Cortisol secretion in response to metabolic and inflammatory challenges in dairy cows.
Cortisol in dairy cows is released in an episodic manner underlying a circadian rhythm. The involvement of cortisol in numerous adaptive processes to cope with adverse conditions such as pain and inflammation is well characterized. Recent studies described contradictory effects of nutrition and metabolism on the secretory pattern of cortisol. However, up to now, the direct effects of single metabolites during various metabolic conditions without the profound endocrine changes around parturition on the glucocorticoid secretion in dairy cows have not been described. The objective of this study was to investigate the effects of long-term (56-h) manipulated metabolic states, that is, manipulated plasma concentrations of glucose and β-hydroxybutyrate (BHBA), on the release of cortisol in midlactation dairy cows. Besides the concentration of cortisol at defined time points, its pulsatile secretory pattern was studied in combination with an acute immune challenge through an intramammary lipopolysaccharide (LPS) challenge. Twenty-five midlactation dairy cows were randomly assigned to 1 of 4 treatments (hyperinsulinemic hypoglycemic clamp [HypoG], hyperinsulinemic–euglycemic clamp [EuG], continuous infusion of BHBA [HyperB], or infusion of saline solution for the control group [Control). Different metabolic states induced by infusion treatments affected the characteristics of cortisol secretion (elevation of baseline [the HypoG and HyperB treatments] and decreased peak length [the HypoG treatment]; P < 0.05), whereas amplitude, peak interval, height, peak area, area under the curve (AUC) above the baseline cortisol concentration (AUCb), and the total AUC (AUCt) were not different between infusion treatments. The induced inflammatory response due to the intramammary LPS challenge at simultaneously maintained infusion treatments diminished the pulsatile nature of cortisol release, whereas AUCb (and AUCt, respectively) was lowest for the HypoG treatment compared with the HyperB and Control treatments (P < 0.05). This study indicates that single metabolites (glucose and BHBA) and their availability or turnover (in case of glucose) have a different impact on the regulation of cortisol secretion resulting in changes of its pulsatile release. Furthermore, cortisol release during intramammary inflammation was found to be greater in the HyperB, EuG, and Control treatments compared with the HypoG treatment (P < 0.05). This finding emphasizes the regulatory role of the current metabolic status on the cortisol release during inflammation.


Hanging manoeuver for a left hepatectomy using Glisson's approach with a focus on tape position in liver hilum.
Successful use of the hanging manoeuver during a hepatic resection requires the tape to be placed anatomically. The aim of this study is to describe the outcomes after variations in tape placement while using the hanging manoeuver during a left hepatectomy. A whole cohort in whom the hanging manoeuver was attempted for a left hepatectomy from March 2003 to October 2011 was divided chronologically into three groups based on the tape position in the hilum along the ligamentum venosum (LV); conventionally between the right and left Glisson's pedicles (group 1), at the ventral side of the LV (group 2), and at the dorsal side of the LV (group 3). Patient characteristics, operative outcomes and complications defined using Clavien's classification were compared. A total of 151 patients were enrolled in one of three groups: group 1 (n = 54), group 2 (n = 35), and group 3 (n = 62). The hanging tape was successfully positioned in all patients as planned in the three groups. In group 2 and 3, the hanging manoeuver was continuously applied during a parenchymal transection. The Glisson's pedicle injury during hilar dissection was more common in group 2 (%, 51.4 versus 5.6 in group 1 and 3.2 in group 3; P = 0.001). Group 3 showed a shorter median operative time (min, 151 versus 210 in group 1 and 220 in group 2; P = 0.001), a shorter median hospital stay (days, 7 versus 10 in group 1 and 2; P = 0.012) and a lower complication rate (%, 1.6 versus 13.0 in group 1 and 37.1 in group 2; P = 0.001) without any operative mortality, major morbidity, blood transfusion or reoperation. The hanging manoeuver had 100% feasibility with good outcomes during a left hepatectomy. The tape should be positioned to surround the left Glisson's pedicle and LV together as this helps to protect the caudate lobe.


A computational study on N2 adsorption in Cu-ZSM-5.
The present computational study investigates the adsorption of N(2) by Cu-ZSM-5, with particular regard to the interaction with pairs of Cu(+) ions, employing simple cluster models in the calculations. It shows that several interaction patterns between N(2) and couples of Cu(+) sites are possible within the Cu-ZSM-5 structure. In particular, when pairs of Cu(+) ions are located at opposite sides of ten-membered rings, in the region where linear and sinusoidal channels intersect each other, a quasi-linear Cu-N-N-Cu adsorption occurs. Although lattice restraints cause small deviations from linearity, such interaction turned out to be more favourable than other adsorption patterns within the Cu-ZSM-5 structure. The linearity of the Cu-N-N-Cu fragment and the relatively low concentration of the related sites cause a low extinction coefficient for the N-N IR stretching mode, which is usually detected with very low intensity or not detected at all. The results of the present calculations may explain the experimental evidence for a nearly IR-silent fraction of nitrogen strongly adsorbed in the Cu-ZSM-5 catalyst which, as shown in a previous work, is linearly related to the number of active sites for NO decomposition.


Organ Shortage: Can We Decrease the Demand?
The shortage of organs for transplant is a universal problem. The World Health Organization is urging every nation to seek self-sufficiency regarding their organ procurement program. Reaching self-sufficiency inevitably requires the provision of a well-developed deceased-donor organ procurement program. Most countries represented by the Middle East Society for Organ Transplantation still rely on living-donor organ donations. Some of these countries have been relatively successful in promoting deceased-donor donation as well. In our region, deceased-donor organs are recovered exclusively from patients who have been declared brain dead. However, with improvements in preventive and therapeutic interventions, the pool of potential brain dead donors is rapidly shrinking. This should, therefore, stimulate our interest in developing a program for recovering organs after cardiac death. However, increasing the pool of donors, even to optimal levels, may still not be enough to meet the growing demand. More resources must be invested in reducing the demand for organs. This is especially true in our region, where primary care programs aimed at slowing or containing disease progression that may lead to organ failure are lacking. This problem is compounded by limited access to such programs and, for that matter, limited access to even the most basic primary care. Continued efforts to increase the supply of donor organs must be pursued. At the same time, we must work to more effectively treat the diseases that could lead to end-stage renal disease and the increased demand for donor organs. A comprehensive approach to the problem of donor organ shortages in countries in the Middle East also must consider the relatively limited financial resources that are available.


Investigation of the response of bread wheat cultivars to salinity by using callus cultures.
In this research, the response of four bread wheat cultivars (Bal-Atilla, Marmara-86, Seyhan-95, and Panda) to different NaCl concentrations (25.6, 51.3, 77.0, 99.4,119.7 mM) were investigated by using callus cultures. In the experiment, callus induction rates (%) and callus weights in solid and liquid MS media, callus weights in liquid MS media with different NaCl concentrations and in liquid MS media free NaCl concentrations, and callus weights and regeneration rates in MS solid media with NaCl concentrations were studied. Callus induction rates and weights were significantly different among genotypes. Callus weights in liquid MS media were higher than those obtained in the MS solid media. Panda cv. had the highest callus weight in the liquid MS media. Callus weights significantly decreased due to increased NaCl stress. Residual effect of NaCl concentrations on Calli weights was significant. Callus weights decreased due to increasing residue effects of NaCl concentrations. There was no cultivar resistance to salinity, high salinity and very high salinity concentrations. However, Panda cv. was more tolerant cultivar at the light salinity concentrations. Gametoclonal regeneration could not be obtained.


Mechanisms of hepatic transport of drugs: implications for cholestatic drug reactions.
Hepatocellular and canalicular transport proteins are major determinants of the hepatic uptake and biliary excretion of xenobiotics and their metabolites. Recent advances in molecular cloning have resulted in the characterization of many of these transport systems. These advances have enabled the identification of a number of drugs that are substrates for the transporters, and it has facilitated studies of mechanisms of drug-induced cholestasis. This review summarizes the normal function of hepatobiliary transporters and their alteration by drugs or other foreign compounds. Although most of these investigations have been performed in animal models of drug-induced cholestasis, the application to human forms of drug-induced cholestasis is also discussed when possible. One important finding is that genetic polymorphisms can result in changes in drug transporter expression and function that could increase susceptibility to cholestatic drug reactions.


Computer-aided detection of prostate cancer in T2-weighted MRI within the peripheral zone.
In this paper we propose a prostate cancer computer-aided diagnosis (CAD) system and suggest a set of discriminant texture descriptors extracted from T2-weighted MRI data which can be used as a good basis for a multimodality system. For this purpose, 215 texture descriptors were extracted and eleven different classifiers were employed to achieve the best possible results. The proposed method was tested based on 418 T2-weighted MR images taken from 45 patients and evaluated using 9-fold cross validation with five patients in each fold. The results demonstrated comparable results to existing CAD systems using multimodality MRI. We achieved an area under the receiver operating curve (A z ) values equal to [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] for Bayesian networks, ADTree, random forest and multilayer perceptron classifiers, respectively, while a meta-voting classifier using average probability as a combination rule achieved [Formula: see text].


Distribution of beta 1 and beta 3 integrins in human fetal and adult kidney.
The distribution of beta 1 and beta 3 integrins was studied in fetal and adult human kidneys by indirect immunofluorescence microscopy. In the developing kidney, the cells of the undifferentiated metanephric blastema displayed strong cell surface-confined beta 1 integrin immunoreactivity, whereas the cells of primary vesicles and comma- and S-shaped bodies reacted more weakly. In mature fetal as well as adult glomeruli, beta 1 integrins were distinctly localized, apparently confining to the basal cell surfaces of endothelial cells and podocytes abutting the glomerular basement membrane. In adult proximal tubules, beta 1 integrin immunoreactivity was strictly confined to the basal aspect of the epithelial cells, being absent laterally, which is unusual for membrane proteins of polarized epithelial cells. A more diffuse overall immunoreactivity was seen in distal tubules and collecting ducts. The epithelial cells of developing proximal and distal tubules displayed an overall distribution of beta 1 integrins. In each case, talin immunoreactivity followed that of beta 1 integrins. Compared with beta 1 integrins, beta 3 integrins showed a more restricted distribution, and differences were seen in the reactions of mono- and polyclonal antibodies. In developing glomeruli, beta 3 integrin immunoreactivity was prominently seen in the cells of Bowman's capsule, possibly revealing the presence of vitronectin receptor. Solitary cells, that reacted also with antibodies to the platelet glycoprotein IIb, were consistently detected in fetal glomeruli, suggesting the presence of megakaryocytes. The results show that during nephrogenesis, beta 1 integrins become distinctly polarized both in glomerular endothelial cells and podocytes, as well as in the epithelial cells of proximal tubules.


Endotoxin tolerance variation over 24 h during porcine endotoxemia: association with changes in circulation and organ dysfunction.
Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-α, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Δ-values) was calculated for all time points. ΔTNF-α was employed as the principal marker of ET and lower ΔTNF-α values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-α and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-α values followed another time concentration curve than those in vivo. ΔTNF-α was at the lowest already at 6 h, followed by an increase during the ensuing hours. ΔTNF-α at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-α concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.


Role of the insulin-like growth factor system in epiphyseal cartilage on the development of Langshan and Arbor Acres chickens, Gallus domesticus.
We measured the mRNA transcript expression patterns for members of the insulin-like growth factor (IGF) system during embryonic and postnatal development in epiphyseal cartilage from Langshan (LS) and Arbor Acres (AA) chickens. Insulin-like growth factor binding protein (IGFBP)-2 expression was positively correlated with IGF-I from embryonic day (E) 14 to postnatal d (P) 0 and with IGF-II from E14 to P14 but negatively correlated with IGF-I from P0 to P42 and IGF-II from P14 to P42. Expression of IGFBP-5 correlated positively with IGF-I from E14 to P0 but negatively from P0 to P28. The results suggest that these genes are regulated in a coordinated fashion during development. A negative correlation was found between IGFBP-7 and IGF-II during P0 to P42. A positive correlation was found between IGFBP-3 (E14 to E18, P14 to P42) and IGF-IR and between IGFBP-3 (E14 to P0, P14 to P42) and IGF-I. The endocrine factors can be integrated with nutrition to regulate animal growth. In our study, AA chickens were fed a nutrient-rich AA diet, and LS chickens were fed either an AA diet or a less-rich diet. The LS and AA chickens fed the same AA diet showed no differences in IGF-I, IGF-I receptor, IGFBP-2, IGFBP-5, IGFBP-7, and IGFBP-3 but did still show differences in IGF-II. Our data indicate that these select genes may show linked expression during certain periods of development and that differences in gene expression respond differently to nutrient intake in LS and AA chickens.


Surgical closure of an atrial septal defect in an 11-year-old girl with Silver-Russell syndrome.
Silver-Russell syndrome is a congenital disease characterized by severe growth retardation and variable dysmorphic features such as a small triangular face, micrognathia, asymmetry (usually of the limbs), syndactyly and clinodactyly. We report a rare case of a girl with extremely low body weight, short stature and an atrial septal defect, who underwent successful surgical repair of the heart abnormality.


Diseases caused by mutations in ORAI1 and STIM1.
Ca(2+) release-activated Ca(2+) (CRAC) channels mediate a specific form of Ca(2+) influx called store-operated Ca(2+) entry (SOCE) that contributes to the function of many cell types. CRAC channels are composed of ORAI1 proteins located in the plasma membrane, which form its ion-conducting pore. ORAI1 channels are activated by stromal interaction molecule (STIM) 1 and STIM2 located in the endoplasmic reticulum. Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes. CRAC channelopathy is caused by loss-of-function mutations in ORAI1 and STIM1 that abolish CRAC channel function and SOCE; it is characterized by severe combined immunodeficiency (SCID)-like disease, autoimmunity, muscular hypotonia, and ectodermal dysplasia, with defects in sweat gland function and dental enamel formation. The latter defect emphasizes an important role of CRAC channels in tooth development. By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca(2+) levels that are associated with an overlapping spectrum of diseases, including nonsyndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes. The latter two syndromes are defined, besides myopathy, by thrombocytopenia, thrombopathy, and bleeding diathesis. The fact that myopathy results from both loss- and gain-of-function mutations in ORAI1 and STIM1 highlights the importance of CRAC channels for Ca(2+) homeostasis in skeletal muscle function. The cellular dysfunction and clinical disease spectrum observed in mutant patients provide important information about the molecular regulation of ORAI1 and STIM1 proteins and the role of CRAC channels in human physiology.


Aortoiliac reconstruction in the setting of in-stent restenosis.
Complex iliac artery obstructions, particularly bilateral stenosis or total iliac artery occlusions, are usually treated with aortofemoral or aortobifemoral graft surgery. However, surgical treatment is associated with 3% mortality rate and significant morbidity such as intestinal ischemia, spinal cord injury, and ureteral damage. Percutaneous interventions of aortic bifurcation offer a promising alternative to surgery with potentially lower morbidity and mortality risk. We report a case of peripheral artery disease who had underwent right transfemoral iliac angioplasty with femoropopliteal bypass presented again with bilateral lower limb ischemia, who was successfully treated with stent implantation with the kissing balloon technique.


Sinking during earthquakes: Critical acceleration criteria control drained soil liquefaction.
This article focuses on liquefaction of saturated granular soils, triggered by earthquakes. Liquefaction is defined here as the transition from a rigid state, in which the granular soil layer supports structures placed on its surface, to a fluidlike state, in which structures placed initially on the surface sink to their isostatic depth within the granular layer. We suggest a simple theoretical model for soil liquefaction and show that buoyancy caused by the presence of water inside a granular medium has a dramatic influence on the stability of an intruder resting at the surface of the medium. We confirm this hypothesis by comparison with laboratory experiments and discrete-element numerical simulations. The external excitation representing ground motion during earthquakes is simulated via horizontal sinusoidal oscillations of controlled frequency and amplitude. In the experiments, we use particles only slightly denser than water, which as predicted theoretically increases the effect of liquefaction and allows clear depth-of-sinking measurements. In the simulations, a micromechanical model simulates grains using molecular dynamics with friction between neighbors. The effect of the fluid is captured by taking into account buoyancy effects on the grains when they are immersed. We show that the motion of an intruder inside a granular medium is mainly dependent on the peak acceleration of the ground motion and establish a phase diagram for the conditions under which liquefaction happens, depending on the soil bulk density, friction properties, presence of water, and peak acceleration of the imposed large-scale soil vibrations. We establish that in liquefaction conditions, most cases relax toward an equilibrium position following an exponential in time. We also show that the equilibrium position itself, for most liquefaction regimes, corresponds to the isostatic equilibrium of the intruder inside a medium of effective density. The characteristic time to relaxation is shown to be essentially a function of the peak ground velocity.


Soil microbial community structure in cucumber rhizosphere of different resistance cultivars to fusarium wilt.
Cucumber fusarium wilt is a common soil-borne disease. We hypothesize that there is a relationship between the severity of disease and soil microbial ecology. In this work, culturable microbial populations, lipid fatty acid and community-level physiological profiles (CLPP) from rhizosphere soils of four different cucumber cultivars were investigated. Comparatively higher actinomycetes, mycorrhizal colonization and higher ratios of bacteria to fungi were found in the two resistant cultivars compared with the two susceptible cultivars. CLPP analysis showed that catabolic diversity indices were higher in the presence of two resistant cultivars. Phospholipid fatty acid (PLFA) profiles suggested that fungal (18:2omega6,9c) PLFA was enriched in the rhizosphere soils of the two susceptible cultivars, but some bacterial (16:0 and 15:0a) PLFAs were found in a lower relative abundance in these soils. The neutral lipid fatty acid 16:1omega5, which is an indicator of arbuscular mycorrhizal fungi, was enriched in the rhizosphere soils of the two resistant cultivars. All the three methods suggested that plant genotype had a significant impact on the soil microbial community composition and activity, and the differences in the rhizosphere microbial community may result in the differences in the resistance to fusarium wilt.


Development of Faraday rotation measurements on Keda Reconnection eXperiment (KRX) device.
The Faraday-effect based polarimeter and interferometer are developed for non-perturbation magnetic field and density measurements on the Keda Reconnection eXperiment (KRX) device. The magnetic reconnection is externally driven by a pair of parallel current plates. To design this instrument and provide an alternative way to facilitate theory-experiment comparisons via forward modeling of the diagnostics process with full plasma dynamics given by simulation, we develop a synthetic diagnostics based on 2D photonic integrated circuit simulation for magnetic reconnection on the KRX. The view-line geometry is optimized and wavelengths (1 mm) of the polarimeter and interferometer are selected to ensure the sensitivity of measurement on the KRX. We have simulated magnetic reconnection on the x-line (x-z plane) with horizontal viewing and vertical viewing for line of sight measurements. It is found that the current sheet width and indicator of magnetic reconnection can be inferred directly from the dynamics of Faraday rotation even with the line-integrated character of polarimeter-interferometer diagnostics.


U.S.-Born Mexican-Origin Women's Descriptions About Their Eating Patterns.
Mexican origin (MO) women comprise the largest Hispanic subgroup of Latinas in the United States. This subgroup has high incidences of obesity and associated chronic diseases. Modifiable risk factors for these include unhealthy diets and eating patterns. Efforts to understand eating patterns of Hispanics have focused on primarily first-generation Hispanics. The purpose of this study was to explore U.S.-born MO women's descriptions about eating patterns. A qualitative exploratory-descriptive study, using a thematic analysis approach, was employed. Fifteen MO women were interviewed. The participants were second to fourth generation and reported higher educational attainment, middle-income socioeconomic brackets, and English proficiency compared with previous groups studied. Five themes were identified: (a) personal agency, (b) relationships with people about food, (c) cultural and familial influences, (d) environments, and (e) time and money. Themes comprised multiple factors to classify the varied aspects of the women's eating patterns. This study provides insights about descriptions of eating patterns from a subgroup, generational, and gender-specific perspective that extended beyond acculturative and homogeneous group viewpoints to a broader structural view. The structural layers that affected the women's eating patterns were multifaceted and complex.


Siglec 15 as a biomarker or a druggable molecule for non-small cell lung cancer.
Lung cancer has been the main cause of cancer mortality worldwide. Furthermore, lung cancer rates of new cases per year evidenced a large incidence of this neoplasm in both men and women. Because there is no biomarker for early detection, it is frequently detected late, at an advanced state. The introduction of multiple lines of tyrosine kinase inhibitors in patients with EGFR, ALK, ROS1, and NTRK mutations has modified the therapy of lung cancer. Immunotherapy advances have resulted in substantial improvements in overall survival and disease-free survival, making immune checkpoint inhibitors (ICIs) a potential option for lung cancer treatment. Current PD-1/PD-L1/CTLA-4 immunotherapies have resulted in important response and survival rates. However, existing medicines only function in around 20% of unselected, advanced NSCLC patients, and primary and acquired resistance remain unsolved obstacles. Therefore, precise predictive indicators must be identified to choose the best patients for ICI treatment. Thus, Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) stands out as a potential tumor biomarker, with distinctive expression in normal tissues, in tumor immune involvement, and a high structural similarity to PD-L1. Understanding the tumor immune response and the search for new therapeutic targets leads to the improvement of therapeutic pathways directed at the tumor microenvironment. The present review aims to analyze Siglec-15 potential as a diagnostic, prognostic, and response biomarker in lung cancer, considering its results evidenced in the current literature.


Characterizing the actin-binding ability of Zasp52 and its contribution to myofibril assembly.
In sarcomeres, α-actinin crosslinks thin filaments and anchors them at the Z-disc. Drosophila melanogaster Zasp52 also localizes at Z-discs and interacts with α-actinin via its extended PDZ domain, thereby contributing to myofibril assembly and maintenance, yet the detailed mechanism of Zasp52 function is unknown. Here we show a strong genetic interaction between actin and Zasp52 during indirect flight muscle assembly, indicating that this interaction plays a critical role during myofibril assembly. Our results suggest that Zasp52 contains an actin-binding site, which includes the extended PDZ domain and the ZM region. Zasp52 binds with micromolar affinity to monomeric actin. A co-sedimentation assay indicates that Zasp52 can also bind to F-actin. Finally, we use in vivo rescue assays of myofibril assembly to show that the α-actinin-binding domain of Zasp52 is not sufficient for a full rescue of Zasp52 mutants suggesting additional contributions of Zasp52 actin-binding to myofibril assembly.


Patient and provider perspectives inform an intervention to improve linkage to care for HIV patients in Ukraine.
Engagement with HIV medical care is critical to successful HIV treatment and prevention efforts. However, in Ukraine, delays in the timely initiation of HIV treatment hamper viral suppression. By January 01, 2016, only 126,604 (57.5%) of the estimated 220,000 people living with HIV (PLWH) had registered for HIV care, and most (55.1%) of those who registered for HIV care in 2015 did that at a late stage of infection. In the US, Anti-Retroviral Treatment and Access to Services (ARTAS) intervention successfully linked newly diagnosed PLWH to HIV services using strengths-based case management with a linkage coordinator. To tailor the ARTAS intervention for Ukraine, we conducted a qualitative study with patients and providers to understand barriers and facilitators that influence linkage to HIV care. During September-October 2014, we conducted 20 in-depth interviews with HIV-positive patients and two focus groups with physicians in infectious disease, sexually transmitted infection (STI), and addiction clinics in Dnipropetrovsk Region of Ukraine. Interviews and focus groups were audio-recorded and transcribed verbatim. We translated illustrative quotes into English. We used thematic analysis for the data analysis. Participants (20 patients and 14 physicians) identified multiple, mostly individual-level factors influencing HIV care initiation. Key barriers included lack of HIV knowledge, non-acceptance of HIV diagnosis, fear of HIV disclosure, lack of psychological support from health providers, and HIV stigma in community. Responsibility for one's health, health deterioration, and supportive provider communication were reported as facilitators to linkage to care. Expected benefits from the case management intervention included psychological support, HIV education, and help with navigating the segmented health system. The findings from the study will be used to optimize the ARTAS for the Ukrainian context. Our findings can also support future linkage-to-care strategies in other countries of Eastern Europe and Central Asia.


Decreased expression of ALDH5A1 predicts prognosis in patients with ovarian cancer.
Aldehyde dehydrogenase 5 family, member A1 (ALDH5A1) belongs to the superfamily of aldehyde dehydrogenases (ALDHs). However, the prognostic value of ALDH5A1 in ovarian cancer remains unclear. The aim of this study was to explore the relationship between ALDH5A1 and the prognosis of patients with ovarian cancer (OC). We compared the expression of ALDH5A1 in OC to that innormal controls, using GSE40595 profiling data. Tissue microarray analysis was conducted for192 OC patients, 14 adjacent normal ovary tissues, and 2 normal ovary tissues. Using the "Kaplan-Meier plotter" (KM plotter) database, updated gene expression data and survival information of a total of 1583 OC patients were used to evaluate the prognostic value of ALDH5A1 in OC patients. We found that ALDH5A1 mRNA expression was downregulated in OC patients compared with that innormal tissues. In survival analyses, we found that ALDH5A1 was positively linked to prognosis in patients with OC, particularly in those with serous ovarian cancer (SOC). In addition, high Ctranscription activity of ALDH5A1 was correlated with better overall survival in SOC patients expressing mutatedTP53, but not in those expressing wild-type TP53. In pathological grades II/III, a high mRNA level of ALDH5A1 was associated with improved overall survival. The positive association between ALDH5A1 and prognosis was found not only in early stages(I and II), but also in advanced stages (III and IV) of SOC patients. results indicate that ALDH5A1 is an excellent predictive factor of OC and may play crucial roles in OC progression.


The myxoma virus TNF-receptor homologue (T2) inhibits tumor necrosis factor-alpha in a species-specific fashion.
The myxoma virus T2 protein shares extensive homology with the ligand binding domains of tumor necrosis factor (TNF) receptors. To characterize the T2-TNF interaction, myxoma T2 protein and rabbit, mouse, and human TNF alpha were expressed independently from vaccinia virus vectors. Growth of the TNF alpha-expressing viruses was significantly attenuated in TNF-hypersensitive L929-8 cells, and these cells were rapidly lysed by all three TNF alpha s. Rabbit cells showed strict species specificity in that RK-13 and SIRC cells were only sensitive to lysis by the homologous rabbit TNF alpha. Although RK-13 cells were hypersensitive to rabbit TNF alpha even in the absence of protein synthesis inhibitors, growth of T2 nonexpressing myxoma and vaccinia viruses in RK-13 cells was only modestly reduced in the presence of rabbit TNF alpha, suggesting that poxviruses possess additional anti-TNF mechanisms. When the ability of the myxoma T2 protein to inhibit biological activities of TNF alpha was assayed, T2 protein effectively protected L929-8 cells from lysis by rabbit, but not human or mouse TNF alpha. These studies show that rabbit TNF receptors may be species-specific for rabbit TNF alpha and we conclude that the myxoma T2 protein evolved to specifically inhibit TNF activities from its natural host, the South American rabbit.


Effects of fenfluramine in hypertriglyceridemic obese subjects.
Forty-four hyperlipidemic obese subjects, selected because of their refractoriness towards diet-therapy, participated voluntarily in a 12-week double-blind study comparing the effects of a long-acting fenfluramine (Ponderal Pacaps) to those of a placebo. In spite of no dietetic intervention, a significant 3-kg weight loss (P less than 0.001) was observed in the fenfluramine-treated group, accompanied by a significant improvement of most atherogenic parameters of plasma lipoproteins. Fenfluramine-induced weight loss produced decrease in total cholesterol (P less than 0.05), total triglycerides (P less than 0.05), LDL cholesterol (P less than 0.05), total apoprotein B (P less than 0.005) and LDL apoprotein B (P less than 0.001). An apoprotein B LDL depletion seemed to occur, as suggested by the reduction of LDL cholesterol/apoprotein B ratio (P less than 0.001). Total plasma apoprotein A did not change but the total apoprotein B/total apoprotein A ratio decreased significantly (P less than 0.005). Moreover, fenfluramine increased both HDL phospholipid (P less than 0.005) and HDL cholesterol (P less than 0.05) resulting in a fall of the atherogenic LDL-cholesterol/HDL cholesterol ratio (P less than 0.001) as well as an elevation of the anti-atherogenic HDL cholesterol/LDL + VLDL cholesterol ratio (P less than 0.001). The placebo group demonstrated some improvement in lipid blood parameters without weight loss, indicating a possible qualitative amelioration of nutritional habits. Thus, fenfluramine reduces the risk for cardiovascular disease in hyperlipidemic obese individuals not responding to behavioral intervention.


Dairy consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis.
The relation between consumption of different types of dairy and risk of type 2 diabetes (T2D) remains uncertain. Therefore, we aimed to evaluate the association between total dairy and individual types of dairy consumptions and incident T2D in US adults. We followed 41,436 men in the Health Professionals Follow-Up Study (1986 to 2010), 67,138 women in the Nurses' Health Study (1980 to 2010), and 85,884 women in the Nurses' Health Study II (1991 to 2009). Diet was assessed by validated food-frequency questionnaires, and data were updated every four years. Incident T2D was confirmed by a validated supplementary questionnaire. During 3,984,203 person-years of follow-up, we documented 15,156 incident T2D cases. After adjustment for age, body mass index (BMI) and other lifestyle and dietary risk factors, total dairy consumption was not associated with T2D risk and the pooled hazard ratio (HR) (95% confidence interval (CI)) of T2D for one serving/day increase in total dairy was 0.99 (0.98, 1.01). Among different types of dairy products, neither low-fat nor high-fat dairy intake was appreciably associated with risk of T2D. However, yogurt intake was consistently and inversely associated with T2D risk across the three cohorts with the pooled HR of 0.83 (0.75, 0.92) for one serving/day increment (P for trend <0.001). We conducted a meta-analysis of 14 prospective cohorts with 459,790 participants and 35,863 incident T2D cases; the pooled relative risks (RRs) (95% CIs) were 0.98 (0.96, 1.01) and 0.82 (0.70, 0.96) for one serving total dairy/day and one serving yogurt/day, respectively. Higher intake of yogurt is associated with a reduced risk of T2D, whereas other dairy foods and consumption of total dairy are not appreciably associated with incidence of T2D.


Splenic irradiation as palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis: a multi-institutional experience.
To evaluate the impact of splenic irradiation as a palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis. Seventeen patients with chronic myelogenous leukemia and 3 with idiopathic polycythaemia presented with splenomegaly, splenic pain and anemia. Due to symptomatic splenomegaly, despite first-line treatment, the patients underwent splenic irradiation. Two patients received two different schedules of external radiotherapy (580 cGy in 5 fractions and 600 cGy in 6 fractions). Eight patients received 980 cGy in 14 fractions. Ten patients received two courses of 360 cGy in 6 fractions, 3 months apart. Median follow-up was 12 months post irradiation. The patients showed excellent response to treatment one month post-radiotherapy, while treatment was well tolerated without severe toxicity. The dimensions of the spleen decreased significantly. Pain-related Visual Analogue Score (VAS) regressed after completion of irradiation. During 12-month follow-up all patients maintained the benefit of radiotherapy. This study indicates that splenic irradiation could be a safe and effective palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis.


Potential association of dengue hemorrhagic fever incidence and remote senses land surface temperature, Thailand, 1998.
A pilot study was designed to analyze a potential association between dengue hemorrhagic fever (DHF) incidence and, temperature computed by satellite. DHF is a mosquito transmitted disease, and water vapor and humidity are known to have a positive effect on mosquito life by increasing survival time and shortening the development cycle. Among other available satellite data, Land Surface Temperature (LST) was chosen as an indicator that combined radiated earth temperature and atmospheric water vapor concentration. Monthly DHF incidence was recorded by province during the 1998 epidemic and obtained as a weekly combined report available from the National Ministry of Public Health. Conversely, LST was calculated using remotely sensed data obtained from thermal infrared sensors of NOAA satellites and computed on a provincial scale. Out of nine selected study provinces, five (58.3%) exhibited an LST with a significant positive correlation with rainfall (p < 0.05). In four out of nineteen surveyed provinces (21.3%), LST showed a significant positive correlation with DHF incidence (p < 0.05). Positive association between LST and DHF incidence was significantly correlated in 75% of the cases during non-epidemic months, while no correlation was found during epidemic months. Non-climatic factors are supposed to be at the origin of this discrepancy between seasonality in climate (LST) and DHF incidence during epidemics.


Control of venous bleeding during dissection near the head of the pancreas.
Avulsion injury to portal vein tributaries can result in worrying haemorrhage during pancreatic gastric, and colonic resection. Attempts to control these avulsion injuries can result in extension of the tear into major portal vein tributaries. Pressure on the bleeding point tends to extend the laceration towards the portal vein, which bleeds torrentially when pressure is released for suturing. A technique is described to control the bleeding from these portal vein tributaries. This technique relies on adequate visualization and control of the torn ends of the portal vein tributaries thus enabling the surgeon to precisely suture the disrupted vessel without any collateral damage. This technique has been used on a number of occasions over the last decade with excellent results.


Liver regeneration therapy through the hepatic artery-infusion of cultured bone marrow cells in a canine liver fibrosis model.
We previously reported regenerative therapies for decompensated cirrhosis based on peripheral venous drip infusion using non-cultured whole bone marrow (BM) cells, or the less invasive cultured BM-derived mesenchymal stem cells (BMSCs). Here, we assessed the efficacy and safety of hepatic arterial infusion using cultured autologous BMSCs, comparing it with peripheral infusion, using our established canine liver fibrosis model. Canine BM cells were harvested and cultured, and the resultant BMSCs were returned to carbon tetrachloride (CCl4)-induced liver cirrhosis model canines via either a peripheral vein (Vein group) or hepatic artery (Artery group). A variety of assays were performed before and 4, 8, and 12 weeks after BMSC infusion, and liver fibrosis and indocyanine green (ICG) half-life (t1/2) were compared to those in a control group that received CCl4 but not BMSCs. The safety of this approach was evaluated by contrast-enhanced computed tomography (CT) and serial blood examinations after infusion. Four weeks after infusing BMSCs, a significant improvement was observed in the Vein group (n = 8) compared to outcome in the Control group (n = 10), along with a decrease in ICG t1/2. In the Artery group (n = 4), ICG t1/2 was significantly shorter than that in the Vein group at 8 weeks (Δt1/2: -3.8 ± 1.7 min vs. +0.4 ± 2.4 min; p < 0.01) and 12 weeks (Δt1/2: -4.2 ± 1.7 min vs. +0.4 ± 2.7 min; p < 0.01) after BMSC administration. Post-infusion contrast-enhanced CT showed no liver infarction, and blood tests showed no elevations in either serum lactate dehydrogenase concentrations or hypercoagulability. We confirmed the efficacy and safety of the hepatic arterial infusion of cultured autologous BMSCs using a canine model, thereby providing non-clinical proof-of-concept.


Regional Variation in the Prevalence of Asthma Symptoms among Omani School Children: Comparisons from Two Nationwide Cross-sectional Surveys Six Years Apart.
The International Study of Asthma and Allergies in Children (ISAAC) highlighted the presence of wide variations in asthma prevalence between and within countries. The aim of this study was to determine the changes in the prevalence of asthma and its symptoms across the different regions of Oman. Two cross-sectional surveys were conducted as part of ISAAC phases I (1995) and III (2001) in two age groups (6-7 and 13-14 years) from nation-wide samples of Omani school children, with 7,067 participants in 1995 (3,893 young and 3,174 older group) and 7,879 participants in 2001 (4,126 young and 3,753 older group). Over the period of six years, the Sharqiya (Eastern) region continued to have the highest prevalence of self-reported asthma diagnosis and all asthma symptoms in both age groups, with a significant increase in the prevalence of wheeze in the past 12 months (from 8.7% to 13.8%; p=0.002) and asthma diagnosis (from 13.8% to 17.8 %; p=0.046) in the young group, and a significant increase in night cough (from 21.6% to 27.8%; p=0.039) in the older group. All other regions had lower prevalence rates in 1995 in both age groups, and showed either no significant change or a decline in one or two of the self-reported asthma symptoms. The prevalence of asthma diagnosis among wheezy children remained unchanged across all regions. In addition, asthma under-diagnosis remains a problem with only 60% of children with severe wheeze reporting asthma diagnosis in both surveys. The geographic variation in the prevalence of self-reported of asthma symptoms among Omani school children persists with further increase in the Sharqiya region. The findings also suggest under-diagnosis and/or poor recognition of asthma which had not improved over time.


Headache in stroke: the Copenhagen Stroke Study.
Many aspects of stroke-related headache, such as its incidence, pathophysiology, risk factors, and relation to stroke severity and outcome, are uncertain. A prospective, community-based study including 1,128 consecutive acute stroke patients; 867 (77%) were able to communicate. Stroke severity and the clinical course were assessed using the Scandinavian Stroke Scale (SSS). CT was performed in 84% of patients. In the data analysis, multivariate regression analyses were used when appropriate. Two hundred forty-one (28%) of the 867 patients had headache in relation to stroke onset. Independent risk factors were age (odds ratio [OR] per 20 years, 0.57; 95% confidence interval [CI], 0.43 to 0.86; p = 0.0001), female sex (OR, 1.6; CI, 1.2 to 2.2; p = 0.003), intracerebral hemorrhage (OR, 2.8; CI, 1.5 to 5.4; p = 0.002), stroke in the vertebrobasilar territory (OR, 1.7; CI, 1.1 to 2.3; p = 0.02), and ischemic heart disease (OR, 1.5; CI, 1.1 to 2.2; p = 0.01). In those patients in whom headache was lateralized (46%), it was ipsilateral to the lesion in 68% of cases (p = 0.01). There was no correlation between headache and (1) initial stroke severity as measured with the SSS (p = 0.75), (2) lesion size (p = 0.77), (3) whether or not CT showed cortical involvement (p = 0.29), (4) stroke outcome as measured with the SSS (p = 0.9), or (5) mortality (p = 0.75). Stroke-related headache is associated with factors such as age and sex. In patients capable of providing reliable headache information, headache is more frequent in strokes confined to the vertebrobasilar than to the carotid territory and is not associated with stroke severity or whether or not the cortex was involved. Stroke-related headache is not related to stroke outcome.


Decreased expression of FOXF2 as new predictor of poor prognosis in stage I non-small cell lung cancer.
Forkhead box F2 (FOXF2) is relatively limited to the adult lung, but its contribution to non-small cell lung cancer (NSCLC) prognosis is unclear. FOXF2 mRNA levels in NSCLC were lower than that in paired normal lung tissues (P = 0.012). The FOXF2low patients had shorter survival time than the FOXF2high patients (P = 0.024) especially in stage I (P = 0.002), chemotherapy (P = 0.018) and < 60 age groups (P = 0.002). Lower FOXF2 mRNA levels could independently predict poorer survival for patients with NSCLC (HR = 2.384, 95% CI = 1.241-4.577; P = 0.009), especially in stage I (HR =4.367, 95% CI =1.599-11.925; P = 0.004). The two independent datasets confirmed our findings. We examined FOXF2 mRNA levels in 84 primary NSCLC and 8 normal lung tissues using qRT-PCR. Rank-sum tests and chi-square tests were used to assess the differences among groups with various clinicopathological factors. Kaplan-Meier tests were used to compare survival status in patients with different FOXF2 mRNA levels. Cox proportional hazards regression model was used to evaluate the predictive value of FOXF2 mRNA level in NSCLC patients. Independent validation was performed using an independent dataset (98 samples) and an online survival analysis software Kaplan-Meier plotter (1928 samples). Our results demonstrated that decreased FOXF2 expression is an independent predictive factor for poor prognosis of patients with NSCLC, especially in stage I NSCLC.


Rat model of the human "Triton" tumor: direct genetic evidence for the myogenic differentiation capacity of schwannoma cells using the mutant neu gene as a cell lineage marker.
Spontaneous myogenic differentiation was observed in 2 out of 15 cases when cells from schwannomas induced in the offspring of BDIX rats by transplacental exposure to N-ethyl-N-nitrosourea (EtNU) were grown in monolayer culture following fluorescence-activated cell sorting with monoclonal antibody (Mab) 217c. Myotubes and numerous mononucleated cells no longer expressed the Schwann cell antigens 217c and S-100 protein, but rather revealed the presence of desmin, the alpha-sarcomeric form (alpha-sr) of actin, and the cell surface antigen specified by Mab RB21-7, a 250 kD glycoprotein sharing an epitope with the neural cell adhesion molecule (N-CAM). Subcutaneous reimplantation of such cells into syngeneic animals led to the appearance of tumors composed of both S-100 positive Schwann cells and desmin and alpha-sr-actin positive rhabdomyoblasts, thus closely resembling the human "Triton" tumor. With the use of the polymerase chain reaction and allele-specific oligonucleotide hybridization, DNA isolated from individual myotubes was analyzed for the presence of a T----A transversion mutation at nucleotide 2012 of the neu gene, which is diagnostic of EtNU-induced rat schwannomas. All of the amplified DNA isolates contained the mutant neu allele, thus providing direct genetic proof for the capacity of mammalian neuroectodermal cells for myogenic differentiation.


Phytogenic pigments in animal nutrition: potentials and risks.
Phytogenic pigments are secondary plant compounds responsible for coloring effects in plant tissues. In particular, phenolic flavonoids and terpenoid carotenoids, but also rare compounds like curcumin and betalain, form this group of biochemical agents used in animal nutrition. From the perspective of ecological mutuality between plants and animals, these compounds are of crucial importance because they serve as visual attraction for herbivores but also signal nutritional and/or health-promoting values. This review focuses on the properties of phytogenic pigments which are likely to impact feed intake and preferences of livestock. Also natural prophylactic and/or therapeutic properties and, in particular, the potential of pigments to enhance quality and health value of animal products for human consumption are important issues. Nevertheless, reasonable limits of use due to possible adverse indications have been suggested recently. Pathways of digestion, metabolism and excretion in animals play a crucial role not only in the evaluation of effectiveness but also in the prediction of potential risks for human consumption. The popularity of natural feed additives is growing; therefore, more research work is needed to better understand metabolic pathways in the animal's body and to better estimate the potentials and risks of pigmenting plant compounds used in animal nutrition.


Glycation of antibodies: Modification, methods and potential effects on biological functions.
Glycation is an important protein modification that could potentially affect bioactivity and molecular stability, and glycation of therapeutic proteins such as monoclonal antibodies should be well characterized. Glycated protein could undergo further degradation into advance glycation end (AGE) products. Here, we review the root cause of glycation during the manufacturing, storage and in vivo circulation of therapeutic antibodies, and the current analytical methods used to detect and characterize glycation and AGEs, including boronate affinity chromatography, charge-based methods, liquid chromatography-mass spectrometry and colorimetric assay. The biological effects of therapeutic protein glycation and AGEs, which ranged from no affect to loss of activity, are also discussed.


Extending the Promise of the Older Americans Act to Persons Aging With Long-Term Disability.
This article discusses the need for Older Americans Act (OAA) programs to evaluate and develop where needed the capacity to serve persons aging with long-term disabilities such as intellectual and/or developmental disabilities and physical disabilities including polio, spinal cord injury, and multiple sclerosis. The rationale for this work is the universal access to OAA programs for all adults over 60, regardless of the disability type, age of onset, or severity, acknowledging that other needs-based criteria often need to be met to receive services. Recommendations for increasing OAA and aging network capacity include addressing long-standing divisions between the fields of aging and disability, a comprehensive review of all Administration for Community Living programs and policies, engaging in program adaptation to build capacity, advancing knowledge and skills of the professional workforce, creating new knowledge to support delivery of evidence-based interventions to all older adults including those with lifelong and early and midlife onset of disability.


Hospital discharge data: can it serve as the sole source of case ascertainment for population-based birth defects surveillance programs?
Because of the relatively high expense of collecting primary data and limited resources, electronically available, population-based hospital discharge data have been increasingly used for disease surveillance by public health researchers. The objective of this study was to compare the New York State Congenital Malformations Registry (CMR) data, which relies on hospital reports, with the hospital discharge files to identify cases in the CMR that were missed in the hospital discharge data files. The ultimate goal was to evaluate whether hospital discharge data can serve as the sole source of case ascertainment for a population-based birth defects surveillance program. CMR cases that were born to the New York State residents for the years 2000 to 2005 were selected and matched to the hospital discharge files from the New York Statewide Planning and Research Cooperative System (SPARCS) for the same birth year period. Since the SPARCS database does not contain patient's name, extensive database matching and manual review by staff members were performed using identifying variables such as the hospital's permanent facility identifier, child's date of birth and medical record number, and mother's medical record number and residential address. Out of 66 757 CMR cases selected for the study period, 62 118 cases (93.1%) were matched to SPARCS hospital discharge records with International Classification of Diseases, Ninth Revision (ICD-9) codes that were reportable to the CMR, 3 444 cases (5.2%) were matched to SPARCS records with ICD-9 codes that were not reportable to the CMR, and 1 195 cases (1.8%) were not matched. The percentage of cases with multiple congenital malformations was significantly higher (21.3%) for the matched cases that had reportable ICD-9 codes in SPARCS, compared with that for matched CMR cases that had no reportable ICD-9 codes in SPARCS (10.2%). The study found that 93% of CMR infants selected for the study were matched to hospital discharge records with at least one ICD-9 code that was reportable to the CMR; 87 percent had reportable ICD codes in SPARCS that were exactly matched to those in the CMR, that is, all the birth defect codes in SPARCS were matched to those in the CMR. Thus, about 7 percent of CMR children with birth defects would have been missed if only hospital discharge files were used to ascertain the birth defect cases, indicating that there are limitations to using hospital discharge files as the sole source of case ascertainment for population-based birth defects surveillance programs.


Brazilian FRED Registry: A Prospective Multicenter Study for Brain Aneurysm Treatment-The BRED Study.
The development of flow diverters has changed the endovascular approach to intracranial aneurysms. On the basis of good results, the indications for flow diverters have expanded to include aneurysms of different shapes, locations, and sizes. The objective of the study was to report on the performance of the Flow Re-Direction Endoluminal Device (FRED) in intracranial aneurysm treatment at early and medium-term follow-up. This single-arm, multicentric, prospective, observational study assessed aneurysm treatment with the FRED. The primary outcome was complete aneurysm occlusion at 6 and 12 months, and the secondary outcome was to evaluate the safety of the FRED with respect to stroke and death rates. Between June 2016 and August 2018, a total of 100 consecutive patients with 131 aneurysms were treated in 107 procedures. Total occlusion rates were 91% and 95% at 6 and 12 months. There was 1 death, and the total final morbidity rate was 1.8%. The complication rate was 4.6%. As reported previously, the FRED has proved to be a safe and effective tool, with high occlusion rates. The design of the stent makes it more difficult to perform balloon angioplasty compared with similar devices. A branch arising from the aneurysm sac was found to be a predictor of nonocclusion at 12 months, though larger series are needed to estimate the magnitude of the association.


Corticosterone Production during Repeated Social Defeat Causes Monocyte Mobilization from the Bone Marrow, Glucocorticoid Resistance, and Neurovascular Adhesion Molecule Expression.
Repeated social defeat (RSD) stress promotes the release of bone marrow-derived monocytes into circulation that are recruited to the brain, where they augment neuroinflammation and cause prolonged anxiety-like behavior. Physiological stress activates the sympathetic nervous system and hypothalamic-pituitary-adrenal gland (HPA) axis, and both of these systems play a role in the physiological, immunological, and behavioral responses to stress. The purpose of this study was to delineate the role of HPA activation and corticosterone production in the immunological responses to stress in male C57BL/6 mice. Here, surgical (adrenalectomy) and pharmacological (metyrapone) interventions were used to abrogate corticosterone signaling during stress. We report that both adrenalectomy and metyrapone attenuated the stress-induced release of monocytes into circulation. Neither intervention altered the production of monocytes during stress, but both interventions enhanced retention of these cells in the bone marrow. Consistent with this observation, adrenalectomy and metyrapone also prevented the stress-induced reduction of a key retention factor, CXCL12, in the bone marrow. Corticosterone depletion with metyrapone also abrogated the stress-induced glucocorticoid resistance of myeloid cells. In the brain, these corticosterone-associated interventions attenuated stress-induced microglial remodeling, neurovascular expression of the adhesion molecule intercellular cell adhesion molecule-1, prevented monocyte accumulation and neuroinflammatory signaling. Overall, these results indicate that HPA activation and corticosterone production during repeated social defeat stress are critical for monocyte release into circulation, glucocorticoid resistance of myeloid cells, and enhanced neurovascular cell adhesion molecule expression.SIGNIFICANCE STATEMENT Recent studies of stress have identified the presence of monocytes that show an exaggerated inflammatory response to immune challenge and are resistant to the suppressive effects of glucocorticoids. Increased presence of these proinflammatory monocytes has been implicated in neuropsychiatric symptoms and the development of chronic cardiovascular, autoimmune, and metabolic disorders. In the current study, we show novel evidence that corticosterone produced during stress enhances the release of proinflammatory monocytes from the bone marrow into circulation, augments their recruitment to the brain and the induction of a neuroinflammatory profile. Overproduction of corticosterone during stress is also the direct cause of glucocorticoid resistance, a key phenotype in individuals exposed to chronic stress. Inhibiting excess corticosterone production attenuates these inflammatory responses to stress.


Learning and adaptation in the management of waterfowl harvests.
A formal framework for the adaptive management of waterfowl harvests was adopted by the U.S. Fish and Wildlife Service in 1995. The process admits competing models of waterfowl population dynamics and harvest impacts, and relies on model averaging to compute optimal strategies for regulating harvest. Model weights, reflecting the relative ability of the alternative models to predict changes in population size, are used in the model averaging and are updated each year based on a comparison of model predictions and observations of population size. Since its inception the adaptive harvest program has focused principally on mallards (Anas platyrhynchos), which constitute a large portion of the U.S. waterfowl harvest. Four competing models, derived from a combination of two survival and two reproductive hypotheses, were originally assigned equal weights. In the last year of available information (2007), model weights favored the weakly density-dependent reproductive hypothesis over the strongly density-dependent one, and the additive mortality hypothesis over the compensatory one. The change in model weights led to a more conservative harvesting policy than what was in effect in the early years of the program. Adaptive harvest management has been successful in many ways, but nonetheless has exposed the difficulties in defining management objectives, in predicting and regulating harvests, and in coping with the tradeoffs inherent in managing multiple waterfowl stocks exposed to a common harvest. The key challenge now facing managers is whether adaptive harvest management as an institution can be sufficiently adaptive, and whether the knowledge and experience gained from the process can be reflected in higher-level policy decisions.


Comparison of parasitic mite retrieval methods in a population of community cats.
Objectives This study compared methods of mite retrieval from community cats in the Ohio River Valley region of the USA and determined incidence of parasitic mites in this region. Methods In total, 493 community cats were humanely trapped and anesthetized for a trap-neuter-return program. Cats received a dermatologic examination, ear swabs, superficial skin scraping, flea combing, acetate tape preparation and feces collection. All samples were examined microscopically. Large volumes of hair and scale from flea combing were dissolved in 10% potassium hydroxide and centrifuged with Sheather's solution. Fecal samples were mixed with Sheather's solution, filtered and centrifuged. Results Ear swabs were significantly ( P <0.05) better than other methods for finding chigger mites and Otodectes cynotis, and skin scraping was significantly better than ear swabs for finding Cheyletiella species. Only cats with O cynotis had clinical lesions. Mites remained identifiable for 6 months at room temperature. Mite incidence rates were as follows: Notoedres cati (1/493 cats), 0.002 (95% confidence interval [CI] 0-0.006); Lynxacarus radovskyi (2/493 cats), 0.004 (95% CI 0-0.01); Demodex gatoi (5/493 cats), 0.01 (95% CI 0.001-0.019); chigger mites (10/493 cats), 0.02 (95% CI 0.008-0.033); Cheyletiella species (12/493 cats), 0.024 (95% CI 0.011-0.038); and O cynotis (124/493 cats), 0.252 (95% CI 0.213-0.29). Conclusions and relevance Ear swabs are recommended when O cynotis or chigger mites are suspected. Skin scraping is more likely to yield positive results than ear swabs, but was not significantly better than acetate tape preparations, flea combing or fecal flotation for finding Cheyletiella species. Mites can remain identifiable for prolonged periods at room temperature. With the exception of O cynotis, the incidence of feline parasitic mites in the Ohio River Valley region of the USA is low; however, D gatoi and L radovskyi were present in the area and should be considered in cats with dermatologic disease attributable to them. In this population of community cats, asymptomatic carriage of mites was common.


Watershed-scale fungal community characterization along a pH gradient in a subsurface environment cocontaminated with uranium and nitrate.
The objective of this study was to characterize fungal communities in a subsurface environment cocontaminated with uranium and nitrate at the watershed scale and to determine the potential contribution of fungi to contaminant transformation (nitrate attenuation). The abundance, distribution, and diversity of fungi in subsurface groundwater samples were determined using quantitative and semiquantitative molecular techniques, including quantitative PCR of eukaryotic small-subunit rRNA genes and pyrosequencing of fungal internal transcribed spacer (ITS) regions. Potential bacterial and fungal denitrification was assessed in sediment-groundwater slurries amended with antimicrobial compounds and in fungal pure cultures isolated from the subsurface. Our results demonstrate that subsurface fungal communities are dominated by members of the phylum Ascomycota, and a pronounced shift in fungal community composition occurs across the groundwater pH gradient at the field site, with lower diversity observed under acidic (pH <4.5) conditions. Fungal isolates recovered from subsurface sediments, including cultures of the genus Coniochaeta, which were detected in abundance in pyrosequence libraries of site groundwater samples, were shown to reduce nitrate to nitrous oxide. Denitrifying fungal isolates recovered from the site were classified and found to be distributed broadly within the phylum Ascomycota and within a single genus of the Basidiomycota. Potential denitrification rate assays with sediment-groundwater slurries showed the potential for subsurface fungi to reduce nitrate to nitrous oxide under in situ acidic pH conditions.


Regeneration of enzymatic activity after sodium dodecyl sulfate/polyacrylamide gel electrophoresis and zinc acetate staining: the example of inositol 1,4,5-trisphosphate 5-phosphatase.
Regeneration of enzyme activity after sodium dodecyl sulfate-gel electrophoresis was investigated with a purified inositol 1,4,5-trisphosphate 5-phosphatase. In order to avoid silver or Coomassie blue staining, we have used zinc acetate. This staining procedure was sensitive, rapid, and reversible provided that zinc cations are chelated and activity is extracted after diffusion out of the gel. The method allows some gel lane staining and identification of the enzyme based on catalytic activity.


Iatrogenic pulmonary nodule in a heart transplant recipient.
A 58-year-old female with a history of non-Hodgkin lymphoma and end-stage nonischemic cardiomyopathy from Adriamycin toxicity underwent orthotic heart transplantation during June 2013. She developed shortness of breath in September 2013 and was suspected to have invasive pulmonary aspergillosis. A flexible bronchoscopy (FB) with a transbronchial biopsy (TBBx) was performed. She was found to have a focal lung nodule in the same location at the site of the TBBx on day 13 after the FB. Spontaneous resolution of the nodule was confirmed on the computed tomography (CT) scan of chest performed at 3 months. We believe that this nodule was as a consequence of the TBBx. Formation of a peripheral pulmonary nodule (PPN) following a TBBx is occasionally encountered among the recipients of the lung transplantation. To our knowledge, this is the first case of TBBx producing a pulmonary nodule in a heart transplant recipient. Physicians caring for the patients with heart transplantation should be cognizant of the iatrogenic nature of such nodule to avoid unnecessary diagnostic work-up.


[Caregiver Stress in Foster and Adoptive Parents of Children with Fetal Alcohol Spectrum Disorders].
Caregiver Stress in Foster and Adoptive Parents of Children with Fetal Alcohol Spectrum Disorders. Foster and adoptive parents of 71 children with fetal alcohol syndrome (FAS) report on developmental and behavioral characteristics, family stress, coping resources and their satisfaction with support. The data reveal an elevated rate of social and emotional problems in the children. In spite positive individual and social resources, the foster and adoptive parents feel a high level of caregiver stress. 30 % of them rate the support they receive from pediatric, therapeutic or educational services as lower than expected. Specifically, they miss early information on the diagnosis, professional knowledge and support for the special challenges of education and managing behavioral problems in their collaboration with social support agencies.


A simple and economical DRB1 typing procedure combining group-specific amplification, DNA heteroduplex and enzyme restriction analysis.
A new procedure for HLA-DRB1 typing is proposed. The method combines six group-specific amplifications with heteroduplex analysis and, in some cases, enzyme restriction analysis. This technique, which is as discriminative as oligotyping, is simple, economical and does not require probes. These characteristics make this approach a valid alternative to other HLA genomic typing procedures, especially in those cases such as donor-recipient pairs matching where a small number of samples has to be managed at once.


"Are there lexicons?" A study of lexical and semantic processing in word-meaning deafness suggests "yes".
A controversial issue in the cognitive neuroscience of language is the question whether independent lexical representations need to be included in cognitive models. Recent models claim to account for the available data without including phonological or orthographic lexicons. These models base their lexical decision ("Is it a word or not?") either on familiarity of the input string or alternatively, on semantic information. These two alternatives were evaluated in a series of experiments with an individual suffering from word-meaning deafness. This is a rare disorder of auditory word comprehension which affects mapping of a word's phonology to its meaning. The participant, BB, was unaffected by the 'word-likeness' of nonwords with comparable accuracy for plausible and abstruse nonwords. She was further able to make lexical decisions despite her severe impairment in comprehending the word's meaning. Lexical and semantic processing were assessed on an item-specific basis providing a methodological advancement over previous studies. The comprehension tasks involved word-picture matching as well as definition tasks. The results suggest that BB's lexical decisions are based neither on familiarity of the input string nor on semantic information, which was largely unavailable. The only alternative are lexical representations on which she could base her decisions.


Genetic and environmental sources of variation in the autogenous chemical defense of a leaf beetle.
Chemical defense plays a central role for many herbivorous insects in their interactions with predators and host plants. The leaf beetle genus Oreina (Coleoptera, Chrysomelidae) includes species able to both sequester pyrrolizidine alkaloids and autogenously produce cardenolides. Sequestered compounds are clearly related to patterns of host-plant use, but variation in de novo synthesized cardenolides is less obviously linked to the environment. In this study, intraspecific variation in cardenolide composition was examined by HPLC-MS analysis in 18 populations of Oreina speciosa spanning Europe from the Massif Central to the Balkans. This revealed the defense secretion to be a complex blend of up to 42 compounds per population. There was considerable geographical variation in the total sample of 50 compounds detected, with only 14 found in all sites. The environmental and genetic influences on defense chemistry were investigated by correlation with distance matrices based on habitat factors, host-plant use, and genetics (sequence data from COI, COII, and 16s rRNA). This demonstrated an influence of both genetics and host-plant use on the overall blend of cardenolides and on the presence of some of the individual compounds. The implications of this result are discussed for the evolution of defense chemistry and for the use of cardenolide compounds as markers of the evolutionary history of the species.


DNA Cleaving "Tandem-Array" Metallopeptides Activated With KHSO5: Towards the Development of Multi-Metallated Bioactive Conjugates and Compounds.
Amino terminal peptides of the general form Gly-Gly-His have been used to introduce single sites of metal binding and redox activity into a wide range of biomolecules to create bioactive compounds and conjugates capable of substrate oxidation. We report here that Gly-Gly-His-like peptides linked in a tandem fashion can also be generated leading to multi-metal binding arrays. While metal binding by the native Gly-Gly-His motif (typically to Cu2+, Ni2+, or Co2+) requires a terminal peptide amine ligand, previous work has demonstrated that an ornithine (Orn) residue can be substituted for the terminal Gly residue to allow solid-phase peptide synthesis to continue via the side chain N-δ. This strategy thus frees the Orn residue N-α for metal binding and permits placement of a Gly-Gly-His-like metal binding domain at any location within a linear, synthetic peptide chain. As we show here, this strategy also permits the assembly of tandem arrays of metal binding units in linear peptides of the form: NH2-Gly-Gly-His-[(δ)-Orn-Gly-His]n-(δ)-Orn-Gly-His-CONH2 (where n = 0, 1, and 2). Metal binding titrations of these tandem arrays monitored by UV-vis and ESI-MS indicated that they bind Cu2+, Ni2+, or Co2+ at each available metal binding site. Further, it was found that these systems retained their ability to modify DNA oxidatively and to an extent greater than their parent M(II)•Gly-Gly-His. These findings suggest that the tandem array metallopeptides described here may function with increased efficiency as "next generation" appendages in the design of bioactive compounds and conjugates.


Evaluation of a novel tool for bone graft delivery in minimally invasive transforaminal lumbar interbody fusion.
Disk material removed (DMR) during L4-5 and L5-S1 transforaminal lumbar interbody fusion (T-LIF) surgery was compared to the corresponding bone graft (BG) volumes inserted at the time of fusion. A novel BG delivery tool (BGDT) was used to apply the BG. In order to establish the percentage of DMR during T-LIF, it was compared to DMR during anterior diskectomy (AD). This study was performed prospectively. Minimal information is available as to the volume of DMR during a T-LIF procedure, and the relationship between DMR and BG delivered is unknown. BG insertion has been empiric and technically challenging. Since the volume of BG applied to the prepared disk space likely impacts the probability of arthrodesis, an investigation is justified. A total of 65 patients with pathology at L4-5 and/or L5-S1 necessitating fusion were treated with a minimally invasive T-LIF procedure. DMR was volumetrically measured during disk space preparation. BG material consisting of local autograft, BG extender, and bone marrow aspirate were mixed to form a slurry. BG slurry was injected into the disk space using a novel BGDT and measured volumetrically. An additional 29 patients who were treated with L5-S1 AD were compared to L5-S1 T-LIF DMR to determine the percent of T-LIF DMR relative to AD. DMR volumes averaged 3.6±2.2 mL. This represented 34% of the disk space relative to AD. The amount of BG delivered to the disk spaces was 9.3±3.2 mL, which is 2.6±2.2 times the amount of DMR. The BGDT allowed uncomplicated filling of the disk space in <1 minute. The volume of DMR during T-LIF allows for a predictable volume of BG delivery. The BGDT allowed complete filling of the entire prepared disk space. The T-LIF diskectomy debrides 34% of the disk relative to AD.


[RNAi-mediated gene silencing of livin synergistic with epirubicin enhance apoptosis of human breast cancer cells].
To observe the effects of silencing of livin gene expression combined with anthracycline chemotherapy on the apoptosis of human breast cancer cells. Double stranded RNA (dsRNA) targeting the livin gene was chemically synthesized in vitro and transfected into human breast cancer cells of the line ZR-75-30 mediated by lipofectamine 2000. The transfection efficiency was observed by fluorescence confocal microscopy. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to detect the expression of livin at mRNA and protein levels. ZR-75-30 cells transfected with dsRNA targeting livin for 24 h were treated with 50 microg/ml epirubicin for 12 h, flow cytometry was used to detect the apoptosis rate of the cells. The livin mRNA expression rates of the livin-siRNA transfected group was (29.68 +/- 2.7)%, with an inhibitory rate of 53.66%, significantly lower than those of the negative control and blank control groups [(52.01 +/- 2.9)% and (51.95 +/- 3.1)% respectively, both P < 0.01]. The livin protein expression rate of the livin-siRNA group was (27.80 +/- 2.1)%, significantly lower than those of the negative control siRNA group and blank control group [(53.80 +/- 3.0)% and (55.12 +/- 2.8)% respectively, both P < 0.01]. 36 h after the treatment of siRNA against livin combined with epirubicin the apoptosis rate was (15.18 +/- 0.05)%, significantly higher than those of the negative control group and blank control group [(2.78 +/- 0.08)% and (2.65 +/- 0.12)% respectively, both P < 0.01]. Sequence specific siRNA targeting livin synergistic with epirubicin is capable of enhancing the apoptosis rate of human breast cancer cells. Silencing of livin gene expression with siRNA combined with anthracycline chemotherapy may hold great promise as a novel therapy for livin expressing breast cancer.


Compact layer free perovskite solar cells with 13.5% efficiency.
The recent breakthrough of organometal halide perovskites as the light harvesting layer in photovoltaic devices has led to power conversion efficiencies of over 16%. To date, most perovskite solar cells have adopted a structure in which the perovskite light absorber is placed between carrier-selective electron- and hole-transport layers (ETLs and HTLs). Here we report a new type of compact layer free bilayer perovskite solar cell and conclusively demonstrate that the ETL is not a prerequisite for obtaining excellent device efficiencies. We obtained power conversion efficiencies of up to 11.6% and 13.5% when using poly(3-hexylthiophene) and 2,2',7,7'-tetrakis(N,N-di(4-methoxyphenyl)amino)-9,9'-spirobifluorene, respectively, as the hole-transport material. This performance is very comparable to that obtained with the use of a ZnO ETL. Impedance spectroscopy suggests that while eliminating the ZnO leads to an increase in contact resistance, this is offset by a substantial decrease in surface recombination.


Regulation of expression of the casbene synthetase gene during elicitation of castor bean seedlings with pectic fragments.
A castor bean cDNA library has been constructed in the expression vector lambda gt11. Screening of 30,000 plaques with antibodies against casbene synthetase yielded six positive clones, from which three purified clones were obtained after sequential screening. The cDNA inserts in these clones ranged in size from 200 to 500 base pairs and were shown to share homologous sequences. One of the clones (pCS4) was examined in hybrid-selected and hybrid-arrested translation experiments and shown to contain a partial sequence of the casbene synthetase coding region. Northern analysis using the pCS4 clone as a probe revealed that the total hybridizable casbene synthetase mRNA amount increased to a maximum at 6 h after treatment of seedlings with pectic fragment elicitor and then decreased steadily with almost the same kinetics as observed previously for the changes in the translatable casbene synthetase mRNA activity under these same conditions. Run-on transcription experiments were performed with nuclei isolated from castor bean seedlings at various time periods after treatment with pectic fragment elicitors. Transcription of the casbene synthetase gene was first detected at 2 h after elicitation, rose to a maximum at 5 h, and fell rapidly thereafter. These results suggest that the accumulation of casbene synthetase, and hence casbene, is governed primarily by the rate of transcription of the casbene synthetase gene during elicitation by pectic fragments.


Caecal carcinomas in the elderly: useful signs in minimal preparation CT.
Frail, elderly and immobile patients frequently have difficulty in tolerating formal colonic investigations. Caecal tumours may account for up to 35% of colonic tumours. Barium enema and colonoscopy have limitations in assessing this region. The aims of this study were to evaluate the accuracy of a minimal preparation CT technique (merely with prolonged oral contrast medium) in identifying caecal carcinomas and to determine helpful radiological signs. The CT technique involved helical acquisition following 2 days of preparation with oral contrast medium. The outcome of 4 years' experience (1995-1998) was reviewed. The gold-standards were pathological and cancer registration records, together with colonoscopy and barium enema where available, with a minimum of 15 months' follow-up. CT correctly identified 27 of 30 caecal carcinomas, and missed three, in a total of 1077 CT studies in 1031 patients (median age 80 years). There were also 21 false-positive cases in which CT incorrectly raised the possibility of a caecal tumour. The sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were 90%, 98%, 99% and 56%, respectively. Serosal margin blurring, tumour length, presence of abnormal peri-colic fat and terminal ileal wall thickening were identified as useful radiological signs. Minimal preparation CT is able to identify caecal carcinomas with fair accuracy. Such evaluation may become important given the increasing population age and evidence of a 'proximal shift' in the site of colonic tumours in the elderly.


[Relationship among sexual knowledge, frequency, satisfaction, marital intimacy and levels of depression in stroke survivors and their spouses].
The purpose of this research was to examine the relationship between sexual knowledge, frequency, satisfaction, marital intimacy, and depression levels in stroke survivors and their spouses. This study was a convenience sample of Korean men who had experienced a stroke and their spouses. The subjects were discharged from the hospital and received physical therapy. Data such as sexual knowledge, frequency, satisfaction, marital intimacy, and depression levels were collected from November 2005 to April 2006. In a comparison of stroke survivors and their spouses, the survivors showed higher mean levels of sexual knowledge and marital intimacy. The levels of knowledge, frequency, satisfaction and marital intimacy were low and depression was mild in the subjects. There were significant correlations between sexual frequency, sexual satisfaction and marital intimacy. Also, subjects with lower levels of sexual satisfaction were more depressed. The spouses who possessed greater levels of sexual knowledge reported a higher frequency of sex and greater marital intimacy. In addition, spouses who reported feeling greater levels of marital intimacy experienced fewer depressive symptoms. These findings demonstrate a need for the development of sexual adaptation programs which could be effective in improving sexual knowledge, frequency, satisfaction, marital intimacy, and depression reported by stroke patients and their spouses. Ideally, these corrective programs should be administered before patients are discharged from the hospital.


Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing.
Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as 'non-self' neo-antigens by the adaptive immune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However, few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing. We sought to simplify the discovery of immunogenic mutant peptides by characterizing their general properties. We developed an approach that combines whole-exome and transcriptome sequencing analysis with mass spectrometry to identify neo-epitopes in two widely used murine tumour models. Of the >1,300 amino acid changes identified, ∼13% were predicted to bind MHCI, a small fraction of which were confirmed by mass spectrometry. The peptides were then structurally modelled bound to MHCI. Mutations that were solvent-exposed and therefore accessible to T-cell antigen receptors were predicted to be immunogenic. Vaccination of mice confirmed the approach, with each predicted immunogenic peptide yielding therapeutically active T-cell responses. The predictions also enabled the generation of peptide-MHCI dextramers that could be used to monitor the kinetics and distribution of the anti-tumour T-cell response before and after vaccination. These findings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.


Inhibition of 3(17)beta-hydroxysteroid dehydrogenase from Pseudomonas testosteroni by steroidal A ring fused pyrazoles.
Several 2,3- and 3,4-steroidal fused pyrazoles have been investigated as potential inhibitors of NAD(P)H-dependent steroid oxidoreductases. These compounds are proven to be potent, specific inhibitors for 3(17) beta-hydroxysteroid dehydrogenase from Pseudomonas testosteroni with Ki values of 6-100 nM. In contrast, the activities of 3 alpha,20 beta-hydroxysteroid dehydrogenase from Streptomyces hydrogenans, steroid 5 alpha-reductase from rat prostate, and 3 alpha-hydroxysteroid dehydrogenase from rat liver were unaffected by micromolar concentrations of these compounds. Product and dead-end inhibition studies indicate an ordered association to the beta-dehydrogenase with the cofactor binding prior to substrate or inhibitor. From the results of double inhibition experiments, it is proposed that inhibition occurs through formation of an enzyme-NAD+-inhibitor ternate. On the basis of pH profiles of Vm/Km, Vm, and 1/Ki and of absorbance difference spectra, a hypothetical mechanism of inhibition by the steroidal pyrazoles, drawn by analogy from the inhibition of liver alcohol dehydrogenase by alkylpyrazoles [Theorell, H., & Yonetani, T. (1963) Biochem. Z. 338, 537-553; Andersson, P., Kvassman, J. K., Lindström, A., Oldén, B., & Pettersson, G. (1981) Eur. J. Biochem. 113, 549-554], is reconsidered. The pH studies and enzyme modification experiments by diethyl pyrocarbonate suggest the involvement of histidine in binding of the inhibitor. A modified proposal for the structure of the enzyme-NAD+-steroidal pyrazole complex is proposed.(ABSTRACT TRUNCATED AT 250 WORDS)


Combining Results from Distinct MicroRNA Target Prediction Tools Enhances the Performance of Analyses.
Target prediction is generally the first step toward recognition of bona fide microRNA (miRNA)-target interactions in living cells. Several target prediction tools are now available, which use distinct criteria and stringency to provide the best set of candidate targets for a single miRNA or a subset of miRNAs. However, there are many false-negative predictions, and consensus about the optimum strategy to select and use the output information provided by the target prediction tools is lacking. We compared the performance of four tools cited in literature-TargetScan (TS), miRanda-mirSVR (MR), Pita, and RNA22 (R22), and we determined the most effective approach for analyzing target prediction data (individual, union, or intersection). For this purpose, we calculated the sensitivity, specificity, precision, and correlation of these approaches using 10 miRNAs (miR-1-3p, miR-17-5p, miR-21-5p, miR-24-3p, miR-29a-3p, miR-34a-5p, miR-124-3p, miR-125b-5p, miR-145-5p, and miR-155-5p) and 1,400 genes (700 validated and 700 non-validated) as targets of these miRNAs. The four tools provided a subset of high-quality predictions and returned few false-positive predictions; however, they could not identify several known true targets. We demonstrate that union of TS/MR and TS/MR/R22 enhanced the quality of in silico prediction analysis of miRNA targets. We conclude that the union rather than the intersection of the aforementioned tools is the best strategy for maximizing performance while minimizing the loss of time and resources in subsequent in vivo and in vitro experiments for functional validation of miRNA-target interactions.


Autologous bone marrow transplantation in the treatment of malignant lymphoma and Hodgkin's disease.
High-dose chemotherapy, both with and without radiotherapy, was pioneered in the treatment of acute leukemia in relapse with allogeneic transplantation, exploiting the steep dose-response curve characteristic of some hematologic neoplasms. Extension to the malignant lymphomas was strengthened by early success in Burkitt's lymphoma and in syngeneic transplantation for lymphoma. The optimal regimen (BACT [carmustine, cytarabine, cyclophosphamide, 6-thioguanine]) and setting are still under investigation for the various grades of lymphomas. The early published experience demonstrated a low ultimate "cure" rate when transplantation was performed in advanced, bulky, and refractory disease. A survey of published reports up to 1986 showed only 16 of 112 long-term, disease-free survivors when autologous bone marrow transplantation (ABMT) was performed in refractory relapse as opposed to 33 of 53 for patients transplanted in second or subsequent remission or in first partial remission. Refractoriness to conventional-dose chemotherapy (no response or progressive disease) cannot be salvaged in the majority of cases. Bone marrow involvement complicates the use of ABMT and may require in vitro elimination with monoclonal antibodies/complement or cytotoxic chemicals. The Dana-Farber Cancer Institute experience shows that the former in vitro treatment does not inhibit bone marrow grafting. When selection criteria for ABMT are applied in drug-sensitive relapse, 50% to 60% long-term, disease-free survival may be expected. Definition of poor prognostic factors in large cell lymphoma may identify patients for ABMT as consolidation of first remission. The issue of marrow purging is unsettled at the present time.(ABSTRACT TRUNCATED AT 250 WORDS)


Differentiated resistance training of the paravertebral muscles in patients with unstable spinal bone metastasis under concomitant radiotherapy: study protocol for a randomized pilot trial.
Metastatic bone disease is a common and severe complication in patients with advanced cancer. Radiotherapy (RT) has long been established as an effective local treatment for metastatic bone disorder. This study assesses the effects of RT combined with muscle-training exercises in patients with unstable bone metastases of the spinal column from solid tumors. The primary goal of this study is to evaluate the feasibility of muscle-training exercises concomitant to RT. Secondly, quality of life, fatigue, overall and bone survival, and local control will be assessed. This study is a single-center, prospective, randomized, controlled, explorative intervention study with a parallel-group design to determine multidimensional effects of a course of exercises concomitant to RT on patients who have unstable metastases of the vertebral column, first under therapeutic instruction and subsequently performed by the patients themselves independently for strengthening the paravertebral muscles. On the days of radiation treatment the patients will be given four different types of exercises to ensure even isometric muscle training of all the spinal muscles. In the control group progressive muscle relaxation will be carried out parallel to RT. The patients will be randomized into two groups: differentiated muscle training or progressive muscle relaxation with 30 patients in each group. Despite the clinical experience that RT is an effective treatment for bone metastases, there is insufficient evidence for a positive effect of the combination with muscle-training exercises in patients with unstable bone metastases. Our previous DISPO-1 trial showed that adding muscle-training exercises to RT is feasible, whereas this was not proven in patients with an unstable spinal column. Although associated with several methodological and practical challenges, this randomized controlled trial is needed. ClinicalTrials.gov, identifier: NCT02847754 . Registered on 27 July 2016.


Marijuana neurobiology and treatment.
Marijuana is the number one illicit drug of abuse worldwide and a major public health problem, especially in the younger population. The objective of this article is to update and review the state of the science and treatments available for marijuana dependence based on a pre-meeting workshop that was presented at ISAM 2006. At the workshop, several papers were presented addressing the neurobiology and pharmacology of marijuana and treatment approaches, both psychotherapy and medications, for marijuana withdrawal. Medicolegal and ethical issues concerning marijuana medical use were also discussed. Concise summaries of these presentations are incorporated in this article, which is meant to be an updated review of the state of the science. Major advances have been made in understanding the underpinning of marijuana dependence and the role of the CNS cannabinoid system, which is a major area for targeting medications to treat marijuana withdrawal and dependence, as well as other addictions. Behavioral therapies are efficacious for facilitating abstinence from marijuana. Nefazadone, Marinol, and buspirone are showing early positive signals for efficacy in ameliorating marijuana withdrawal symptoms. Effective psychotherapeutic approaches are available and promising medications studies need to be confirmed in outpatient trials. The next few years looking promising for translational research efforts to make treatment widely accessible to patients with marijuana dependence.


Probing the structure of human tRNA3Lys in the presence of ligands using docking, MD simulations and MSM analysis.
The tRNA3Lys, which acts as a primer for human immunodeficiency virus type 1 (HIV-1) reverse transcription, undergoes structural changes required for the formation of a primer-template complex. Small molecules have been targeted against tRNA3Lys to inhibit the primer-template complex formation. The present study aims to understand the kinetics of the conformational landscape spanned by tRNA3Lys in apo form using molecular dynamics simulations and Markov state modeling. The study is taken further to investigate the effect of small molecules like 1,4T and 1,5T on structural conformations and kinetics of tRNA3Lys, and comparative analysis is presented. Markov state modeling of tRNA3Lys apo resulted in three metastable states where the conformations have shown the non-canonical structures of the anticodon loop. Based on analyses of ligand-tRNA3Lys interactions, crucial ion and water mediated H-bonds and free energy calculations, it was observed that the 1,4-triazole more strongly binds to the tRNA3Lys compared to 1,5-triazole. However, the MSM analysis suggest that the 1,5-triazole binding to tRNA3Lys has brought rigidity not only in the binding pocket (TΨC arm, D-TΨC loop) but also in the whole structure of tRNA3Lys. This may affect the easy opening of primer tRNA3Lys required for HIV-1 reverse transcription.


Distinct neurolinguistic symptom clusters in Alzheimer's-type dementia and primary progressive aphasia.
Mesulam's (1982) report describing six patients with a slowly progressive aphasia without accompanying signs of dementia led to the recognition of a syndrome now known as Primary Progressive Aphasia (PPA). Many more patients have been described since Mesulam's description was published (see Westbury & Bub, 1997, for a review). However, the published literature is both unsystematic and incomplete, making it difficult to place the findings into a coherent theoretical framework. In addition, little previous work (see Mesulam, 1987) has specifically attempted to specify the difference between PPA and dementia of Alzheimer's type (DAT), although the two disorders are easily confused since many language deficits can masquerade on early presentation as memory or cognitive deficits. In this paper, the linguistic deficits of 11 PPA patients are analyzed, and contrasted with the linguistic deficits of a group of 11 DAT patients. Patients in both groups were tested using an extensive battery of language tests, the Psycholinguistic Assessment of Language Battery (Caplan & Bub, 1990; Caplan, 1992). We consider seven linguistic symptom clusters that differentiate the two groups.