Association of Secondary Health Conditions With Future Chronic Health Conditions Among Persons With Traumatic Spinal Cord Injury.
Secondary health conditions (SHC) are physical and mental health conditions that are causally related to disabilities. Studies have found that SHC increase risk of negative health outcomes among people with traumatic spinal cord injury (TSCI). However, little has been done to assess the association of SHC with the risk of chronic health conditions (CHC) after TSCI. To identify the prevalence of CHC in adults with TSCI, changes in CHC at follow-up, and the associations of baseline SHC with future CHC. Participants included 501 adults with TSCI of at least 1-year duration, identified through a population-based surveillance system. Baseline and follow-up self-report assessments were completed. We measured seven SHC: fatigue, spasticity, pain, pressure ulcers, subsequent injury, fracture, and anxiety disorder, and measured seven CHC: diabetes, heart attack, coronary artery disease, stroke, cancer, hypertension, and high blood cholesterol. Control variables included gender, race/ethnicity, age at injury, years post injury, injury severity, smoking status, binge drinking, and taking prescription medication. We implemented a Poisson regression model for the multivariate analyses. The total number of CHC, the percentage of participants having at least one CHC, and prevalence of three individual CHC (diabetes, cancer, and high cholesterol) increased from baseline to follow-up. After controlling for demographic, injury characteristics, and behavioral factors, pain interference and anxiety disorder at baseline were associated with the total number of CHC at follow-up. CHC are common among adults with TSCI and increase significantly over time. Pain and anxiety disorders appear to be risk factors for future CHC.


Analysis of clinicopathologic characteristics and prognosis of gastric cancer in patients <40 years.
An increase trend and a bad prognosis toward gastric cancer (GC) in individuals <40 years have been observed over the past few decades. GC in Young adult needs further evaluation to identify clear risk factors for early screening and better prognosis. A total of 126 young adult patients with gastric cancer (individuals <40 years) (YG) were collected in Liaocheng hospital in China from Jan 2003 to Dec 2019. The overall median follow-up was 96.5 months (rang 1-192 months). Survival was determined by the Kaplan-Meier method and the difference in survival among different subgroups were assessed using the log-lank test. Correlations between risk factors and overall survival were assessed by univariate and multivariate Cox proportional hazards regression analysis. Advanced stage cancer at onset and undifferentiated histologic tumor type were the prominent clinicopathological features of YG. The 5-year overall survival of the YG was 31.7%. The 5-year survival of the YG differed from tumor staging and treatment methods. The 5-year survival was 100% in stage I group, 58.8% in stage II group, 22.6% in stage III group, and 8.3% in stage IV group respectively. The 5-year survival was 52.1% in the curative resection group versus 3.8% in the non-curative resection group. Multivariate analysis displayed that tumor staging (P = .002) and treatment method (P = .034) were 2 independent prognostic predictors for survival. GC in young adult patients have unique clinicopathological features. Upper gastrointestinal endoscopy should regularly perform for young adult especially those symptomatic patients. Early diagnosis and then proceed to a successful curative resection are vital for a better prognosis.


Elicitation of Casbene Synthetase Activity in Castor Bean : THE ROLE OF PECTIC FRAGMENTS OF THE PLANT CELL WALL IN ELICITATION BY A FUNGAL ENDOPOLYGALACTURONASE.
Endopolygalacturonase isolated from culture filtrates of the fungus Rhizopus stolonifer was shown previously to act as an elicitor of biosynthetic capacity for the antifungal agent, casbene, in castor bean (Ricinus communis L.) seedlings (S.-C. Lee, C.A. West 1981 Plant Physiology 67:633-639). Selective amidation of exposed carboxyl groups of the pure fungal endopolygalacturonase using intermediate activation with a water-soluble carbodiimide under mild conditions leads to inactivation of its enzymic activity. Tests of active and partially inactivated preparations of the enzyme reveal a close correlation between the levels of catalytic and elicitor activities. This suggests that the catalytic activity of the enzyme is necessary for its function as an elicitor. Treatment of the cell-free particulate fraction of homogenates of castor bean seedlings with the active fungal endopolygalacturonase results in the production of a heat-stable, water-soluble component which is highly active as an elicitor of casbene synthetase activity. Several additional lines of evidence, including the susceptibility of the heat-stable elicitor fraction to partial inactivation following prolonged treatment with endopolygalacturonase, indicate that the heat-stable elicitor is most likely a pectic fragment of the plant cell wall and that it is a required intermediate in the process of elicitation of casbene synthetase activity by the fungal endopolygalacturonase.


Erectile dysfunction: a need for greater awareness.
Research has led to effective treatment regimes for erectile dysfunction (ED). Convincing evidence links vascular risk factors (hypertension, diabetes mellitus, hyperlipidaemia and smoking) with ED. This association is not surprising since the corpus cavernosum is a modified vascular tissue. This review presents a brief account of the aetiology, diagnosis and treatment of ED. There is a need to raise awareness of this condition and to make appropriate treatment available to patients.


Translational gene expression control in Chlamydia trachomatis.
The human pathogen Chlamydia trachomatis proceeds through a multi phenotypic developmental cycle with each cell form specialized for different roles in pathogenesis. Understanding the mechanisms regulating this complex cycle has historically been hampered by limited genetic tools. In an effort to address this issue, we developed a translational control system to regulate gene expression in Chlamydia using a synthetic riboswitch. Here we demonstrate that translational control via a riboswitch can be used in combination with a wide range of promoters in C. trachomatis. The synthetic riboswitch E, inducible with theophylline, was used to replace the ribosome binding site of the synthetic promoter T5-lac, the native chlamydial promoter of the pgp4 plasmid gene and an anhydrotetracycline responsive promoter. In all cases the riboswitch inhibited translation, and high levels of protein expression was induced with theophylline. Combining the Tet transcriptional inducible promoter with the translational control of the riboswitch resulted in strong repression and allowed for the cloning and expression of the potent chlamydial regulatory protein, HctB. The ability to control the timing and strength of gene expression independently from promoter specificity is a new and important tool for studying chlamydial regulatory and virulence genes.


Dapagliflozin attenuates hypoxia/reoxygenation-caused cardiac dysfunction and oxidative damage through modulation of AMPK.
Emerging evidence demonstrated dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, prevented various cardiovascular events. However, the detailed mechanisms underlying its cardioprotective properties remained largely unknown. In the present study, we sought to investigate the effects of DAPA on the cardiac ischemia/reperfusion (I/R) injury. Results from in vitro experiments showed that DAPA induced the phosphorylation of AMPK, resulting in the downregulation of PKC in the cardiac myoblast H9c2 cells following hypoxia/reoxygenation (H/R) condition. We demonstrated that DAPA treatment diminished the H/R-elicited oxidative stress via the AMPK/ PKC/ NADPH oxidase pathway. In addition, DAPA prevented the H/R-induced abnormality of PGC-1α expression, mitochondrial membrane potential, and mitochondrial DNA copy number through AMPK/ PKC/ NADPH oxidase signaling. Besides, DAPA reversed the H/R-induced apoptosis. Furthermore, we demonstrated that DAPA improved the I/R-induced cardiac dysfunction by echocardiography and abrogated the I/R-elicited apoptosis in the myocardium of rats. Also, the administration of DAPA mitigated the production of myocardial infarction markers. In conclusion, our data suggested that DAPA treatment holds the potential to ameliorate the I/R-elicited oxidative stress and the following cardiac apoptosis via modulation of AMPK, which attenuates the cardiac dysfunction caused by I/R injury.


Aiming higher for maternal and child nutrition in South Asia.
The sustainable development of nations relies on children developing to their full potential and leading healthy, productive, and prosperous lives. Poor nutrition in early life threatens the growth and development of children, especially so in South Asia, which has the highest burdens of stunting, wasting, and anaemia in the world. Targeted actions to reduce stunting and other forms of child malnutrition in South Asia should be informed by an understanding of what drives poor nutrition in children, who is most affected, and effective programme approaches. To this end, the UNICEF Regional Office for South Asia commissioned a series of papers in 2016-2017 to fill knowledge gaps in the current body of evidence on maternal and child nutrition in South Asia, including analyses of: (a) the links between anthropometric failure in children and child development; (b) the time trends, current distribution, disparities and inequities of child stunting, wasting and anaemia, and their direct and underlying causes, including maternal anaemia, low birth weight, breastfeeding, and complementary feeding; (c) policy and programme actions to increase the coverage of nutrition interventions during pregnancy, improve breastfeeding practices, and care for severely wasted children. This overview paper summarizes the evidence from these analyses and examines the implications for the direction of future advocacy, policy, and programme actions to improve maternal and child nutrition in South Asia.


Widowhood in the Israeli Arab Muslim Society.
Adjustment of Israeli Arab Muslim widows to the traumatic loss of their husbands was examined by comparing their reported ways of coping with those of married women of their community by means of the Two-Track-Bereavement Model. Participants included 93 widows and 86 comparable married women who were mostly middle aged and of middle class. We hypothesized that widows will express concurrently greater suffering and higher resilience to adverse life events compared with married women. It was hypothesized further that positive and close relations to a deceased husband will be reported by Arab widows as well as Arab married women. However, positive relationships of married women will correlate with their own coping supporting attributes, whereas positive relations of widows to their deceased husband will not be associated with their individual characteristics. Results indicated a fourfold factor structure of the bereavement and coping scale which differed from those obtained by Israeli Jewish women and generally supported these hypotheses. It appears that traumatic loss of a husband may enhance widows' resilience.


Predicting the sorption of fatty alcohols and alcohol ethoxylates to effluent and receiving water solids.
Alcohol ethoxylates (AEs) are an important group of nonionic surfactants. Commercial AEs consist of a mixture of several homologues of varying carbon chain length (Cx) and degree of ethoxylation (EOy). The major disposal route of AE is down the drain to municipal wastewater treatment plants that discharge into receiving surface waters. Sorption of AE homologues onto activated sludge and river water solids is an important factor in assessing exposure of AE in the environment. This study presents the experimental determination of sorption coefficients for a wide array of AE homologues including five alcohols under environmentally relevant conditions and combines these data with literature data to generate a predictive model for the sorption of AEs in the environment. These results demonstrate that sorption can be effectively modeled using a log Kd vs. Cx and EOy predictive equation having the form log Kd = 0.331C - 0.00897EO - 1.126(R2 = 0.64).


Early blood gas abnormalities and the preterm brain.
The authors explored associations between blood gas abnormalities in more than 1,000 preterm infants during the first postnatal days and indicators of neonatal brain damage. During 2002-2004, women delivering infants before 28 weeks' gestation at one of 14 participating institutions in 5 US states were asked to enroll in the study. The authors compared infants with blood gas values in the highest or lowest quintile for gestational age and postnatal day (extreme value) on at least 1 of the first 3 postnatal days with the remainder of the subjects, with separate analyses for blood gas abnormalities on multiple days and for partial pressure of oxygen in the alveolar gas of <35. Outcomes analyzed were ventriculomegaly and an echolucent lesion on an ultrasound scan in the neonatal intensive care unit, and cerebral palsy, microcephaly, and a low score on a Bayley Scale of Infant Development at 24 months. Every blood gas derangement (hypoxemia, hyperoxemia, hypocapnia, hypercapnia, and acidosis) was associated with multiple indicators of brain damage. However, for some, the associations were seen with only 1 day of exposure; others were evident with 2 or more days' exposure. Findings suggest that individual blood gas derangements do not increase brain damage risk. Rather, the multiple derangements associated with indicators of brain damage might be indicators of immaturity/vulnerability and illness severity.


Insulin resistance and hypertension.
The author has reviewed the development of the concept that insulin resistance is related not only to the hypertensive state but potentially to the initiation and maintenance of high blood pressure. Potential sequelae of insulin resistance and hyperinsulinemia, as they apply to atherogenesis, are also discussed. The impact of present antihypertensive pharmacologic therapy on insulin resistance is addressed, as are future directions in pharmacologic and nonpharmacologic management of hypertension. In addition, the author speculates on possible mechanisms leading to insulin resistance in hypertension.


Isozymes of ribonuclease and the changes in their relative levels during development in the cellular slime mould Dictyostelium discoideum.
The isozymes of ribonuclease were analyzed in cell-free, crude extracts of Dictyostelium discoideum by activity staining of polyacrylamide gels after electrophoresis. The relative levels of three isozymes were then examined during the growth and during the first stages of multicellular development. We observed the replacement of two of these three isozymes by two other isozymes at the pseudoplasmodial stage. These isozymes were different from ribonuclease T1 in terms of their mobility in polyacrylamide gels during electrophoresis. The mobilities of two of the isozymes, DdI and DdII, were 59 and 42% of that of ribonuclease T1. The changes in the relative levels of the isozymes during development are discussed.


Plasma from hemorrhaged mice activates CREB and increases cytokine expression in lung mononuclear cells through a xanthine oxidase-dependent mechanism.
Hemorrhage rapidly increases plasma xanthine oxidase levels as well as the expression of proinflammatory and immunoregulatory cytokines in the lungs. To determine the role of circulating xanthine oxidase (XO), as well as other plasma factors, in affecting pulmonary cytokine expression, we conducted studies in which plasma from hemorrhaged mice was transferred into unhemorrhaged recipient mice. Administration of posthemorrhage plasma to recipient mice increased the levels of mRNA for interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta 1 (TGF-beta 1) in lung mononuclear cells. No enhancement of mRNA levels for these cytokines was found in the lungs of mice given allopurinol-treated posthemorrhage plasma or fed a tungsten-enriched, XO-depleting diet prior to transfer of posthemorrhage plasma. Among the nuclear transcriptional regulatory factors examined, only the cyclic AMP response-element binding protein (CREB) was activated in nuclear extracts from lung mononuclear cells of mice that were given posthemorrhage plasma. No activation of nuclear factor-kappa B (NF-kappa B), nuclear factor interleukin 6 (NF-IL6), activating protein-1 (AP-1), or serum protein-1 (SP-1) was found. These results suggest that the mechanism for hemorrhage-induced increases in pulmonary cytokine expression is by activation of the enhancer CREB through a tissue XO-dependent pathway initiated by plasma-borne mediators.


[Amenorrhea in athletic adolescents : the tip of the iceberg].
The female athletic triad refers to the interaction between menstrual function, energy availability and bone density. When an imbalance appears between energy input and output, the global health of the athletic teenager is at risk of somatic and/or psychological complications as defined by the RED-S (Relative Energy Deficiency in Sports). In athletic girls menstrual disorder should be seen as an alert. It may be difficult to distinguish it from menstrual irregularity due to immature hypothalamic-hyphophysic-gonadal axis, which can be physiological at that age. A multidisciplinary approach is needed. The challenge is to find a balance between sport practice and prevention of complications due to lack of estrogens.


Effect of Leaf Detachment on Chlorophyll Fluorescence during Chilling Experiments.
The effect of leaf detachment on chlorophyll fluorescence was analyzed for Zea mays, Cucumis sativus, Phaseolus vulgaris, and Echinochloa crus-galli. Results clearly indicate that detachment hastens the decrease in chlorophyll fluorescence during the course of chilling experiments. For maize and bean, the activity of photosystem II of chloroplasts isolated from detached leaves is lower than that of chloroplasts isolated from attached leaves. There are also large differences in ionic loss between detached and attached leaves of barnyard grass which could correlate with changes in leaf water status. The detached leaves lost some 50% of their total ionic content. Finally, detachment alters the ranking of the species with regard to their chilling tolerance.


Adherence to pharmacotherapy in patients with alcohol and opioid dependence.
An important factor that has thus far limited the effectiveness of pharmacotherapies for patients with alcohol and opioid dependence is poor adherence to medication regimens. This paper presents a review of issues related to medication adherence in patients with these substance use disorders. A literature review was conducted of English language publications relating to medication adherence among patients with alcohol or opioid dependence. The paper places the topic in the context of adherence difficulties among patients with a variety of chronic medical and psychiatric illnesses. Difficulties measuring adherence are discussed, and strategies to improve medication adherence are reviewed. These include specific interventions that prescribing clinicians can implement in their individual meetings with patients; the use of external reinforcers, such as positive and negative contingencies, and involvement of family members or significant others; and specific prescribing and dosing practices that may improve adherence. As the use of pharmacotherapy for substance-dependent patients increases, rigorous and innovative approaches to encourage medication adherence should be sought.


MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells.
Natural killer (NK) cells recognize stress‑activated NK group 2, member D (NKG2D) ligands in tumors. In the present study, the expression levels of NKG2D ligands were examined in four lung cancer cell lines (A549, PLA801D, NCI‑H157 and NCI‑H520). In the A549 cells, the expression of MHC class I polypeptiderelated sequence (MIC)A/B and UL16 binding protein (ULBP)1 was weak, the expression of ULBP2 was typical, and neither ULBP3 nor ULBP4 were expressed. The mechanism underlying the regulatory effect of a cancer treatment agent on the expression of NKG2D ligands was investigated using the proteasome inhibitor MG132. Following treatment for 8 h with MG132, the transcription levels of MICB and ULBP1 were upregulated 10.62‑ and 11.09‑fold, respectively, and the expression levels of MICB and ULBP1 were increased by 68.18 and 23.65%, respectively. Notably, MICB exhibited significant time‑dependent change. MG132 increased the transcription of MICB by acting at a site in the 480‑bp MICB upstream promoter. The activity of the MICB promoter was upregulated 1.77‑fold following treatment with MG132. MG132 treatment improved the cytotoxicity of NK cells, which was partially blocked by an antibody targeting NKG2D, and more specifically the MICB molecule. The expression of MICB induced by MG132 was inhibited by KU‑55933 [ataxia telangiectasia mutated (ATM) kinase inhibitor], wortmannin (phosphoinositide 3 kinase inhibitor) and caffeine (ATM/ATM‑Rad3‑related inhibitor). The phosphorylation of checkpoint kinase 2 (Chk2), an event associated with DNA damage, was observed following treatment with MG132. These results indicated that MG132 selectively upregulates the expression of MICB in A549 cells, and increases the NKG2D‑mediated cytotoxicity of NK cells. The regulatory effect of MG132 may be associated with the activation of Chk2, an event associated with DNA damage. The combination of MG132 with NK cell immunotherapy may have a synergistic effect that improves the therapeutic effect of lung cancer treatment.


Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. 4. 2-Substituted dipyridodiazepinones as potent inhibitors of both wild-type and cysteine-181 HIV-1 reverse transcriptase enzymes.
The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT). An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wild-type and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 2-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (L100I RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.


Validity and reliability of the FSS in Greek MS patients.
The study provided validity and reliability evidence of the Fatigue Severity Scale (FSS) in Greek patients with multiple sclerosis (MS). The FSS was administered to 72 MS patients, without co morbid fatigue and 75 matched paired controls with respect to gender and age. Both groups responded to the FSS, SF-36v2, BDI-II and a demographic questionnaire on two time points separated by a 1-week interval. Exploratory and confirmatory factor analysis was performed to test construct validity, concurrent and divergent validity, internal and test-retest reliability were also examined. Exploratory and confirmatory factor analysis, intercorrelations with BDI-II (r = 0.552, p < 0.01) and SF-36v2 vitality (r = -0.715, p < 0.01) and physical functioning (r = -0.673, p < 0.01) subscales, and differences between patients and non patients (t (145) = 6.007, p < 0.001), revealed sufficient construct, concurrent and divergent validity evidence. The factor analysis demonstrated a unidimensional structure Cronbach alpha (0.953) and ICC (0.889) was high, indicating that the responses of our sample were internally consistent and stable across time. The Greek version of FSS is valid and reliable and may be used by clinicians and researchers to assess fatigue of Greek MS patients.


Learning State Assessment in Online Education Based on Multiple Facial Features Detection.
Considering that most of online training is not effectively supervised, this article presents an online leaning state assessment approach which combines blink detection, yawn detection, and head pose estimation. Blink detection is realized by computing the eye aspect ratio and the ratio of closed eye frames to the total frames per unit time to evaluate the degree of eye fatigue. Yawn detection is implemented by computing the aspect ratio of the mouth by using the feature points of the inner lip and combining it with the time of opening mouth to distinguish the mouth state. Head pose estimation is first implemented by calculating the head rotation matrix by matching the feature points of 2D face with the 3D face model and then calculating the Euler angle of the head according to the rotation matrix to evaluate the change of the head pose. Especially in yawn detection, we employ the feature points of inner lips in the calculation of the mouth aspect ratio to avoid the impact of lip thickness of various participants. Furthermore, the blink detection, yawn detection, and head pose estimation are first calculated based on the two-dimensional grayscale image of human face, which could reduce the computational complexity and improve the real-time performance of detection. Finally, combining the values of blinking, yawning, and head pose, multiple groups of experiments are carried out to assess the state of different online learners; then, the learning state is evaluated by analyzing the numerical changes of the three characteristics. Experimental results show that our approach could effectively evaluate the state of online learning and provide support for the development of online education.


Thermoresponsive Molecular Brushes with a Rigid-Chain Aromatic Polyester Backbone and Poly-2-alkyl-2-oxazoline Side Chains.
A new polycondensation aromatic rigid-chain polyester macroinitiator was synthesized and used to graft linear poly-2-ethyl-2-oxazoline as well as poly-2-isopropyl-2-oxazoline by cationic polymerization. The prepared copolymers and the macroinitiator were characterized by NMR, GPC, AFM, turbidimetry, static, and dynamic light scattering. The molar masses of the polyester main chain and the grafted copolymers with poly-2-ethyl-2-oxazoline and poly-2-isopropyl-2-oxazoline side chains were 26,500, 208,000, and 67,900, respectively. The molar masses of the side chains of poly-2-ethyl-2-oxazoline and poly-2-isopropyl-2-oxazoline and their grafting densities were 7400 and 3400 and 0.53 and 0.27, respectively. In chloroform, the copolymers conformation can be considered as a cylinder wormlike chain, the diameter of which depends on the side chain length. In water at low temperatures, the macromolecules of the poly-2-ethyl-2-oxazoline copolymer assume a wormlike conformation because their backbones are well shielded by side chains, whereas the copolymer with short side chains and low grafting density strongly aggregates, which was visualized by AFM. The phase separation temperatures of the copolymers were lower than those of linear analogs of the side chains and decreased with the concentration for both samples. The LCST were estimated to be around 45 °C for the poly-2-ethyl-2-oxazoline graft copolymer, and below 20 °C for the poly-2-isopropyl-2-oxazoline graft copolymer.


Polymorphous light eruption: experimental reproduction of skin lesions by whole-body UVA irradiation.
Fifty patients suffering from polymorphous light eruption (PLE), selected by criteria pointing to UVA sensitivity, were phototested with 2 different polychromatic UVA sources for reproduction of skin lesions. To simulate natural conditions, the patients were whole-body irradiated for up to 5 consecutive days. In 64% of the patients successful reproduction of PLE lesions was obtained by 1 to 4 irradiations. The total dosage ranged from 20 to 280 J/cm2, and the total exposure times from 10 to 60 min. Our results suggest that irradiation of the whole body in UVA-sensitive PLE patients does not provide more convincing test results than phototesting of small previously involved skin sites, as has been done by other groups.


Stable single-frequency he-ne laser.
A simple single-frequency He-Ne laser is described in which the cavity ength is designed to be of high stability. The components are precision-made by standard workshop methods so that the laser requires no adjustments after assembly and the reflectors and capillary plasma tube are readily replaceable. Over a period of hours, frequency stability was within 0.01 ppm, with the krypton-86 primary wavelength standard as reference.


Optimal configuration of a three-rod ortho-bridge system in the treatment of Vancouver type B1 periprosthetic femoral fractures: A finite element analysis.
Periprosthetic femoral fractures (PFF) represent an increasing clinical and economic burden. This study aims to determine the optimal configuration of a bridge-combined internal fixation system in the treatment of Vancouver type B1 PFF, using finite element analysis. A three-rod ortho-bridge system (OBS) fixation model was used to evaluate the optimal configuration of four target parameters: position of the third rod; intersection angle between the proximal screws; connecting rod diameter; and number of screws used. Femoral displacement and the maximum von Mises stress of the OBS were used as the evaluation indices, to analyze the PFF and to determine the optimal use of an OBS. For each parameter, various candidate options were tested. Finite element analysis revealed that the rate of femoral displacement and the maximum von Mises stress of the OBS were at a minimum when there was a 35 mm downward movement of the third rod from the baseline. Therefore, the optimal position of third rod fixation was 35 mm below the fovea capitis of the femur. The optimal intersection angles between the proximal screws were found to be 71.92° or 84°. A 6 mm diameter connecting rod proved to be most effective. Configuration d, utilizing 7 screws, represented the most clinically appropriate screw number configuration, despite configuration f, utilizing 9 screws, eliciting the best evaluation indices. An OBS used in the above-described configuration is well suited to the characteristics of PFF and provides an effective and reliable means for their treatment.


A novel oral iron-complex formulation: Encapsulation of hemin in polymeric micelles and its in vitro absorption.
Anemia resulting from iron deficiency is one of the most prevalent diseases in the world. As iron has important roles in several biological processes such as oxygen transport, DNA synthesis and cell growth, there is a high need for iron therapies that result in high iron bioavailability with minimal toxic effects to treat patients suffering from anemia. This study aims to develop a novel oral iron-complex formulation based on hemin-loaded polymeric micelles composed of the biodegradable and thermosensitive polymer methoxy-poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl)methacrylamide-dilactate], abbreviated as mPEG-b-p(HPMAm-Lac2). Hemin-loaded micelles were prepared by addition of hemin dissolved in DMSO:DMF (1:9, one volume) to an aqueous polymer solution (nine volumes) of mPEG-b-p(HPMAm-Lac2) followed by rapidly heating the mixture at 50°C to form hemin-loaded micelles that remain intact at room and physiological temperature. The highest loading capacity for hemin in mPEG-b-p(HPMAm-Lac2) micelles was 3.9%. The average particle diameter of the hemin-micelles ranged from 75 to 140nm, depending on the concentration of hemin solution that was used to prepare the micelles. The hemin-loaded micelles were stable at pH 2 for at least 3 h which covers the residence time of the formulation in the stomach after oral administration and up to 17 h at pH 7.4 which is sufficient time for uptake of the micelles by the enterocytes. Importantly, incubation of Caco-2 cells with hemin-micelles for 24 h at 37°C resulted in ferritin levels of 2500ng/mg protein which is about 10-fold higher than levels observed in cells incubated with iron sulfate under the same conditions. The hemin formulation also demonstrated superior cell viability compared to iron sulfate with and without ascorbic acid. The study presented here demonstrates the development of a promising novel iron complex for oral delivery.


Periostin deficiency increases bone damage and impairs injury response to fatigue loading in adult mice.
Bone damage removal and callus formation in response to fatigue loading are essential to prevent fractures. Periostin (Postn) is a matricellular protein that mediates adaptive response of cortical bone to loading. Whether and how periostin influences damage and the injury response to fatigue remains unknown. We investigated the skeletal response of Postn(-/-) and Postn(+/+) mice after fatigue stimulus by axial compression of their tibia. In Postn(+/+) mice, cracks number and surface (CsNb, CsS) increased 1h after fatigue, with a decrease in strength compared to non-fatigued tibia. At 15 days, CsNb had started to decline, while CtTV and CtBV increased in fatigued vs non-fatigued tibia, reflecting a woven bone response that was present in 75% of the fatigued bones. Cortical porosity and remodelling also prominently increased in the fatigued tibia of Postn(+/+) mice. At 30 days, paralleling a continuous removal of cortical damage, strength of the fatigued tibia was similar to the non-fatigue tibia. In Postn(-/-) mice, cracks were detectable even in the absence of fatigue, while the amount of collagen crosslinks and tissue hardness was decreased compared to Postn(+/+). Fatigue significantly increased CsNb and CsS in Postn(-/-), but was not associated with changes in CtTV and CtBV, as only 16% of the fatigued bones formed some woven bone. Cortical porosity and remodelling did not increase either after fatigue in Postn(-/-), and the level of damage remained high even after 30 days. As a result, strength remained compromised in Postn(-/-) mice. Contrary to Postn(+/+), which osteocytic lacunae showed a change in the degree of anisotropy (DA) after fatigue, Postn(-/-) showed no DA change. Hence periostin appears to influence bone materials properties, damage accumulation and repair, including local modeling/remodeling processes in response to fatigue. These observations suggest that the level of periostin expression could influence the propensity to fatigue fractures.


A population-based study of 135 lymphomas after solid organ transplantation: The role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival.
Epstein-Barr virus (EBV) plays a major role in the development of post-transplant lymphoproliferative disorder (PTLD), but there is an increasing awareness of EBV-negative PTLD. The clinical presentation of EBV-negative PTLD has not been as well characterised as EBV-positive cases. Further, there is limited knowledge on the clinical importance of diffuse large B-cell lymphoma (DLBCL) cell of origin subtype post-transplant. We studied the role of EBV, hepatitis C (HCV) and DLBCL subtype in clinical presentation and survival in 135 post-transplant lymphomas diagnosed 1980-2006 in a population-based cohort of 10 010 Swedish solid organ transplant recipients. The lymphomas were re-evaluated according to WHO 2008, examined for EBV, and clinical data were collected from medical records. Lymphoma incidence rate was 159/100 000 person-years and is also reported by lymphoma subtype. EBV-negative lymphomas constituted 48% and were associated with HCV infection (p = 0.02), bone marrow involvement (p < 0.001), and T-cell phenotype (p = 0.002). Among DLBCL, 78% were of non-germinal centre subtype, which was associated with EBV-positivity (69%, p = 0.001), early occurrence (p = 0.03), heart/liver/lung/pancreas recipients (p = 0.02), anti-T-cell globulin (p = 0.001), and tacrolimus treatment (p = 0.02). DLBCL subtypes had similar overall survival. Five-year overall survival was 42% in all treated patients. Independent poor prognostic factors were older age, B symptoms, ECOG 2-4, kidney/pancreas/heart recipients, T-cell lymphoma, and HCV-infection. With long follow-up, a large part of PTLD is EBV-negative, due to a high proportion of T-cell lymphomas and low of polymorphic PTLD. EBV-negative PTLD have a different clinical presentation. HCV may play an aetiological role in late-onset PTLD and was revealed as a new prognostic factor for inferior survival that needs to be confirmed in larger studies. The heavier immunosuppression in non-kidney transplantations seems to play a role in the development of non-germinal centre DLBCL. DLBCL cell of origin subtype lacks prognostic importance in the transplant setting.


A prophage-encoded nonclassical secretory protein of "Candidatus Liberibacter asiaticus" induces a strong immune response in Nicotiana benthamiana and citrus.
Huanglongbing (HLB), associated with "Candidatus Liberibacter asiaticus" (CLas), is a globally devastating plant disease. The highly reduced genome of CLas encodes a number of secretory proteins. The conserved prophage-encoded protein AGH17470 is herein identified as a nonclassical secretory protein. We confirmed that the N-terminal and C-terminal sequences jointly determine the secretion of AGH17470. The transient expression of AGH17470 protein in Nicotiana benthamiana caused hypersensitive response (HR) cell death in infiltrated leaves and systemically infected leaves as well as the dwarfing of the entire plant, suggesting that AGH17470 is involved in the plant immune response, growth, and development. Overexpression of AGH17470 in N. benthamiana and citrus plants up-regulated the transcription of pathogenesis-related and salicylic acid (SA)-signalling pathway genes and promoted SA accumulation. Furthermore, transient expression of AGH17470 enhanced the resistance of sweet orange to Xanthomonas citri subsp. citri. To our knowledge, AGH17470 is the first prophage-encoded secretory protein demonstrated to elicit an HR and induce a strong plant immune response. The findings have increased our understanding of prophage-encoded secretory protein genes, and the results provide clues as to the plant defence response against CLas.


Effects of intracerebral hemorrhage and subsequent minimally invasive hematoma aspiration on expression of apoptosisrelated genes in rats.
This study was to investigate the effects of intracerebral hemorrhage (ICH) and subsequent minimally invasive hematoma aspiration on the expression of apoptosis-related genes in rats. IV-collagenase was injected to the caudate nucleus of the rats to make ICH models. In the control group, 30 Sprague-Dawley (SD) rats were mock treated with saline instead of collagenase. Thirty SD rats with successful modeling were designated as the ICH group. Twenty-five SD rats with successful modeling and subsequent minimally invasive hematoma aspiration were designated as the therapy group. Expression of heat shock protein 70 (Hsp70), B-cell leukemia/lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) in the brain tissues was detected by immunohistochemical assays. The expression of Hsp70, Bcl-2 and Bax in the control group was very low, and significantly increased in the ICH group and the therapy group. At each indicated time point, Hsp70 expression in the therapy group was significantly lower than that of the ICH group, Bax expression in the therapy group was significantly lower than that of the ICH group and Bcl-2 expression in the therapy group was significantly higher than that of the ICH group. These results suggest that ICH led to increased expression of apoptosis-related genes in the brain tissues. Hematoma aspiration up-regulated ICH induced Bcl-2 expression while down-regulated ICH induced Hsp70 and Bax expression.


Mechanism of intestinal mucosal barrier dysfunction in a rat model of chronic obstructive pulmonary disease: An observational study.
The aim of the present study was to investigate intestinal mucosal barrier dysfunction in a rat model of chronic obstructive pulmonary disease (COPD). Male Sprague Dawley rats (n=40) were evenly randomized into control and COPD groups and the COPD model was established by regulated exposure to cigarette smoke for 6 months. Histopathological changes of the lung and intestinal tissues were detected by hematoxylin and eosin staining. Expression of the tight junction proteins occludin and zona occludens-1 (ZO-1) in the intestinal tissues were analyzed by western blotting, serum diamine oxidase (DAO) activity was detected by spectrophotometry, the urinary lactulose to mannitol ratio (L/M) was evaluated by high performance liquid chromatography, and intestinal tissue secretion of tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-8 were detected by ELISA. Lung histopathology revealed thinned alveolar walls, ruptured alveolar septa, enlarged and deformed alveoli, and the formation of bullae and emphysema due to alveolar fusion in the COPD group, while intestinal histopathology indicated clearly swollen intestines with darkened and gray mucosa, neutrophil infiltration of the intestinal mucosal and regional epithelial shedding. The occludin and ZO-1 expression levels were significantly lower in the COPD group compared with those in the corresponding control group (P<0.05), while the urinary L/M ratio was significantly higher (P<0.05). Furthermore, the serum DAO activity and secretion of TNF-α, IFN-γ and IL-8 in the intestinal tissues were significantly higher in the COPD group than in the control group (each P<0.05). Dysfunctional and structural changes were observed in the intestinal mucosal barrier in COPD model rats, which may be associated with the increased intestinal inflammatory responses.


Using a Cyclic Ion Mobility Spectrometer for Tandem Ion Mobility Experiments.
Accurate characterization of chemical structures is important to understand their underlying biological mechanisms and functional properties. Mass spectrometry (MS) is a popular tool but is not always sufficient to completely unveil all structural features. For example, although carbohydrates are biologically relevant, their characterization is complicated by numerous levels of isomerism. Ion mobility spectrometry (IMS) is an interesting complement because it is sensitive to ion conformations and, thus, to isomerism. Furthermore, recent advances have significantly improved the technique: the last generation of Cyclic IMS instruments offers additional capabilities compared to linear IMS instruments, such as an increased resolving power or the possibility to perform tandem ion mobility (IMS/IMS) experiments. During IMS/IMS, an ion is selected based on its ion mobility, fragmented, and reanalyzed to obtain ion mobility information about its fragments. Recent work showed that the mobility profiles of the fragments contained in such IMS/IMS data can act as a fingerprint of a particular glycan and can be used in a molecular networking strategy to organize glycomics datasets in a structurally relevant way. The goal of this protocol is thus to describe how to generate IMS/IMS data, from sample preparation to the final Collision Cross Section (CCS) calibration of the ion mobility dimension that yields reproducible spectra. Taking the example of one representative glycan, this protocol will show how to build an IMS/IMS control sequence on a Cyclic IMS instrument, how to account for this control sequence to translate IMS arrival time into drift time (i.e., the effective separation time applied to the ions), and how to extract the relevant mobility information from the raw data. This protocol is designed to clearly explain the critical points of an IMS/IMS experiment and thus help new Cyclic IMS users perform straightforward and reproducible acquisitions.


Effect of STOP technique on safety climate in a construction company.
Safety programs are a core part of safety management in workplaces that can reduce incidents and injuries. The aim of this study was to investigate the influence of Safety Training Observation Program (STOP) technique as a behavior modification program on safety climate in a construction company. This cross-sectional study was carried out on workers of the Petrochemical Construction Company, western Iran. In order to improve safety climate, an unsafe behavior modification program entitled STOP was launched among workers of project during 12 months from April 2013 and April 2014. The STOP technique effectiveness in creating a positive safety climate was evaluated using the Safety Climate Assessment Toolkit. 76.78% of total behaviors were unsafe. 54.76% of total unsafe acts/ at-risk behaviors were related to the fall hazard. The most cause of unsafe behaviors was associated with habit and unavailability of safety equipment. After 12 month of continuous implementation the STOP technique, 55.8% of unsafe behaviors reduced among workers. The average score of safety climate evaluated using of the Toolkit, before and after the implementation of the STOP technique was 5.77 and 7.24, respectively. The STOP technique can be considered as effective approach for eliminating at-risk behavior, reinforcing safe work practices, and creating a positive safety climate in order to reduction incidents/injuries.


Antibodies to Schmallenberg virus in domestic livestock in Turkey.
This, partly retrospective study, was designed to determine the seroprevalence of Schmallenberg virus (SBV), a new Orthobunyavirus first reported in Germany in late 2011, in domestic ruminants from the Middle Black Sea, West, and Southeast regions of Turkey. An indirect enzyme-linked immunosorbent assay was used to screen serum samples collected from slaughterhouse animals between 2006 and 2013. The overall seroprevalence was 335/1,362 (24.5 %) with 325/816 (39.8 %), 5/307 (1.6 %), 3/109 (2.8 %), and 2/130 (1.5 %) recorded in cattle, sheep, goats, and Anatolian water buffalo, respectively. This is the first study to demonstrate the presence of antibodies to SBV in Turkish ruminants; it indicates that cattle are more susceptible to infection than sheep, goats, or buffalo and that exposure of domestic ruminants to SBV in Turkey may have occurred up to 5 years prior to the first recorded outbreak of the disease in 2011.


Rosuvastatin may reduce the incidence of cardiovascular events in patients with acute coronary syndromes receiving percutaneous coronary intervention by suppressing miR-155/SHIP-1 signaling pathway.
The beneficial effect of rosuvastatin against percutaneous coronary intervention (PCI) related procedural myocardial injury has been determined mostly in patients with acute coronary syndromes (ACS). However, the detailed therapeutic mechanism has not been well studied. Patients with ACS receiving PCI (n = 159) were randomized to control group (placebo treatment) or to rosuvastatin group (20 mg 12 h before PCI, and a further 20 mg 2 h preprocedure dose). Levels of INF-γ, TNF-α, IL-6, miR-155/SHIP-1, and CD4(+)FoxP3(+)Treg in peripheral blood were detected before PCI and 24 h after PCI. Clinical data of these patients were also collected in this prospective study. Compared with placebo, rosuvastatin treatment significantly reduced the incidence of periprocedural myocardial infarction (PMI) and levels of cardiac troponin I (cTnI) associated with decreased relative expression of serum miR-155, levels of inflammatory cytokines (INF-γ, TNF-α, and IL-6), increased SHIP-1 expression and CD4(+)FoxP3(+)Treg percentage values (P < 0.05). In addition, patients with rosuvastatin pretreatment also reduced incidence of 30 days major adverse cardiac events (MACE) compared to the patients with placebo treatment (16 patients vs. 28 patients, P = 0.038). Our study suggests that high loading dose rosuvastatin pretreatment may reduce the incidence of cardiovascular events and levels of inflammatory markers in patients with ACS receiving PCI, which may be explained at least in part, by mechanism involving suppression of miR-155/SHIP-1 signaling pathway.


Withdraw Sedation Gently or Face Withdrawal Syndrome!
How to cite this article: Poddar B. Withdraw Sedation Gently or Face Withdrawal Syndrome! Indian J Crit Care Med 2020;24(6):381-382.


Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003).
The spectrum of activity and potency of doripenem, a broad-spectrum parenteral carbapenem currently in clinical development, was evaluated using 16 008 clinical bacterial isolates collected as part of an international surveillance project during 2003. Using reference broth microdilution methods, doripenem was found to be highly active against oxacillin-susceptible Staphylococcus aureus and coagulase-negative staphylococci (2705 and 297 isolates, respectively; MIC90s 0.06 mg/L), with a potency greater than that of other carbapenem antibiotics. Against enterococci (1474 isolates), with the exception of Enterococcus faecium, doripenem displayed modest activity (MIC50 4). Doripenem was among the most potent agents tested against Streptococcus pneumoniae, viridans group streptococci and beta-haemolytic streptococci (885, 140 and 397 isolates; MIC(90)s 0.5, 0.5 and 0.03 mg/L, respectively). For Enterobacteriaceae (> 6200 isolates), doripenem was four- to 32-fold more active than imipenem against wild-type isolates (MIC90s 0.03-0.5 mg/L). MIC90s for confirmed extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae (121 and 155 isolates; 0.06 and 0.12 mg/L, respectively) were two-fold higher than for wild-type isolates. Doripenem was also active against Citrobacter spp., Enterobacter spp. and Serratia spp. (MIC90s 0.06-0.25 mg/L), including ceftazidime-resistant isolates. Doripenem and meropenem were the most active agents among all beta-lactams against Pseudomonas aeruginosa (829 isolates; MIC50/90s 0.5/8 and 0.5/16 mg/L, respectively), whereas doripenem and imipenem were the most active agents against Acinetobacter spp. (155 isolates; MIC50/90s 0.5/4 and <or= 0.5/2 mg/L, respectively). Doripenem was slightly more potent (MIC50 2 mg/L) than ertapenem and imipenem (MIC50 4 mg/L), and had a potency similar to that of meropenem (MIC50 2 mg/L), against Burkholderia cepacia (20 isolates). Both Haemophilus influenzae (1824 isolates) and Moraxella catarrhalis (108 isolates), including beta-lactamase-positive isolates, were susceptible to doripenem (MIC90s 0.25 and 0.03 mg/L, respectively). Doripenem displays the favourable characteristics of other carbapenems, and appears to offer certain advantages in terms of potency, spectrum and beta-lactamase stability when compared with some carbapenems used currently to treat nosocomial infections.


Polyalkyl cyanoacrylate nanocapsules.
In-situ polymerized methyl cyanoacrylate (MCA), ethyl cyanoacrylate (ECA), and butyl cyanoacrylate (BCA) were used to prepare nanocapsules of fluorescein or doxorubicin as markers by a w/o emulsion interfacial polymerization technique. Different concentrations of MCA were also used to show the effect of monomer concentration. The nanocapsules were characterized by electron microscopy, particle size analysis, holding capacity and in-vitro release of the marker substances. After selection of the polymerization solvent system, nearly spherical nanocapsules were obtained using each of the monomers. Most of the nanocapsules prepared were in the particle size range 500-1500 nm diameter. They were able to hold 55-74% of the marker initially present in aqueous solution. In-vitro dissolution studies showed that release of marker was retarded variably in an increasing order from nanocapsules containing MCA, ECA then BCA. Increasing the concentration of the monomer in the nanocapsules led to retardation of marker release.


Basal metabolic rate can evolve independently of morphological and behavioural traits.
Quantitative genetic analyses of basal metabolic rate (BMR) can inform us about the evolvability of the trait by providing estimates of heritability, and also of genetic correlations with other traits that may constrain the ability of BMR to respond to selection. Here, we studied a captive population of zebra finches (Taeniopygia guttata) in which selection lines for male courtship rate have been established. We measure BMR in these lines to see whether selection on male sexual activity would change BMR as a potentially correlated trait. We find that the genetic correlation between courtship rate and BMR is practically zero, indicating that the two traits can evolve independently of each other. Interestingly, we find that the heritability of BMR in our population (h(2)=0.45) is markedly higher than was previously reported for a captive zebra finch population from Norway. A comparison of the two studies shows that additive genetic variance in BMR has been largely depleted in the Norwegian population, especially the genetic variance in BMR that is independent of body mass. In our population, the slope of BMR increase with body mass differs not only between the sexes but also between the six selection lines, which we tentatively attribute to genetic drift and/or founder effects being strong in small populations. Our study therefore highlights two things. First, the evolvability of BMR may be less constrained by genetic correlations and lack of independent genetic variation than previously described. Second, genetic drift in small populations can rapidly lead to different evolvabilities across populations.


Defunctioning colostomy for low anterior resection: a selective approach.
Seventy-seven consecutive low anterior resections of the rectum were performed with a selective approach to the use of a defunctioning colostomy. A defunctioning colostomy was performed in seven patients (9 per cent) where there was concern about the anastomosis due to difficult dissection (three), incomplete doughnuts (three) and tension on the anastomosis (one). The mean level of the tumour in the defunctioned group was 7.6 cm. Clinical anastomotic leakage occurred in two patients (3 per cent) in the non-defunctioned group, both of which were controlled with subsequent transverse colostomies. There were no perioperative deaths. Selective defunctioning of low colorectal anastomoses can produce low rates of anastomotic dehiscence while reducing the morbidity associated with a temporary stoma.


Biomechanical Effects of Ball Position on Address Position Variables of Elite Golfers.
The purpose of this study was to investigate address position variables in response to changes in ball position in golfers. Eleven male professional golfers were instructed to perform their golf swing. A three-dimensional motion analysis system, with eight infrared cameras and two force platforms, was used to capture the address positions. A golf ball has a diameter of 4.27 cm, and a radius of 2.14 cm. Even small movements of ball position in the mediolateral (M-L) and anteroposterior (A-P) directions significantly changed the address position. When the ball was moved to the left, the shoulder rotation and club-face aim rotated toward the left of the target, and the left vertical ground reaction force increased. When the ball was moved to the right, the opposite findings were observed. When the ball was moved closer, the trunk, hip, knee, ankle, and absolute arm angle extended; the lie angle of the golf club increased; and the center of pressure moved toward the posterior direction. These changes were reversed when the ball was moved further away. The M-L ball position critically changed the address positions of the upper extremities in the horizontal plane, and the A-P ball position critically changed the angles of whole body parts in the sagittal plane. Furthermore, club-head kinematics at impact such as club-face aim, club path, and angle of attack were significantly changed in the M-L ball position; and club-head speed and angle of attack were significantly changed in the A-P ball position. This in-depth understanding of the address position in association with the ball position could provide valuable data for swing coaches when finding a golfer's optimal address position.


Generalizable EHR-R-REDCap pipeline for a national multi-institutional rare tumor patient registry.
To develop a clinical informatics pipeline designed to capture large-scale structured Electronic Health Record (EHR) data for a national patient registry. The EHR-R-REDCap pipeline is implemented using R statistical software to remap and import structured EHR data into the Research Electronic Data Capture (REDCap)-based multi-institutional Merkel Cell Carcinoma (MCC) Patient Registry using an adaptable data dictionary. Clinical laboratory data were extracted from EPIC Clarity across several participating institutions. Laboratory values (Labs) were transformed, remapped, and imported into the MCC registry using the EHR labs abstraction (eLAB) pipeline. Forty-nine clinical tests encompassing 482 450 results were imported into the registry for 1109 enrolled MCC patients. Data-quality assessment revealed highly accurate, valid labs. Univariate modeling was performed for labs at baseline on overall survival (N = 176) using this clinical informatics pipeline. We demonstrate feasibility of the facile eLAB workflow. EHR data are successfully transformed and bulk-loaded/imported into a REDCap-based national registry to execute real-world data analysis and interoperability.


Mutation of BAX occurs infrequently in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas.
Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHLs) consistently derive from B cells, are histologically heterogeneous, and are associated with distinct molecular pathways depending upon histology. Recently, it has been proposed that inactivating mutations of the bax death agonist may contribute to the pathogenesis of human tumors. In particular, among B-cell malignancies, BAX mutations have been detected at a certain frequency in Burkitt lymphomas. This study is aimed at defining the status of the BAX gene throughout the clinicopathologic spectrum of AIDS-NHL (n = 54), including AIDS-related Burkitt lymphoma (n = 14), AIDS-related Burkitt-like lymphoma (n = 8), AIDS-related diffuse large cell lymphoma (n = 15), AIDS-related primary central nervous system lymphoma (n = 6), and AIDS-related primary effusion lymphoma (n = 11). All 6 BAX exons and flanking sequences were subjected to mutational analysis by polymerase chain reaction-single strand conformation polymorphism followed by DNA direct sequencing of positive cases. Mutations of BAX among AIDS-NHL were restricted to a cell line of AIDS-related primary effusion lymphoma, which harbored a frameshift mutation causing the introduction of a proximal stop codon. All other AIDS-NHL displayed wild-type BAX alleles. In order to investigate whether BAX inactivation in AIDS-NHL may occur through mechanisms other than gene mutation, bax protein expression was investigated by Western blot analysis or immunohistochemistry in selected cases. All AIDS-NHL analyzed expressed normal bax proteins. Overall, this study indicates that deregulation of apoptotic control in AIDS-NHL is not caused by BAX alterations. Genes Chromosomes Cancer 27:177-182, 2000.


Development and psychometric exploration of the professional practice environment assessment scale.
Development of the Professional Practice Environment Assessment Scale (PPEAS) was based on the assumptions that a positive professional practice environment is more than and different from the absence of negative, abusive, or disrespectful behaviors by physicians; a positive professional practice environment improves patient outcomes as well as nurse and physician satisfaction; and a positive professional practice environment is characterized by mutual respect, understanding of roles, collaborative decision making, effective communication, and beliefs in the importance of nurse-physician relationships on patient outcomes. The PPEAS is intended as both a research tool and a method of assessing and monitoring changes in an organization's professional practice environment as it relates specifically to the impact the nurse and physician relationship has on the professional practice environment. The purpose of this study was to examine the psychometric properties of the PPEAS and determine if it was a valid and reliable instrument for assessing the positive attributes of the professional practice environment. A large acute care facility in the Midwestern section of the United States provided the setting for this psychometric study. The sample (N= 1,332) consisted of 801 nurses and 531 physicians. Psychometric examination, which included principal component analysis with varimax rotation and assessment of internal consistency, was conducted to validate the reliability and validity of the PPEAS. Analysis identified a four-factor solution. The four factors were classified as positive physician characteristics (five items), positive nurse characteristics (three items), collaborative decision making (two items), and positive beliefs in the value of the nurse-physician relationship (three items). Cronbach's α for the entire scale was .86, with subscales ranging from .73 to .89. Findings from this analysis support our model and provide evidence of the usefulness of this scale for assessing the presence of a positive professional practice environment. Using the total score, organizations can examine the status of their professional practice environment and examine changes in the environment over time. Subscale analysis can identify specific areas where the organization performs well and those areas in need of improvement. The professional practice environment has been implicated as a variable that impacts patient outcomes. The absence of negative physician behaviors is an inadequate measure for assessing the positive attributes of the professional practice environment. Instruments for assessing the professional practice environment typically looked at the presence of negative physician behaviors or examined a single aspect of the nurse-physician relationship. This article provides a theoretical framework that can be used to guide both practice and research. The PPEAS was developed within a theoretical framework that can be adapted to a variety of settings, cultures, and countries. The PPEAS is a valid and reliable instrument that can be used to assess the professional practice environment in a variety of settings.


Genetic Regulation of Flowering in Grafts on Pisum sativum L.
Lf, E, Sn, and Hr are major loci that condition the flowering and photoperiod responses of Pisum sativum L. Genetic lines containing the dominant alleles of these loci are characterized by flowering in long days, but having a prolonged (>50 node) vegetative phase in short days. A representative of this class, response type G, was used as a receptor in short days for donors of other flowering response types. The qualitative and quantitative flowering response of G receptors depended on the genotype of the donor. Donors containing sn hr induced the earliest development, followed by sn Hr and Sn hr donors. The Lf and E loci in foliar donors apparently did not affect flowering of G. Five-leaved > single-leaved > cotyledonary donors in effecting a flowering response in G, in part due to the longer life of the foliar donors. The responses of G to the various donors were generally consistent with the proposed roles of Lf, E, and Sn, but the role of Hr in these grafts was unclear.


[Reasons for Encounter in Out-of-Hours Care in Emergency Departments and Emergency Practices - A Mixed Methods Trial].
Since 2006, with the opening of emergency practices (EP) in Germany, out-of-hours patient care has been carried out by general practitioners. Additionally, emergency departments (ED) of the hospitals ensure acute care. Thus, optimal coordination of care is a much discussed subject. The aim of this study was to provide reasons for encounter and subjective reasons to visit each of these institutions. In a mixed method trial, patients with non-urgent conditions (Manchester Triage System level 4 and 5) were interviewed in 2 ED in Schleswig-Holstein and 2 EP in Baden-Württemberg regarding their reasons for encounter from July 2015 to August 2016 during the out of hours primary care practices. Data collection was carried out using a paper-based questionnaire and a semi-structured interview. The statistical program SPSS was used for descriptive analysis, text data analysis was carried out with the method of qualitative content analysis. In total, 398 patients were interviewed. Most frequently, reasons for encounter in ED and EP were related to musculoskeletal complaints (39%, n=116 and 23%, n=23, respectively). Within technical examination services, the laboratory diagnostics were used as a priority in ED (59%, n=175). In the EP, one patient (2%) underwent laboratory diagnostics. The main reasons for encounter in both facilities were increasing complaints (50%, n=147 in ED; 70%, n=70 in EP) and a desire for quick diagnosis (73%, n=217 in ED; 48%, n=48 in EP). In total, 112 patients (28%) had a medication plan, and 67 (60%) brought it into the facility. Two-thirds of ED patients (n=197) were handed over to outpatient care. In EP, 89% (n=89) continued as outpatient. Qualitative content analysis revealed similar complaint categories in both facilities, but with significant differences in the severity and experienced urgency. In both facilities, patients expected to have their symptoms clarified. In ED, the desire for a rapid and specific diagnosis was expressed more frequently. Indications for medical treatment were seen in most consultations in both care facilities. There was a distinction between the ED and EP in the urgency of the consultations.


An unusual cause of hydronephroureter.
Intrauterine contraceptive device (IUCD) is a common method of contraception among women because of its low cost and high efficacy. Perforations are possible resulting in multiple complications including urinary complications. Obstructive hydronephrosis and hydroureter is one of the main clinical concerns in genitourinary practice leading to radiological investigations for determination of the cause. Determination of the cause leads to early treatment, hence saving the renal function. In this case report, we describe hydronephrosis and hydroureter secondary to a migrated/displaced IUCD.


From raw data to a score: comparing quantitative methods that construct multi-level composite implementation strength scores of family planning programs in Malawi.
Data that capture implementation strength can be combined in multiple ways across content and health system levels to create a summary measure that can help us to explore and compare program implementation across facility catchment areas. Summary indices can make it easier for national policymakers to understand and address variation in strength of program implementation across jurisdictions. In this paper, we describe the development of an index that we used to describe the district-level strength of implementation of Malawi's national family planning program. To develop the index, we used data collected during a 2017 national, health facility and community health worker Implementation Strength Assessment survey in Malawi to test different methods to combine indicators within and then across domains (4 methods-simple additive, weighted additive, principal components analysis, exploratory factor analysis) and combine scores across health facility and community health worker levels (2 methods-simple average and mixed effects model) to create a catchment area-level summary score for each health facility in Malawi. We explored how well each model captures variation and predicts couple-years protection and how feasible it is to conduct each type of analysis and the resulting interpretability. We found little difference in how the four methods combined indicator data at the individual and combined levels of the health system. However, there were major differences when combining scores across health system levels to obtain a score at the health facility catchment area level. The scores resulting from the mixed effects model were able to better discriminate differences between catchment area scores compared to the simple average method. The scores using the mixed effects combination method also demonstrated more of a dose-response relationship with couple-years protection. The summary measure that was calculated from the mixed effects combination method captured the variation of strength of implementation of Malawi's national family planning program at the health facility catchment area level. However, the best method for creating an index should be based on the pros and cons listed, not least, analyst capacity and ease of interpretability of findings. Ultimately, the resulting summary measure can aid decision-makers in understanding the combined effect of multiple aspects of programs being implemented in their health system and comparing the strengths of programs across geographies.


Magnetic resonance spectroscopy with transcranial direct current stimulation to explore the underlying biochemical and physiological mechanism of the human brain: A systematic review.
A large body of molecular and neurophysiological evidence connects synaptic plasticity to specific functions and energy metabolism in particular areas of the brain. Furthermore, altered plasticity and energy regulation has been associated with a number of neuropsychiatric disorders. A favourable approach enabling the modulation of neuronal excitability and energy in humans is to stimulate the brain using transcranial direct current stimulation (tDCS) and then to observe the effect on neurometabolites using magnetic resonance spectroscopy (MRS). In this way, a well-defined modulation of brain energy and excitability can be achieved using a dedicated tDCS protocol to a predetermined brain region. This systematic review was guided by the preferred reporting items for systematic reviews and meta-analysis and summarises recent literature studying the effect of tDCS on neurometabolites in the human brain as measured by proton or phosphorus MRS. Limitations and recommendations are discussed for future research. The findings of this review provide clear evidence for the potential of using tDCS and MRS to examine and understand the effect of neurometabolites in the in vivo human brain.


Nebivolol increases survival in cardiomyopathic hamsters with congestive heart failure.
The genetically inbred cardiomyopathic Syrian hamster provides a valuable model of congestive cardiomyopathy: myocytolytic necrosis at 30-50 days of age is followed by cardiac hypertrophy at 150-250 days, and finally by congestive failure and death at 250-350 days. Successful drug treatment has been reported in the prenecrotic stage, but not when started during congestive failure. The present study evaluated survival of the cardiomyopathic hamster treated with the new beta-adrenoceptor blocker nebivolol, which was initiated during congestive failure. Fifty animals (BIO82.62, either sex, age 200 days) were acclimated to an environmentally controlled room for 20 days, receiving food and water ad libitum; seven hamsters died, indicating development of congestive failure. The remaining animals were then randomly assigned to one of three groups: 15 animals received control food; food for the others was supplemented with nebivolol, yielding a daily intake of either 0.1 mg/kg (n = 14) or 1 mg/kg (n = 14). At the lower nebivolol dose, death rate was unaltered in comparison with controls. However, at 1 mg/kg, survival was markedly improved (p = 0.042). Nebivolol treatment, started during congestive failure, thus significantly delays mortality in the cardiomyopathic hamster.


Breakpoint sites disclose the role of the V(D)J recombination machinery in the formation of T-cell receptor (TCR) and non-TCR associated aberrations in T-cell acute lymphoblastic leukemia.
Aberrant recombination between T-cell receptor genes and oncogenes gives rise to chromosomal translocations that are genetic hallmarks in several subsets of human T-cell acute lymphoblastic leukemias. The V(D)J recombination machinery has been shown to play a role in the formation of these T-cell receptor translocations. Other, non-T-cell receptor chromosomal aberrations, such as SIL-TAL1 deletions, have likewise been recognized as V(D)J recombination associated aberrations. Despite the postulated role of V(D)J recombination, the extent of the V(D)J recombination machinery involvement in the formation of T-cell receptor and non-T-cell receptor aberrations in T-cell acute lymphoblastic leukemia is still poorly understood. We performed a comprehensive in silico and ex vivo evaluation of 117 breakpoint sites from 22 different T-cell receptor translocation partners as well as 118 breakpoint sites from non-T-cell receptor chromosomal aberrations. Based on this extensive set of breakpoint data, we provide a comprehensive overview of T-cell receptor and oncogene involvement in T-ALL. Moreover, we assessed the role of the V(D)J recombination machinery in the formation of chromosomal aberrations, and propose an up-dated mechanistic classification on how the V(D)J recombination machinery contributes to the formation of T-cell receptor and non-T-cell receptor aberrations in human T-cell acute lymphoblastic leukemia.


Acidity adjustment of HZSM-5 zeolites by dealumination and realumination with steaming and citric acid treatments.
This article describes a novel method for acidity adjustment of HZSM-5 zeolites with steaming and citric acid treatments and demonstrates the realumination effect of citric acid on HZSM-5 zeolites dealuminated by steaming. A series of modified HZSM-5 zeolites were prepared by streaming and/or acid treatments and characterized by means of X-ray diffraction (XRD), X-ray fluorescence spectroscopy (XRF), (27)Al MAS NMR spectroscopy, hydroxyl infrared spectroscopy (OH-IR), pyridine-adsorbed infrared spectroscopy, and N(2) adsorption in the present investigation. The results showed that compared with single HCl or citric acid treatment, steaming treatment, and steaming/HCl treatments, citric acid treatment after steaming exclusively increased the amount of framework Al due to reinsertion of extraframework Al into the defective sites of the steamed HZSM-5 framework. This realumination effect of the citric acid treatment on the steamed HZSM-5 zeolite, which is reported here for the first time to the best of our knowledge, could nearly recover the pore structure of the steamed zeolite to that of the parent HZSM-5 zeolite and appropriately tailor the amount and strength of different acid sites, which sheds light on optimizing the physicochemical properties of HZSM-5 zeolites. It was also found that the steaming treatment prior to the citric acid treatment was the precondition of the realumination of HZSM-5 zeolites, suggesting that the lattice defect sites generated during steaming were necessary for citric acid to work.


Ochroconis globalis infecting Atlantic salmon (Salmo salar), with a review of Ochroconis species in cold-blooded animals.
Necropsy examination of an adult Atlantic salmon (Salmo salar) from the Dalälven River in Sweden revealed numerous large, white nodules, with spherical cysts and granulomata in kidney and liver. Histopathology showed dark, septate, thin-walled hyphae. The aetiologic agent was found to be an Ochroconis species (Venturiales) that differed from known fish-associated species of the genus. Molecular phylogenetic studies of the culture (strain UIII09 = CBS 135766) demonstrated that Ochroconis globalis was concerned. The isolate proved to be susceptible to all investigated antifungals, as it is known for another Ochroconis species. The role of Ochroconis in opportunism of cold-blooded animals was discussed, and the diagnostic methods using DNA sequences for routine identification of the fungus were proposed.


Genetic Diversity and Phenotypic Variation in an Introgression Line Population Derived from an Interspecific Cross between Oryza glaberrima and Oryza sativa.
The introduction of closely related species genomic fragments is an effective way to enrich genetic diversity and creates new germplasms in crops. Here, we studied the genetic diversity of an introgression line (IL) population composed of 106 ILs derived from an interspecific tetra cross between O. glaberrima and O. sativa (RAM3/Jin23B//Jin23B///YuetaiB). The proportion of O. glaberrima genome (PGG) in the ILs ranged from 0.3% to 36.7%, with an average value of 12.32% which is close to the theoretically expected proportion. A total of 250 polymorphic alleles were amplified by 21 AFLP primer combinations with an average of 12 alleles per primer. Population structure analysis revealed that the IL population can be divided into four genetically distinct subpopulations. Both principal component analysis and neighbor-joining tree analysis showed that ILs with a higher PGG displayed greater genetic diversity. Canonical discriminant analysis identified six phenotypic traits (plant height, yield per plant, filled grain percentage, panicle length, panicle number and days to flowering) as the main discriminatory traits among the ILs and between the subpopulations and showed significant phenotypic distances between subpopulations. The effects of PGG on phenotypic traits in the ILs were estimated using a linear admixed model, which showed a significant positive effect on grain yield per plant (0.286±0.117), plant height (0.418 ± 0.132), panicle length (0.663 ± 0.107), and spikelet number per panicle (0.339 ± 0.128), and a significant negative effect on filled grain percentage (-0.267 ± 0.123) and days to flowering (-0.324 ± 0.075). We found that an intermediate range (10% - 20%) of PGG was more effective for producing ILs with favorable integrated agronomic traits. Our results confirm that construction of IL population carrying O. glaberrima genomic fragments could be an effective approach to increase the genetic diversity of O. sativa genome and an appropriate level of PGG could facilitate pyramiding more favorable genes for developing more adaptive and productive rice.


A Machine Learning Classification Model for Monitoring the Daily Physical Behaviour of Lower-Limb Amputees.
There are currently limited data on how prosthetic devices are used to support lower-limb prosthesis users in their free-living environment. Possessing the ability to monitor a patient's physical behaviour while using these devices would enhance our understanding of the impact of different prosthetic products. The current approaches for monitoring human physical behaviour use a single thigh or wrist-worn accelerometer, but in a lower-limb amputee population, we have the unique opportunity to embed a device within the prosthesis, eliminating compliance issues. This study aimed to develop a model capable of accurately classifying postures (sitting, standing, stepping, and lying) by using data from a single shank-worn accelerometer. Free-living posture data were collected from 14 anatomically intact participants and one amputee over three days. A thigh worn activity monitor collected labelled posture data, while a shank worn accelerometer collected 3-axis acceleration data. Postures and the corresponding shank accelerations were extracted in window lengths of 5-180 s and used to train several machine learning classifiers which were assessed by using stratified cross-validation. A random forest classifier with a 15 s window length provided the highest classification accuracy of 93% weighted average F-score and between 88 and 98% classification accuracy across all four posture classes, which is the best performance achieved to date with a shank-worn device. The results of this study show that data from a single shank-worn accelerometer with a machine learning classification model can be used to accurately identify postures that make up an individual's daily physical behaviour. This opens up the possibility of embedding an accelerometer-based activity monitor into the shank component of a prosthesis to capture physical behaviour information in both above and below-knee amputees. The models and software used in this study have been made open source in order to overcome the current restrictions of applying activity monitoring methods to lower-limb prosthesis users.


Relationship between postoperative complications and survival after gastrectomy for cancer.
Surgical resection remains the main curative treatment for gastric cancer but is still affected by high postoperative morbidity and mortality rates, especially in Western countries. We've analyzed patients treated for gastric cancer at our Operative Unit of ent, extent of lymphadenectomy and survival. General Surgery and Organ Transplantation of the University Hospital of Parma from January 2006 till December 2010, relating the occurrence of eventual complications to sex, age at diagnosis, definitive histological examination, type and duration of surgical treatment. The surgically treated cases were 152 (30.4 gastrectomies per year on average). 62 patients developed at least one adverse event during the postoperative period, reaching 108 total events. Among these, 71 were minor complications (grade I-II in Clavien-Dindo's classification), while 26 were major ones (grade III). Postoperative mortality affected 8 patients (5.3%). Data analysis did not stress any statistically significant correlation between the valued variables and the global incidence of complications. For severe ones, some risk factors emerged such as the type of gastrectomy, the execution of a multi-visceral resection and the operative time. Five-year overall survival has been 36.7%, lower in patients with severe complications (29%) when compared to patients without severe complications (38%). Radicality of operation, the lymph node involvement and the occurrence of severe complication emerged as significant prognostic factors for five-year overall survival. Surgery is still the mainstay of treatment for gastric cancer and the only one able to grant a curative therapy. When performed in high-volume centres, with more than 20 gastrectomies per year, it represents a safe treatment, affected by low mortality. Attention must be paid to careful preoperative selection, to treatment of pre-existent comorbidities, to plan a therapeutical strategy to minimize surgical stress, to postoperative monitoring and to managing complications', as they're able to impact not only low-term outcomes but also overall and disease-free survival. The poor prognosis for these patients is mainly related to advanced stage at presentation, thus confirming the need to increase early diagnosis in order to detect in larger percentages the tumor in its early stage. Complications, Gastrectomy, Gastric Cancer, Survival.


The pH ruler: a Java applet for developing interactive exercises on acids and bases.
In introductory biochemistry courses, it is often a struggle to teach the basic concepts of acid-base chemistry in a manner that is relevant to biological systems. To help students gain a more intuitive and visual understanding of abstract acid-base concepts, a simple graphical construct called the pH ruler Java applet was developed. The applet allows students to visualize the abundance of different protonation states of diprotic and triprotic amino acids at different pH values. Using the applet, the student can drag a widget on a slider bar to change the pH and observe in real time changes in the abundance of different ionization states of this amino acid. This tool provides a means for developing more complex inquiry-based, active-learning exercises to teach more advanced topics of biochemistry, such as protein purification, protein structure and enzyme mechanism.


The Role of Scaffolds in Tendon Tissue Engineering.
Tendons are unique forms of connective tissue aiming to transmit the mechanical force of muscle contraction to the bones. Tendon injury may be due to direct trauma or might be secondary to overuse injury and age-related degeneration, leading to inflammation, weakening and subsequent rupture. Current traditional treatment strategies focus on pain relief, reduction of the inflammation and functional restoration. Tendon repair surgery can be performed in people with tendon injuries to restore the tendon's function, with re-rupture being the main potential complication. Novel therapeutic approaches that address the underlying pathology of the disease is warranted. Scaffolds represent a promising solution to the challenges associated with tendon tissue engineering. The ideal scaffold for tendon tissue engineering needs to exhibit physiologically relevant mechanical properties and to facilitate functional graft integration by promoting the regeneration of the native tissue.


Developmental profile of serum nerve growth factor levels in Rett complex.
Rett syndrome (RS) is a progressive neurodevelopmental disorder predominant in females, characterised by mental deficiency, stereotyped hand-washing and apraxia. Notwithstanding the recent identification of the MECP2 gene likely involved in the pathogenesis of SR, the neurobiological bases of this syndrome are still largely unknown. Converging evidence shows that the brain levels of nerve growth factor (NGF), a neurotrophin regulating the development and functioning of central cholinergic neurons, are decreased in RS girls. In this study, the serum levels of NGF were measured in classic RS, in the preserved speech variant (PSV) and in normal controls. Overall analysis failed to evidence significant differences among the three groups. However, whereas NGF levels increased significantly with age in controls, the opposite profile was observed in classic RS, with a progressive age-dependent decrease of NGF. In PSV subjects NGF levels remained constant with age. These findings strengthen the hypothesis of NGF involvement in the pathogenesis of RS.


Risk factors for residual thrombotic occlusion after proximal deep vein thrombosis of the legs.
Residual thrombotic occlusion (RTO) after deep vein thrombosis (DVT) is considered as a risk factor of recurrent venous thromboembolism (VTE). We searched for risk factors associated with RTO after proximal DVT at the lower extremities. Using compression ultrasound, we evaluated the presence of RTO at 6 months after DVT (RTO defined as a residual thrombus occupying, at maximum compressibility, >/=20% of the vein lumen before compression). We examined 126 Czech patients: mean age 57.5 years; 50.0% women, 68.3% femoral location of DVT (otherwise popliteal), RTO found in 45.2%. While accounting for covariates, in the whole population, RTO was significantly associated with following factors: (OR; 95% confidence limit; p value): male sex (2.01; 1.27-3.19; P=0.003), femoral location (2.76; 1.59-4.78; P=0.0003). In women, but not in men, an association was demonstrated for: concurrent pulmonary embolism (PE) (18.51; 1.85-185.7; P=0.0131), diabetes mellitus (4.62; 1.38-15.51; P=0.0133) and statin use (0.11; 0.02-0.62; P=0.0125). In contrast, in men RTO was associated with an unprovoked DVT (2.6; 1.26-5.34; P=0.0094). In the whole study population, male sex and femoral location of DVT were positively associated with RTO. In women, concurrent PE and diabetes mellitus were risk factors for RTO, while the use of statins was a protective factor. There was a positive association between RTO and unprovoked DVT in men. These findings deserve further evaluation in a larger study.


Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes.
Given its critical role in T-cell signaling, interleukin-2-inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.


[Effects of lower body negative pressure in the first and last week during 21 d head-down bed rest on orthostatic tolerance and cardiac function].
To investigate the changes of orthostatic tolerance and cardiac function during 21 d head-down tilt (HDT) bed rest and effect of lower body negative pressure (LBNP) in the first and the last weeks in humans. Twelve healthy male volunteers were exposed to -6 degrees HDT bed rest for 21 d. Six subjects received -30 mmHg LBNP sessions for 1 h/d from the 1st to the 7th day and from the 15th to the 21st day of the HDT, and the other six who did not receive LBNP served as control. Orthostatic tolerance was assessed by means of standard tilt test. The cardiac pumping function and cardiac systolic function were measured before and during HDT. Before HDT, all the subjects in the two groups completed the tilt tests. After 10 d and 21 d of HDT, all the subjects of the control group and one subject of the LBNP group could not complete the tilt test due to presyncopal or syncopal symptoms. The mean time of upright standing in the control group (15.0 +/- 3.2 min) was significantly shorter than those in the LBNP group (19.7 +/- 0.9 min). The stroke volume and cardiac output decreased significantly in the control group on days 3 and 10 of HDT, but remained unchanged throughout HDT in the LBNP group. A significant increase in preejection period (PEP)/left ventricular ejection time (LVET) was observed on days 3 and 14 of HDT in both groups. The PEP/LVET in the LBNP group was significantly lower than those in the control group on days 3 of HDT, while LVET in LBNP group was significantly higher than those in the control group on days 3, 7 and 14 of HDT. It is suggested that the brief daily LBNP sessions in the first and the last weeks were effective in preventing orthostatic intolerance and the reduction of cardiac pumping function and cardiac systole function induced by 21 d HDT bed rest.


Effect of the Darrieus-Landau instability on turbulent flame velocity.
The propagation of turbulent premixed flames influenced by the intrinsic hydrodynamic flame instability (the Darrieus-Landau instability) is considered in a two-dimensional case using the model nonlinear equation proposed recently by Bychkov [Phys. Rev. Lett. 84, 6122 (2000)]. The nonlinear equation takes into account both the influence of external turbulence and the intrinsic properties of a flame front, such as small but finite flame thickness and realistically large density variations across the flame front. Dependence of the flame velocity on the turbulent length scale, turbulent intensity, and density variations is investigated in the case of weak nonlinearity and weak external turbulence. It is shown that the Darrieus-Landau instability influences the flamelet velocity considerably. The obtained results are in agreement with experimental data on the turbulent burning of moderate values of the Reynolds number.


Binding and elution of serum glycoproteins from agarose.
Evidence in support of previous observations by different authors that agarose is not an entirely inert support in affinity chromatography is presented. In the present communication it is shown that 8% granulated agarose adsorb serum glycoproteins in 10mM phosphate buffer, pH 7.2 and desorb these in 200mM NaCl in 10mM phosphate buffer, pH 7.2. The desorbed glycoproteins retained their abilities to react with antibodies elicited in sheep to normal human serum glycoproteins, despite the loss of mannose and galactose following the agarose treatment.


ATF4 Contributes to Ovulation via Regulating COX2/PGE2 Expression: A Potential Role of ATF4 in PCOS.
Ovulatory disorder is common in patients with hyperprolactinemia or polycystic ovary syndrome (PCOS). Previous studies have shown that ATF4 plays critical role in apoptosis and glucose homeostasis, but its role in regulating reproductive function was not explored. The present study investigated the role of ATF4 in ovarian ovulatory function. Human granulosa cells (hGCs) from 48 women newly diagnosed with PCOS and 37 controls were used to determine ATF4 expression. In vitro cultured hGCs were used to detect the upstream and downstream genes of ATF4. A shRNA- Atf4 lentiviral vector (shAtf4) was injected into rat ovaries to establish an in vivo gene knockdown model to further assess the in vivo relevance of the results from PCOS women. We found that ATF4 expression was lower in hGCs from PCOS patients than in hGCs from non-PCOS women. Many pivotal transcripts involved in cumulus-oocyte complex (COC) expansion, extracellular matrix (ECM) remodeling, and progesterone production were significantly down-regulated after ATF4 knockdown. ChIP-qPCR assays indicated that ATF4 could directly bind to the COX2 promoter and that ATF4 knockdown could attenuate human chorionic gonadotropin (hCG)-induced COX2 expression and PGE2 production. The in vivo study showed that shRNA-lentivirus mediated Atf4 knockdown in rat ovaries led to reduced number of retrieved oocytes. Collectively, these findings suggested previously unknown roles of ATF4 in ovulation. Furthermore, ATF4 malfunction in PCOS patients may impact the ovulation process, which could contribute, in part, to the pathogenesis of PCOS.


Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha.
The transcription factor NF-kappa B regulates genes participating in immune and inflammatory responses. In T lymphocytes, NF-kappa B is sequestered in the cytosol by the inhibitor I kappa B-alpha and released after serine phosphorylation of I kappa B-alpha that regulates its ubiquitin-dependent degradation. We report an alternative mechanism of NF-kappa B activation. Stimulation of Jurkat T cells with the protein tyrosine phosphatase inhibitor and T cell activator pervanadate led to NF-kappa B activation through tyrosine phosphorylation but not degradation of I kappa B-alpha. Pervanadate-induced I kappa B-alpha phosphorylation and NF-kappa B activation required expression of the T cell tyrosine kinase p56ick. Reoxygenation of hypoxic cells appeared as a physiological effector of I kappa B-alpha tyrosine phosphorylation. Tyrosine phosphorylation of I kappa B-alpha represents a proteolysis-independent mechanism of NF-kappa B activation that directly couples NF-kappa B to cellular tyrosine kinase.


Biopolymer-Drug Conjugate Nanotheranostics for Multimodal Imaging-Guided Synergistic Cancer Photothermal-Chemotherapy.
Some of the biomedical polymer-drug conjugates are being translated into clinical trials; however, they intrinsically lack photothermal and multi-imaging capabilities, hindering them from imaging-guided precision cancer therapy and complete tumor regression. We introduce a new concept of all-in-one biopolymer-drug conjugate nanotheranostics and prepare a kind of intracellular pH-sensitive polydopamine-doxorubicin (DOX) conjugate nanoparticles (PDCNs) under mild conditions. Significantly, this strategy integrates polymeric prodrug-induced chemotherapy (CT), near-infrared (NIR) light-mediated photothermal therapy (PT), and triple modalities including DOX self-fluorescence, photothermal, and photoacoustic (PA) imaging into one conjugate nanoparticle. The PDCNs present excellent photothermal property, dual stimuli-triggered drug release behavior, and about 12.4-fold blood circulation time compared to free DOX. Small animal fluorescent imaging technique confirms that PDCNs have preferential tumor accumulation effect in vivo, giving a 12.8-fold DOX higher than the control at 12 h postinjection. Upon NIR laser irradiation (5 min, 808 nm, and 2 W·cm-2), the PDCN-mediated photothermal effect can quickly elevate the tumor over 50 °C, exhibiting good photothermal and PA imaging functions, of which the PA amplitude is 3.6-fold greater than the control. In vitro and in vivo assays persuasively verify that intravenous photothermal-CT of PDCNs produces synergistic antitumor activity compared to single PT or CT, achieving complete tumor ablation during the evaluation period.