect on the expression of c-myc or p27(kip1) and weakly attenuated the expression of cyclin D(1). These findings support the conclusion that the suppression of VSMC mitogenesis by cAMP and TGF-beta(1) is independent of ERK inhibition. Anti-mitogenic effects of cAMP might be primarily mediated by events in late G(1).


Reducing children's classroom sitting time using sit-to-stand desks: findings from pilot studies in UK and Australian primary schools.
This research examined the influence of sit-to-stand desks on classroom sitting time in primary school children. Pilot controlled trials with similar intervention strategies were conducted in primary schools in Melbourne, Australia, and Bradford, UK. Sit-to-stand desks replaced all standard desks in the Australian intervention classroom. Six sit-to-stand desks replaced a bank of standard desks in the UK intervention classroom. Children were exposed to the sit-to-stand desks for 9-10 weeks. Control classrooms retained their normal seated desks. Classroom sitting time was measured at baseline and follow-up using the activPAL3 inclinometer. Thirty UK and 44 Australian children provided valid activPAL data at baseline and follow-up. The proportion of time spent sitting in class decreased significantly at follow-up in both intervention groups (UK: -9.8 ± 16.5% [-52.4 ± 66.6 min/day]; Australian: -9.4 ± 10% [-43.7 ± 29.9 min/day]). No significant changes in classroom sitting time were observed in the UK control group, while a significant reduction was observed in the Australian control group (-5.9 ± 11.7% [-28.2 ± 28.3 min/day]). Irrespective of implementation, incorporating sit-to-stand desks into classrooms appears to be an effective way of reducing classroom sitting in this diverse sample of children. Longer term efficacy trials are needed to determine effects on children's health and learning.


Maternal and antenatal risk factors for stillbirths and neonatal mortality in rural Bangladesh: a case-control study.
To identify maternal and antenatal factors associated with stillbirths and neonatal deaths in rural Bangladesh. A prospective cohort study is being conducted to evaluate a maternal and child nutrition program in rural Bangladesh. Cases were all stillbirths and neonatal deaths that occurred in the cohort between March 7, 2011 and December 30, 2011. Verbal autopsies were used to determine cause of death. For each case, four controls were randomly selected from cohort members alive at age 3-months. Multivariable logistic regression was used to identify factors associated with these deaths. Overall, 112 adverse pregnancy outcomes (44 stillbirths, 19/1,000 births; 68 neonatal deaths, 29/1,000 live births) were reported. Of the stillbirths 25 (56.8%) were fresh. The main causes of neonatal death were birth asphyxia (35%), sepsis (28%) and preterm birth (19%). History of bleeding during pregnancy was the strongest risk factor for stillbirths (adjusted odds ratio 22.4 [95% confidence interval 2.5, 197.5]) and neonatal deaths (adjusted odds ratio 19.6 [95% confidence interval 2.1, 178.8]). Adequate maternal nutrition was associated with decreased risk of neonatal death (adjusted odds ratio 0.4 [95% confidence interval 0.2, 0.8]). Identifying high-risk pregnancies during gestation and ensuring adequate antenatal and obstetric care needs to be a priority for any community-based maternal and child health program in similar settings.


Fifteen-minute consultation: Vaccine-hesitant parents.
Vaccination is a proven, highly effective intervention to protect against potentially serious infectious diseases. UK vaccine uptake rates are high overall, but considerable variation exists within and between districts. The main reason for under vaccination is difficulty accessing vaccination services for practical or logistical reasons. While some parents decline specific vaccines, only a small minority decline them all. It is unsurprising that many parents have questions about vaccination, but most are easily addressed. This article provides practical guidance on how to engage effectively with parents with the ultimate aim of supporting informed vaccination decisions. The focus will be on conversations with parents whose concerns make them unsure whether to accept vaccination or who have previously delayed or declined vaccines. In view of recent outbreaks of measles, the example question concerns MMR (measles, mumps and rubella) vaccine. Although conversations with some parents, especially those who are determinedly anti-vaccine, can be uncomfortable, even challenging, it is important to offer all parents the opportunity to discuss their concerns. Even though advice may go unheeded or even be unwelcome, parents can change their minds about previous decisions. Health professionals and the National Health Service are trusted sources of advice about vaccinations and have a responsibility to ensure parents are appropriately informed.


[A prospective study on the incidence of missed injuries in trauma patients].
Missed injuries in trauma patients are injuries not identified during a primary and secondary trauma survey (Advanced Trauma Life Support, ATLS). These injuries are important because of the delay in correct treatment. There is a particularly important sub-group consisting of clinically significant missed injuries, which may cause serious complications in the patient or even death. A prospective study on missed injuries and clinically significant missed injuries. The study includes all trauma patients older than 16 years admitted to the resuscitation area or who had died during the first 24 hours. We collected injuries, time of their diagnosis and their treatment for each patient. For injuries detected later than 24 hours (i.e. missed injuries) we specified whether it was a clinically significant missed injury and its possible cause. From March of 2006 to January of 2007, 122 trauma patients were recorded with a mean Injury Severity Store of 20 +/- 15.8. Of those, 40.3% had some missed injury, fractures being the most frequent miss (42.7%), followed by chest and abdominal injuries. A clinically significant injury (38.7% of all missed injuries) were found in 17% of trauma patients, the most frequent being spine, abdominal and chest injuries. There is a statistically significant relationship between the presence of missed injuries, high ISS and intubation before or after admission to hospital. The rate of missed injuries and clinically significant missed injuries is high. Severe trauma patients and intubated patients have higher rates of missed injuries.


Increased metabolic rate in X-linked hypophosphatemic mice.
Hyp mice are a model for human X-linked hypophosphatemia, the most common form of vitamin D-resistant rickets. It has previously been observed that Hyp mice have a greater food consumption per gram body weight than do normal mice. This led to the search for some alteration in metabolism in Hyp mice. We found that oxygen consumption was significantly higher in Hyp mice than in normal C57BL/6J mice and this was accompanied by an increased percentage of cardiac output being delivered to organs of heat production (liver and skeletal muscle), to the skin, and to bone and a decreased percentage to the gastrointestinal tract of Hyp mice. The increased oxygen consumption in Hyp mice was not associated with increased plasma free T4 levels and was not affected by alterations in plasma phosphate produced by a low phosphate diet. The cause of the increased oxygen consumption is not known, and the role that this change and reported changes in distribution of cardiac output may play in the development of X-linked hypophosphatemia is also unknown. Study of the cardiovascular and thermoregulatory systems in Hyp mice should help increase understanding of the underlying mechanisms of this disease.


Cascades between Light and Heavy Fermions in the Normal State of Magic-Angle Twisted Bilayer Graphene.
We present a framework for understanding the cascade transitions and the Landau level degeneracies of twisted bilayer graphene. The Coulomb interaction projected onto narrow bands causes the charged excitations at an integer filling to disperse, forming new bands. If the excitation moves the filling away from the charge neutrality point, then it has a band minimum at the moiré Brillouin zone center with a small mass that compares well with the experiment; if towards the charge neutrality point, then it has a much larger mass and a higher degeneracy. At a nonzero density away from an integer filling the excitations interact. The system on the small mass side has a large bandwidth and forms a Fermi liquid. On the large mass side the bandwidth is narrow, the compressibility is negative and the Fermi liquid is likely unstable. This explains the observed sawtooth features in compressibility, the Landau fans pointing away from charge neutrality and their degeneracies. The framework sets the stage for superconductivity at lower temperatures.


High serotonin levels during brain development alter the structural input-output connectivity of neural networks in the rat somatosensory layer IV.
Homeostatic regulation of serotonin (5-HT) concentration is critical for "normal" topographical organization and development of thalamocortical (TC) afferent circuits. Down-regulation of the serotonin transporter (SERT) and the consequent impaired reuptake of 5-HT at the synapse, results in a reduced terminal branching of developing TC afferents within the primary somatosensory cortex (S1). Despite the presence of multiple genetic models, the effect of high extracellular 5-HT levels on the structure and function of developing intracortical neural networks is far from being understood. Here, using juvenile SERT knockout (SERT(-/-)) rats we investigated, in vitro, the effect of increased 5-HT levels on the structural organization of (i) the TC projections of the ventroposteromedial thalamic nucleus toward S1, (ii) the general barrel-field pattern, and (iii) the electrophysiological and morphological properties of the excitatory cell population in layer IV of S1 [spiny stellate (SpSt) and pyramidal cells]. Our results confirmed previous findings that high levels of 5-HT during development lead to a reduction of the topographical precision of TCA projections toward the barrel cortex. Also, the barrel pattern was altered but not abolished in SERT(-/-) rats. In layer IV, both excitatory SpSt and pyramidal cells showed a significantly reduced intracolumnar organization of their axonal projections. In addition, the layer IV SpSt cells gave rise to a prominent projection toward the infragranular layer Vb. Our findings point to a structural and functional reorganization of TCAs, as well as early stage intracortical microcircuitry, following the disruption of 5-HT reuptake during critical developmental periods. The increased projection pattern of the layer IV neurons suggests that the intracortical network changes are not limited to the main entry layer IV but may also affect the subsequent stages of the canonical circuits of the barrel cortex.


Atrial fibrillation is not an independent predictor of outcome in patients with aortic stenosis.
To examine the prognostic significance of atrial fibrillation (AF) versus sinus rhythm (SR) on the management and outcomes of patients with severe aortic stenosis (AS). 1847 consecutive patients with severe AS (aortic valve area ≤1.0 cm2 and aortic valve systolic mean Doppler gradient ≥40 mm Hg or peak velocity ≥4 m/s) and left ventricular ejection fraction ≥50% were identified. The independent association of AF and all-cause mortality was assessed. Age was 76±11 years and 46% were female; 293 (16%) patients had AF and 1554 (84%) had SR. In AF, 72% were symptomatic versus 71% in SR. Survival rate at 5 years for AF (41%) was lower than SR (65%) (age- and sex-adjusted HR=1.66 (1.40-1.98), p<0.0001). In multivariable analysis, factors associated with mortality included age (HR per 10 years=1.55 (1.42-1.69), p<0.0001), dyspnoea (HR=1.58 (1.33-1.87), p<0.0001), ≥ moderate mitral regurgitation (HR=1.63 (1.22-2.18), p=0.001), right ventricular systolic dysfunction (HR=1.88 (1.52-2.33), p<0.0001), left atrial volume index (HR per 10 mL/m2=1.13 (1.07-1.19), p<0.0001) and aortic valve replacement (AVR) (HR=0.44 (0.38-0.52), p<0.0001). AF was not a predictor of mortality independent of variables strongly correlated HR=1.02 (0.84-1.25), p=0.81). The 1-year probability of AVR following diagnosis of severe AS was lower in AF (49.8%) than SR (62.5%) (HR=0.73 (0.62-0.86), p<0.001); among patients with AF not referred for AVR, symptoms were frequently attributed to AF instead of AS. AF was associated with poor prognosis in patients with severe AS, but apparent differences in outcomes compared with SR were explained by factors other than AF including concomitant cardiac abnormalities and deferral of AVR due to attribution of cardiac symptoms to AF.


Biochemical effects of petroleum exposure in hornyhead turbot (Pleuronichthys verticalis) exposed to a gradient of sediments collected from a natural petroleum seep in CA, USA.
Concentrations of serum/plasma estradiol, biliary fluorescent aromatic compounds (FACs), levels of hepatic CYP1A expression, and DNA damage were measured in sexually mature hornyhead turbot (Pleuronichthys verticalis) exposed in the laboratory for 7 days to a gradient of sediments collected from a natural petroleum seep in the Santa Barbara Channel. Coal oil point (COP) sediments were homogenized and divided into four treatments containing 0 (sediment from the Orange County Sanitation District's reference location), 33, 66, and 100% (COP) sediments. Sediment concentrations of 20 PAHs ranged from below the detection limit for the 0% COP sediment treatments to 105 microg/g in the 100% treatments with lower molecular weight compounds predominating. Concentrations of biliary FACs were not linear with COP treatment but levels of hepatic DNA damage increased linearly with increasing concentrations of high molecular weight PAHs. Hepatic CYP1A expression was elevated only in the 100% treatments. A reduction of plasma estradiol in male and female fish was observed in all COP exposures. These results demonstrate that acute sediment-only exposure of flatfish to naturally-derived PAHs elicits alterations in biochemical endpoints indicative of PAH bioavailability and adverse effects with different sensitivities.


Using RNA interference to identify specific modifiers of a temperature-sensitive, embryonic-lethal mutation in the Caenorhabditis elegans ubiquitin-like Nedd8 protein modification pathway E1-activating gene rfl-1.
The essential Caenorhabditis elegans gene rfl-1 encodes one subunit of a heterodimeric E1-activating enzyme in the Nedd8 ubiquitin-like protein conjugation pathway. This pathway modifies the Cullin scaffolds of E3 ubiquitin ligases with a single Nedd8 moiety to promote ligase function. To identify genes that influence neddylation, we used a synthetic screen to identify genes that, when depleted with RNAi, enhance or suppress the embryonic lethality caused by or198ts, a temperature-sensitive (ts) mutation in rfl-1. We identified reproducible suppressor and enhancer genes and employed a systematic specificity analysis for each modifier using four unrelated ts embryonic lethal mutants. Results of this analysis highlight the importance of specificity controls in identifying genetic interactions relevant to a particular biological process because 8/14 enhancers and 7/21 suppressors modified lethality in other mutants. Depletion of the strongest specific suppressors rescued the early embryonic cell division defects in rfl-1(or198ts) mutants. RNAi knockdown of some specific suppressors partially restored Cullin neddylation in rfl-1(or198ts) mutants, consistent with their gene products normally opposing neddylation, and GFP fusions to several suppressors were detected in the cytoplasm or the nucleus, similar in pattern to Nedd8 conjugation pathway components in early embryonic cells. In contrast, depletion of the two strongest specific enhancers did not affect the early embryonic cell division defects observed in rfl-1(or198ts) mutants, suggesting that they may act at later times in other essential processes. Many of the specific modifiers are conserved in other organisms, and most are nonessential. Thus, when controlled properly for specificity, modifier screens using conditionally lethal C. elegans mutants can identify roles for nonessential but conserved genes in essential processes.


Prevalence and outcomes of co-infection and superinfection with SARS-CoV-2 and other pathogens: A systematic review and meta-analysis.
The recovery of other pathogens in patients with SARS-CoV-2 infection has been reported, either at the time of a SARS-CoV-2 infection diagnosis (co-infection) or subsequently (superinfection). However, data on the prevalence, microbiology, and outcomes of co-infection and superinfection are limited. The purpose of this study was to examine the occurrence of co-infections and superinfections and their outcomes among patients with SARS-CoV-2 infection. We searched literature databases for studies published from October 1, 2019, through February 8, 2021. We included studies that reported clinical features and outcomes of co-infection or superinfection of SARS-CoV-2 and other pathogens in hospitalized and non-hospitalized patients. We followed PRISMA guidelines, and we registered the protocol with PROSPERO as: CRD42020189763. Of 6639 articles screened, 118 were included in the random effects meta-analysis. The pooled prevalence of co-infection was 19% (95% confidence interval [CI]: 14%-25%, I2 = 98%) and that of superinfection was 24% (95% CI: 19%-30%). Pooled prevalence of pathogen type stratified by co- or superinfection were: viral co-infections, 10% (95% CI: 6%-14%); viral superinfections, 4% (95% CI: 0%-10%); bacterial co-infections, 8% (95% CI: 5%-11%); bacterial superinfections, 20% (95% CI: 13%-28%); fungal co-infections, 4% (95% CI: 2%-7%); and fungal superinfections, 8% (95% CI: 4%-13%). Patients with a co-infection or superinfection had higher odds of dying than those who only had SARS-CoV-2 infection (odds ratio = 3.31, 95% CI: 1.82-5.99). Compared to those with co-infections, patients with superinfections had a higher prevalence of mechanical ventilation (45% [95% CI: 33%-58%] vs. 10% [95% CI: 5%-16%]), but patients with co-infections had a greater average length of hospital stay than those with superinfections (mean = 29.0 days, standard deviation [SD] = 6.7 vs. mean = 16 days, SD = 6.2, respectively). Our study showed that as many as 19% of patients with COVID-19 have co-infections and 24% have superinfections. The presence of either co-infection or superinfection was associated with poor outcomes, including increased mortality. Our findings support the need for diagnostic testing to identify and treat co-occurring respiratory infections among patients with SARS-CoV-2 infection.


[The health status of children in the new type of educational institutions].
The impact of a teaching process on the working capacity of schoolchildren at new-type educational establishments (lycées, colleges), as well as at general educational schools was studied. There was a correlation between the pupils' health status and immunity and the level of educational workload, the air environment of institutional rooms, regimens.


Stance and Swing Detection Based on the Angular Velocity of Lower Limb Segments During Walking.
Lower limb exoskeletons require the correct support magnitude and timing to achieve user assistance. This study evaluated whether the sign of the angular velocity of lower limb segments can be used to determine the timing of the stance and the swing phase during walking. We assumed that stance phase is characterized by a positive, swing phase by a negative angular velocity. Thus, the transitions can be used to also identify heel-strike and toe-off. Thirteen subjects without gait impairments walked on a treadmill at speeds between 0.5 and 2.1 m/s on level ground and inclinations between -10 and +10°. Kinematic and kinetic data was measured simultaneously from an optical motion capture system, force plates, and five inertial measurement units (IMUs). These recordings were used to compute the angular velocities of four lower limb segments: two biological (thigh, shank) and two virtual that were geometrical projections of the biological segments (virtual leg, virtual extended leg). We analyzed the reliability (two sign changes of the angular velocity per stride) and the accuracy (offset in timing between sign change and ground reaction force based timing) of the virtual and biological segments for detecting the gait phases stance and swing. The motion capture data revealed that virtual limb segments seem superior to the biological limb segments in the reliability of stance and swing detection. However, increased signal noise when using the IMUs required additional rule sets for reliable stance and swing detection. With IMUs, the biological shank segment had the least variability in accuracy. The IMU-based heel-strike events of the shank and both virtual segment were slightly early (3.3-4.8% of the gait cycle) compared to the ground reaction force-based timing. Toe-off event timing showed more variability (9.0% too early to 7.3% too late) between the segments and changed with walking speed. The results show that the detection of the heel-strike, and thus stance phase, based on IMU angular velocity is possible for different segments when additional rule sets are included. Further work is required to improve the timing accuracy for the toe-off detection (swing).


Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([124I]IPAG).
Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors. [124I]IPAG was synthesized from a tributyltin precursor dissolved in ethanol using chloramine-T as oxidant. Purity was analyzed using HPLC. In vitro and in vivo studies were performed using the breast cancer cell line MCF-7. Competitive inhibition studies were performed using haloperidol and cold IPAG. Tumors were established in athymic nude mice by injecting 107 cells subcutaneously. Mice were imaged on micro-positron emission tomography (PET) at 4, 24, 48, 72, and 144 h post i.v. injection. Biodistribution studies were performed at same time points. In vivo tracer dilution studies were performed using excess of IPAG and haloperidol. The efficacy of [124I]IPAG to image tumors was evaluated in LNCaP tumor-bearing mice as well. [124I]IPAG was synthesized in quantitative yield and in vitro studies indicated that [124I]IPAG binding was specific to S1R. PET imaging studies in MCF7 tumor-bearing mice reveal that [124I]IPAG accumulates in tumor and is preferentially retained while clearing from non-target organs. The tumor to background increases with time, and tumors could be clearly visualized starting from 24 h post administration. Similar results were obtained in mice bearing LNCaP tumors. In vivo tracer dilution studies showed that the uptake of [124I]IPAG could be competitively inhibited by excess of IPAG and haloperidol. [124I]IPAG was synthesized successfully in high yields, and in vitro and in vivo studies demonstrate specificity of [124I]IPAG. [124I]IPAG shows specific accumulation in tumors with increasing tumor to background ratio at later time points and therefore has high potential for imaging S1R-overexpressing cancers.


Stress and vascular responses: atheroprotective effect of laminar fluid shear stress in endothelial cells: possible role of mitogen-activated protein kinases.
Atherosclerosis preferentially occurs in areas of turbulent blood flow and low fluid shear stress, whereas laminar blood flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent findings suggest a steady laminar blood flow decreases EC apoptosis and inhibits TNF-mediated EC activation. EC apoptosis or activation is suggested to be involved in plaque erosion, which may lead to platelet aggregation. TNF-alpha regulates gene expression in ECs, in part, by stimulating mitogen-activated protein (MAP) kinases, which phosphorylate transcription factors. We hypothesized that steady laminar flow inhibits cytokine-mediated activation of MAP kinases in ECs. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm(2)) on TNF-alpha-stimulated activity of three MAP kinases in human umbilical vein ECs (HUVEC): extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. TNF-alpha activated ERK1/2, JNK, and p38 maximally at 15 min in HUVEC. Pre-exposing HUVEC for 10 min to flow inhibited TNF-alpha activation of JNK, but showed no significant effect on ERK1/2 or p38 activation. Incubation of HUVEC with PD98059, a specific ERK1/2 inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Transfection studies with dominant-negative constructs of the protein kinase MEK5 suggested an important role for big mitogen-activated protein kinase 1 (BMK1) in flow-mediated regulation of EC activation by TNF-alpha. Understanding the mechanisms by which steady laminar flow regulates JNK activation by cytokines may provide insight into the atheroprotective mechanisms induced by laminar blood flow.


Social and Structural Drivers of Health and Transition to Adult Care.
Youth with chronic health conditions experience challenges during their transition to adult care. Those with marginalized identities likely experience further disparities in care as they navigate structural barriers throughout transition. This scoping review aims to identify the social and structural drivers of health (SSDOH) associated with outcomes for youth transitioning to adult care, particularly those who experience structural marginalization, including Black, Indigenous, and 2-spirit, lesbian, gay, bisexual, transgender, queer or questioning, and others youth. Medline, Embase, CINAHL, and PsycINFO were searched from earliest available date to May 2022. Two reviewers screened titles and abstracts, followed by full-text. Disagreements were resolved by a third reviewer. Primary research studying the association between SSDOH and transition outcomes were included. SSDOH were subcategorized as social drivers, structural drivers, and demographic characteristics. Transition outcomes were classified into themes. Associations between SSDOH and outcomes were assessed according to their statistical significance and were categorized into significant (P < .05), nonsignificant (P > .05), and unclear significance. 101 studies were included, identifying 12 social drivers (childhood environment, income, education, employment, health literacy, insurance, geographic location, language, immigration, food security, psychosocial stressors, and stigma) and 5 demographic characteristics (race and ethnicity, gender, illness type, illness severity, and comorbidity). No structural drivers were studied. Gender was significantly associated with communication, quality of life, transfer satisfaction, transfer completion, and transfer timing, and race and ethnicity with appointment keeping and transfer completion. Studies were heterogeneous and a meta-analysis was not possible. Gender and race and ethnicity are associated with inequities in transition outcomes. Understanding these associations is crucial in informing transition interventions and mitigating health inequities.


Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production.
The mobilization of bone marrow-derived cells (BMDC) to distant tissues before the arrival of disseminated tumor cells has been shown preclinically to facilitate metastasis through the establishment of metastatic niches. Primary tumor hypoxia has been demonstrated to play a pivotal role in the production of chemokines and cytokines responsible for the mobilization of these BMDCs, especially in breast cancer. Carbonic anhydrase IX (CAIX, CA9) expression is highly upregulated in hypoxic breast cancer cells through the action of hypoxia-inducible factor-1 (HIF1). Preclinical evidence has demonstrated that CAIX is required for breast tumor growth and metastasis; however, the mechanism by which CAIX exerts its prometastatic function is not well understood. Here, we show that CAIX is indispensable for the production of granulocyte colony-stimulating factor (G-CSF) by hypoxic breast cancer cells and tumors in an orthotopic model. Furthermore, we demonstrate that tumor-expressed CAIX is required for the G-CSF-driven mobilization of granulocytic myeloid-derived suppressor cells (MDSC) to the breast cancer lung metastatic niche. We also determined that CAIX expression is required for the activation of NF-κB in hypoxic breast cancer cells and constitutive activation of the NF-κB pathway in CAIX-depleted cells restored G-CSF secretion. Together, these findings identify a novel hypoxia-induced CAIX-NF-κB-G-CSF cellular signaling axis culminating in the mobilization of granulocytic MDSCs to the breast cancer lung metastatic niche.


Cross-reactivity between organ extracts of gnotobiotic mice and enterobacterial common antigen.
Organs of gnotobiotic mice were assessed for an Ag (CRA) which cross-reacts with common enterobacterial Ag(CA). To this end, extracts of homogenates of spleens, livers, paired kidneys and colons were examined for their capacities to engender humoral and cellular events in rabbits. The immjnogenicity of CRA in the rabbit cannot be predicted on the basis of CA hemagglutinin-inhibition studies alone. According to this parameter, CRA was present in mouse spleens, livers and paired kidneys but absent in colons. However, the identical preparations, including colons, primed rabbits to engender specific CA hemaglutinins after a single administration of enterobacterial CA. Also, spleens of these same rabbits were colonized with rosette-forming cells against sheep red blood cells treated with various enterobacterial sources of CA. These findings may account, in part, for the apparent refractiveness or equivocal response mice have to administered CA and infectious challenge.


[Smeglutide inhibits high glucose-induced proliferation of myocardial fibroblasts by downregulating TGFβ/Smad3 signaling].
To investigate the effect of semaglutide on high glucose-induced proliferation of cardiac fibroblasts (CFs) and explore its possible mechanism. Primary mouse CFs, identified by detecting vimentin expression, were stimulated with 25 mmol/L and treated with 5-20 nmol/L semaglutide, and the cell proliferation was examined with CKK-8 assay for concentration screening.Cultured CFs exposed to high glucose (25 mmol/L) were treated with 5 nmol/L semaglutide, and the changes in cell cycle were detected using Cell Cycle Staining Kit; The mRNA expressions of α-smooth muscle actin (α-SMA), transforming growth factor-β1(TGF-β1) and Smad3 were detected using RT-qPCR, and the levels of type Ⅰ collagen (CoLⅠ) and type Ⅲ collagen (CoLIII) in the cell cultures were determined with ELISA. Compared with the control cells, the CFs cultured in high glucose exhibited significantly enhanced proliferative activity (P<0.05) with increased percentage of S-phase cells.Semagutide treatment obviously inhibited high glucose-induced proliferation of the CFs (P<0.05) and reduced the percentage of S-phase cells.High glucose stimulation significantly increased the mRNA expressions of α-SMA, CoL Ⅰ and CoLIII in the cells (P<0.01), which were effectively lowered by semaglutide treatment (P<0.01).The expressions of TGF-β1 and Smad3 were significantly increased in high glucose-stimulated CFs (P<0.01) and were lowered by semaglutide treatment (P<0.01). Semaglutide can inhibit high glucose-induced proliferation and collagen synthesis in mouse CFs possibly by downregulating the TGFβ/Smad3 signaling pathway.