Cryptococcus neoformans Mating and Genetic Crosses.
The Cryptococcus pathogenic species complex is a group of opportunistic human fungal pathogens that cause cryptococcal meningoencephalitis, an infection associated with unacceptably high mortality rates. The public health relevance of these pathogens has galvanized extensive research over the past several decades and led to characterization of their sexual cycles. This research has allowed several Cryptococcus species to develop into model fungal organisms for both pathogenesis and basic science studies. Many of these studies require observation of the meiotic process and its associated mating structures as well as generation of meiotic progeny with novel phenotypes and genotypes. Herein, we describe how to set up genetic crosses between Cryptococcus strains and observe their mating phenotypes as well as how to recover progeny from these crosses for further analysis. © 2019 by John Wiley & Sons, Inc.


Risk of elevation of serum creatine kinase among HIV-positive individuals receiving dolutegravir-based combination antiretroviral therapy.
We aimed to compare the risks of creatine kinase (CK) elevation between patients receiving dolutegravir-based antiretroviral therapy (ART) and those receiving non-integrase strand transfer inhibitor (InSTI)-based ART.HIV-positive patients seeking HIV outpatient care between February 2017 and March 2018 were retrospectively reviewed to collect information on ART, practices of vigorous exercise, and laboratory tests including CK level, plasma HIV RNA load, and concurrent medications. The incidences of CK elevation were estimated among patients receiving dolutegravir-based ART and those receiving non-InSTI-based ART.During the 14-month study period, 1406 patients (mean age 39.4 years and 96.9% being male) were included. The incidence rate of grade 3 or grade 4 CK elevation (>10-fold of the upper limit of normal) was 2.0 per 100 person-years of follow-up (PYFU) and 1.3 per 100 PYFU in the dolutegravir and non-InSTI group, respectively (P = .32). While dolutegravir group had a higher rate of CK elevation of any level than non-InSTI group (22.9 vs 17.4 per 100 PYFU, P = .01), the risk was associated with weight (adjusted odds ratio [aOR], per 10-kg increase, 1.03; 95% CI, 1.02-1.04), duration of exercise (aOR, per 1-hour increase, 1.02; 95% CI 1.01-1.03), but not with dolutegravir-based ART (aOR, 1.00; 95% CI, 0.99-1.06) after adjusting for the testing frequency of serum CK in the multivariate generalized estimating equation model. No patients were hospitalized or switched ART due to CK elevation.Serum CK elevation was associated with weight and duration of exercise among HIV-positive patients receiving ART, but not with dolutegravir-based ART.


Leukoaraiosis severity and post-reperfusion outcomes in acute ischaemic stroke: A meta-analysis.
Severity of leukoaraiosis may mediate outcomes after reperfusion therapy in acute ischaemic stroke (AIS) patients. However, the level of the association remains poorly understood. We performed a meta-analysis to investigate the impact of leukoaraiosis severity on functional outcome, survival, haemorrhagic complications, and procedural success in AIS patients treated with intravenous thrombolysis and/or endovascular thrombectomy. PubMed, EMBASE and the Cochrane library were searched for studies on leukoaraiosis in AIS receiving reperfusion therapy. A random-effects meta-analysis was conducted for post-reperfusion outcomes in AIS patients with absent-to-mild leukoaraiosis and moderate-to-severe leukoaraiosis. The strength of association between moderate-to-severe leukoaraiosis and poor outcomes was quantified using odds ratios (OR). A total of 15 eligible studies involving 6460 patients (1451 with moderate-to-severe leukoaraiosis and 5009 with absent-to-mild leukoaraiosis) were included in the meta-analysis. Moderate-to-severe leukoaraiosis was significantly associated with poor 90-day functional outcome (OR 3.16; 95% confidence interval (CI) 2.69-3.72; p < .0001), 90-day mortality (OR 3.11; 95% CI 2.27-4.26; p < .0001) and increased risk of symptomatic intracerebral haemorrhage (OR 1.69; 95% CI 1.24-2.32; p = .001) after reperfusion therapy. Overall, no significant association of leukoaraiosis severity with haemorrhagic transformation (HT) and angiographic recanalization status were observed. However, subgroup analysis revealed a significant association of WML severity with HT in patients receiving EVT. Leukoaraiosis is a useful prognostic biomarker in AIS. Patients with moderate-to-severe leukoaraiosis on baseline imaging are likely to have worse clinical and safety outcomes after reperfusion therapy.


Lpp positions peptidoglycan at the AcrA-TolC interface in the AcrAB-TolC multidrug efflux pump.
The multidrug efflux pumps of Gram-negative bacteria are a class of complexes that span the periplasm, coupling both the inner and outer membranes to expel toxic molecules. The best-characterized example of these tripartite pumps is the AcrAB-TolC complex of Escherichia coli. However, how the complex interacts with the peptidoglycan (PG) cell wall, which is anchored to the outer membrane (OM) by Braun's lipoprotein (Lpp), is still largely unknown. In this work, we present molecular dynamics simulations of a complete, atomistic model of the AcrAB-TolC complex with the inner membrane, OM, and PG layers all present. We find that the PG localizes to the junction of AcrA and TolC, in agreement with recent cryo-tomography data. Free-energy calculations reveal that the positioning of PG is determined by the length and conformation of multiple Lpp copies anchoring it to the OM. The distance between the PG and OM measured in cryo-electron microscopy images of wild-type E. coli also agrees with the simulation-derived spacing. Sequence analysis of AcrA suggests a conserved role for interactions with PG in the assembly and stabilization of efflux pumps, one that may extend to other trans-envelope complexes as well.


The two-way mixed model: a long and winding controversy.
With the 2-way mixed model, one a fixed factor and the other random, the procedure followed to test statistical significance of the random factor has been the focus of a heated controversy in theoretical and applied statistics, and the debating continues even now. One of the main consequences of this controversy is that the position defended in the classical ANOVA texts on the hypothesis of the significance of the random effect is not the same as that defended in almost all of the professional statistical software programs. In this paper, we deal with a detailed analysis about the controversy of mixed model and the decision about one of two basic options, the non restrictive and the restrictive model. Three key questions we consider to go beyond the controversy are: (1) the two classical models are equivalent, (2) the marginality principle do not allow to test main effects in presence of interactive significant effects and (3) the relevance of linear mixed approach to analyze models with fixed and random effects. We propose the simple solution of using the mixed linear approach with REML estimation instead of the classical linear approach, which is really unapplicable in this context.


Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation.
Rationale: Myocardial vulnerability to ischemia/reperfusion (I/R) injury is strictly regulated by energy substrate metabolism. Branched chain amino acids (BCAA), consisting of valine, leucine and isoleucine, are a group of essential amino acids that are highly oxidized in the heart. Elevated levels of BCAA have been implicated in the development of cardiovascular diseases; however, the role of BCAA in I/R process is not fully understood. The present study aims to determine how BCAA influence myocardial energy substrate metabolism and to further clarify the pathophysiological significance during cardiac I/R injury. Methods: Parameters of glucose and fatty acid metabolism were measured by seahorse metabolic flux analyzer in adult mouse cardiac myocytes with or without BCAA incubation. Chronic accumulation of BCAA was induced in mice receiving oral BCAA administration. A genetic mouse model with defective BCAA catabolism was also utilized. Mice were subjected to MI/R and the injury was assessed extensively at the whole-heart, cardiomyocyte, and molecular levels. Results: We confirmed that chronic accumulation of BCAA enhanced glycolysis and fatty acid oxidation (FAO) but suppressed glucose oxidation in adult mouse ventricular cardiomyocytes. Oral gavage of BCAA enhanced FAO in cardiac tissues, exacerbated lipid peroxidation toxicity and worsened myocardial vulnerability to I/R injury. Etomoxir, a specific inhibitor of FAO, rescued the deleterious effects of BCAA on I/R injury. Mechanistically, valine, leucine and their corresponding branched chain α-keto acid (BCKA) derivatives, but not isoleucine and its BCKA derivative, transcriptionally upregulated peroxisome proliferation-activated receptor alpha (PPAR-α). BCAA/BCKA induced PPAR-α upregulation through the general control nonderepresible-2 (GCN2)/ activating transcription factor-6 (ATF6) pathway. Finally, in a genetic mouse model with BCAA catabolic defects, chronic accumulation of BCAA increased FAO in myocardial tissues and sensitized the heart to I/R injury, which could be reversed by adenovirus-mediated PPAR-α silencing. Conclusions: We identify BCAA as an important nutrition regulator of myocardial fatty acid metabolism through transcriptional upregulation of PPAR-α. Chronic accumulation of BCAA, caused by either dietary or genetic factors, renders the heart vulnerable to I/R injury via exacerbating lipid peroxidation toxicity. These data support the notion that BCAA lowering methods might be potentially effective cardioprotective strategies, especially among patients with diseases characterized by elevated levels of BCAA, such as obesity and diabetes.


Resonance with subthreshold oscillatory drive organizes activity and optimizes learning in neural networks.
Network oscillations across and within brain areas are critical for learning and performance of memory tasks. While a large amount of work has focused on the generation of neural oscillations, their effect on neuronal populations' spiking activity and information encoding is less known. Here, we use computational modeling to demonstrate that a shift in resonance responses can interact with oscillating input to ensure that networks of neurons properly encode new information represented in external inputs to the weights of recurrent synaptic connections. Using a neuronal network model, we find that due to an input current-dependent shift in their resonance response, individual neurons in a network will arrange their phases of firing to represent varying strengths of their respective inputs. As networks encode information, neurons fire more synchronously, and this effect limits the extent to which further "learning" (in the form of changes in synaptic strength) can occur. We also demonstrate that sequential patterns of neuronal firing can be accurately stored in the network; these sequences are later reproduced without external input (in the context of subthreshold oscillations) in both the forward and reverse directions (as has been observed following learning in vivo). To test whether a similar mechanism could act in vivo, we show that periodic stimulation of hippocampal neurons coordinates network activity and functional connectivity in a frequency-dependent manner. We conclude that resonance with subthreshold oscillations provides a plausible network-level mechanism to accurately encode and retrieve information without overstrengthening connections between neurons.


Hypoxia: Animal experiments and clinical implications.
The developing fetus has some unique physiological properties that differ from properties in extra-uterine life. The fetus exists in a hypoxemic condition as a result of the presence of the placenta, which serves as a limiting interface between maternal and fetal circulation. In addition, the fetus is prone to be exposed to uterine contractions, which place it under a further hypoxic burden. Thus, the fetal response to hypoxic insults is important. There has been marked progression in the understanding of fetal physiology since the introduction of the 'chronic preparation model'. Based upon information from animal research, we now utilize medical technologies in daily medical care, for example, fetal heart rate monitoring and high-resolution ultrasonographic devices. In this review, we discuss the main findings in relation to fetal physiology and their clinical relevance.


Evidence for a calmodulin-dependent phospholipase A2 that inhibits Na-K-ATPase.
We tested whether calnaktin, a proposed Ca/calmodulin (CaM)-dependent protein that inhibits the Na-K-ATPase, was a kinase, a phosphatase, a phospholipase A2 (PLA2), or a Ca-dependent protease. Human red blood cell membranes were extracted to remove associated calmodulin but to retain the proposed endogenous calnaktin. Exclusively cytoplasmic proteins and cofactors were presumably absent. In these membranes, free Ca inhibited the Na-K-ATPase with an inhibition constant (K[i]) of > or = 9 microM at a Na concentration of 18 mM. Addition of 100 nM CaM decreased the Ki to < 2 microM and increased the percent inhibition at 2 microM free Ca from 18 +/- 1 to 68 +/- 2%. The inhibitory effect of Ca/CaM was reversible, indicating that calnaktin is not a protease. Neither staurosporine (500 nM), 1-(N,O-bis[5-isoquinolinesulfonyl]-N-methyl-L-tyrosyl)-4-phenylpipera zin e (5 microM), nor genistein (100 microM) diminished Ca/CaM inhibition of the Na-K-ATPase. Thus there is no evidence that this protein is a kinase. Likewise, the phosphatase inhibitors microcystin (1 microM) and okadaic acid (10 microM) had no effect. PLA2 inhibitors arachidonyl trifluoromethyl ketone (AACOCF3), parabromophenacyl bromide (pBPB), and quinacrine all abolished Ca/CaM inhibition of the Na-K-ATPase. Ca/CaM also increased PLA2 activity, as reflected by an increase in the slope of fluorescence signal of 10-pyrene phosphatidylcholine, a substrate for PLA2. This Ca/CaM-induced change in slope was inhibited by both pBPB and AACOCF3. These data suggest that human red cell membranes contain a form of PLA2 that is activated by Ca/CaM and that this enzyme may mediate Ca/CaM inhibition of the Na-K-ATPase.


Elevated serum levels of estrogen and prolactin in daughters of patients with breast cancer.
Demographic risk factors in sisters and daughters of 150 patients with breast cancer were compared to those of controls. Plasma hormone levels in 36 teen-age daughters of patients and 31 controls were also studied to ascertain whether an "abnormal" hormone pattern underlies these risk factors. The patients' sisters had, on the average, menarche four months earlier and first full-term pregnancy 12 months later than the controls. The patients' daughters did not show these differences -- apparently owing to low fertility in the patients with early menarche. The patients' daughters had higher 22d-day estradiol-plus-estrone levels than controls (24.4 vs. 19.1 ng per 100 ml, P less than 0.05). Sixth-day prolactin was also elevated (19.0 vs. 14.2 ng per 100 ml, P less than 0.05). About half the patients' daughters could clearly be distinguished from the controls' daughters by means of the sixth-day information on both estrogens and prolactin. Hypersecretion of these hormones may be important factors in breast cancer.


Fine mapping for double podding gene in chickpea.
For the first time, fine mapping for sfl locus was carried out using a battery of new STMS and SNP markers. The target region was delimited to 92.6 Kb where seven annotated genes were found that could be candidate genes for the simple/double podding trait in chickpea. Four recombinant inbred populations (RIP-1, RIP-7, RIP-11, and CPR-01) were used to map the double podding gene (sfl) in chickpea. In RIP-1, the gene was initially mapped on linkage group (LG) 6 between the two sequence-tagged microsatellite site (STMS) markers TA120 and TR1. Eight new STMS markers were added onto LG6 in the target region and sfl locus was finally located between CAGM27819 and CAGM27777 markers within an interval of 2 cM. Seven out of the eight markers were mapped in RIP-7 and its reciprocal RIP-11 confirming the location of the sfl locus to a 4.8 cM interval flanked by TR44 and CAGM27705. Furthermore, using a high-density single nucleotide polymorphism (SNP) map of CPR-01, sfl was mapped to the same genomic region in a 5.1 cM interval between TR44 and the SNP scaffold1646p97220. Five pairs of near isogenic lines (NILs) and eight recombinant inbred lines (RILs) were used to refine this region in the chickpea physical map. Combining data from linkage analysis in four RIPs, marker physical positions and recombination events obtained in both pairs of NILs and selected RILs, sfl could be placed within a genomic window of 92.6 Kb. Seven annotated genes were extracted from this region. The regulator of axillary meristem-predicted gene could be a candidate gene for the simple/double podding gene. This study provides additional set of markers flanking and tightly linked to sfl locus that are useful for marker-assisted selection.


[Target-controlled infusions of remifentanil and propofol in elderly patients].
To investigate the clinical reliability and feasibility of target-controlled infusion (TCI) with different plasma concentration remifentanil and propofol. Thirty ASA I-II patients, > or =65 years old, undergoing selective lower abdominal operation were divided into 3 groups, group A with anesthesia using propofol combined with epidural block, group B with anesthesia using propofol and remifentanil (plasma concentration 4 microg/L), group C with anesthesia using propofol and remifentanil (plasma concentration 7 microg/L). BIS value, heart rate, blood pressure, heart rate variability and so on, were recorded during anesthesia and operation. Radial arterial blood samples for analysis of plasma concentration of propofol were taken during operation. (1) The intubation response of groups B and C was lower than that of group A . (2) The depth of anesthesia was enough during operation (BIS value=45-60). (3) TCI propofol combined with remifentanil didn't lengthen the awaking time of patients; (4) MDPE of target-controlled infusion using propofol with Marsh parameters was 11.17%, MDAPE was 12.16% in Chinese elderly patients. Remifentanil with plasma concentration of 4 and 7 microg/L combined with propofol could be safely used during clinical anesthesia of old patient, but monitoring must be strengthened during induction when plasma concentration of remifentanil was 7 microg/L. TCI propofol with Marsh parameters could be applied to Chinese elderly patients safely and efficiently.


Myofascial pain syndrome affecting the piriformis and the obturator internus muscle.
The obturator internus muscle is an external rotator of the hip. Obturator internus injury may occur and be hidden by the piriformis syndrome. Clinical symptoms may offer some clues to the clinician. The selective injection technique described here facilitates precise diagnosis.


Tuning Adsorption Duration To Control the Diffusion of a Nanoparticle in Adsorbing Polymers.
Controlling the nanoparticle (NP) diffusion in polymers is a prerequisite to obtain polymer nanocomposites (PNCs) with desired dynamical and rheological properties and to achieve targeted delivery of nanomedicine in biological systems. Here we determine the suppression mechanism of direct NP-polymer attraction to hamper the NP mobility in adsorbing polymers and then quantify the dependence of the effective viscosity ηeff felt by the NP on the adsorption duration τads of polymers on the NP using scaling theory analysis and molecular dynamics simulations. We propose and confirm that participation of adsorbed chains in the NP motion break up at time intervals beyond τads due to the rearrangement of polymer segments at the NP surface, which accounts for the onset of Fickian NP diffusion on a time scale of t ≈ τads. We develop a power law, ηeff ∼ (τads)ν, where ν is the scaling exponent of the dependence of polymer coil size on the chain length, which leads to a theoretical basis for the design of PNCs and nanomedicine with desired applications through tuning the polymer adsorption duration.


HY5, Circadian Clock-Associated 1, and a cis-element, DET1 dark response element, mediate DET1 regulation of chlorophyll a/b-binding protein 2 expression.
DET1 is a pleiotropic regulator of Arabidopsis development and controls the expression of many light-regulated genes. To gain a better understanding of the mechanism by which DET1 controls transcription from light-regulated promoters, we identified elements in the chlorophyll a/b-binding protein 2 (CAB2) promoter that are required for DET1-mediated expression. Using a series of reporter constructs in which the luciferase gene is controlled by CAB2 promoter fragments, we defined two DET1-responsive elements in the CAB2 promoter that are essential for proper CAB2 transcription. A 40-bp DET1 dark-response element (DtRE) is required for both dark and root-specific repression of CAB2, whereas the known CAB upstream factor-1 element is required for DET1 activation-associated effects in the light and repression in the roots. HY5, a factor that binds CAB upstream factor-1, is also required for DET1 effects in the light. DtRE binds two distinct activities in Arabidopsis seedling extracts: a novel activity with binding site CAAAACGC that we have named CAB2 DET1-associated factor 1 plus an activity that is likely to be the myb transcription factor Circadian Clock-Associated 1. Both activities are altered in dark-grown det1 extracts as compared with wild type, correlating a change in extractable DNA binding activity with a major change in CAB2 expression. We conclude that DET1 represses the CAB2 promoter in the dark by regulating the binding of two factors, CAB2 DET1-associated factor 1 and Circadian Clock-Associated 1, to the DtRE.


Effects of atrial natriuretic peptide, dopamine, and ouabain on aldosterone synthesis.
This study was undertaken to examine the effects of atrial natriuretic peptide (ANP), dopamine, and ouabain, which each are considered to be a kind of natriuretic factor, on aldosterone synthesis in vivo and in vitro. In the in vivo experiments, during infusion of one of the natriuretic factors, ANP (64 pmol X min-1 X kg-1), dopamine (20 nmol X min-1 X kg-1) or ouabain (684 II pmol x min-1 x kg-1), the stimulatory action of angiotensin (20 pmol X min-1 X kg-1) or adrenocorticotropin (ACTH, 7 pmol X min-1 X kg-1) on aldosterone synthesis was investigated in 36 anaesthetized (pentobarbital, 40 mg/kg, iv) female rabbits. In the basal condition, aldosterone synthesis was suppressed slightly by each of the natriuretic factors. The stimulatory actions of angiotensin II and ACTH on aldosterone synthesis were significantly attenuated by pre-treatment with ANP and dopamine. However, ouabain infusion did not induce any changes in the synthesis of aldosterone, 18-hydroxycorticosterone (18-OHB), and corticosterone (B) in either the basal or the stimulated conditions. For the in vitro experiments, rabbit adrenal glomerulosa cells (10(5) cells/tube) were used. The effects of ANP and dopamine on the aldosterone synthesis revealed results identical to those from the in vivo study. However, in contrast to the in vivo study, ouabain completely inhibited the synthesis of aldosterone, 18-OHB and B. The above results obtained in vivo and in vitro suggest that ANP inhibits corticosterone methyloxidase II activity and dopamine inhibits corticosterone methyloxidase I activity. However, from the present study we were unable to specify the action of ouabain on the synthesis of aldosterone and its related substances.


Trans-thoracic venous bullet embolism.
Bullet emboli from peripheral wounds occur with sufficient frequency that they must be considered in every case of missile injury not accompanied by an exit wound. A case is presented which demonstrated a venous migration of such a bullet from the axillary vein into the femoral vein through the heart, presumably by gravity.


Simulation study of field-induced morphological changes in a proton-conducting ionomer.
A simulation study was made of the effects of strong electric fields on the morphology of a Nafion-like ionomer at various levels of hydration. The results of united-atom molecular-dynamics computations showed a self-organization of the side chain terminal groups into cylindrical clusters. The walls of these clusters contain the sulfonate dipoles, while the interior holds the majority of the water molecules. These cylindrical structures then align to form an hexatic array aligned along the direction of the applied electric field. The hexatic morphology persists after the removal of the field. A calculation by means of the Kirkwood coupling parameter method shows the Helmholtz free energy of the hexatic morphology of the poled membrane to be lower than that of the initial isotropic material, even in the absence of the applied field.


Torsional properties of rat femora.
The torsional behaviour of the femur has been studied in 145 male Wistar rats, aged 3-36 weeks. The ultimate torsional moment and the torsional stiffness of the femora increased with increasing animal age. In contrast, the femoral deformation at failure, the ultimate torsional angle, was almost constant for all age levels. The strength and stiffness of cortical bone as a material, the ultimate torsional stress and the modulus of rigidity reached a plateau when the rats were about 14 weeks old, and had a body weight and femoral length of about 350 g and 35 mm, respectively. In conclusion, cortical bone of Wistar rats probably reaches maturity at an age of about 14 weeks.


Transcriptional profiling of spiny lobster metamorphosis reveals three new additions to the nuclear receptor superfamily.
The Crustacea are an evolutionarily diverse taxon which underpins marine food webs and contributes significantly to the global economy. However, our knowledge of crustacean endocrinology and development is far behind that of terrestrial arthropods. Here we present a unique insight into the molecular pathways coordinating crustacean metamorphosis, by reconciling nuclear receptor (NR) gene activity from a 12-stage, 3-replicate transcriptome in the ornate spiny lobster (Panulirus ornatus) during larval development. We annotated 18 distinct nuclear receptor genes, including three novel NRs which are upregulated prior to metamorphosis and have hence been named the "molt-associated receptors" (MARs). We also demonstrate the ecdysone-responsive expression of several known molt-related NRs including ecdysone receptor, fushi-tarazu-F1 and E75. Phylogenetic analysis of the curated NR family confirmed gene annotations and suggested that the MARs are a recent addition to the crustacean superfamily, occurring across the Malacostraca from the Stomatopoda to the Decapoda. The ligand-binding domain of these receptors appears to be less conserved than that of typical group-1 NRs. Expression data from two other crustacean species was utilized to examine MAR expression. The Y-organ of the tropical land crab showed a decline in expression of all MARs from intermolt to post-molt. Tissue distributions showed gonad-enriched expression in the Eastern rock lobster and antennal gland-enriched expression in the tropical land crab, although expression was evident across most tissues. By mining transcriptome data, we have curated an extensive list of NR genes expressed during the metamorphic molts of P. ornatus, including three novel crustacean NRs which appear to play a role in the molting process. Divergence of the E-region of these new receptors indicates that they may have adopted a function that is unconventional for NRs. Based on expression patterns, we can confirm that a number of NRs play a role in the ecdysone cassette which regulates molting in crustaceans. This study describes in detail the molecular events surrounding crustacean molting and metamorphosis by taking advantage of the distinctive life history unique to achelatan crustaceans.


Molecular Property eXplorer: a novel approach to visualizing SAR using tree-maps and heatmaps.
The tremendous increase in chemical structure and biological activity data brought about through combinatorial chemistry and high-throughput screening technologies has created the need for sophisticated graphical tools for visualizing and exploring structure-activity data. Visualization plays an important role in exploring and understanding relationships within such multidimensional data sets. Many chemoinformatics software applications apply standard clustering techniques to organize structure-activity data, but they differ significantly in their approaches to visualizing clustered data. Molecular Property eXplorer (MPX) is unique in its presentation of clustered data in the form of heatmaps and tree-maps. MPX employs agglomerative hierarchical clustering to organize data on the basis of the similarity between 2D chemical structures or similarity across a predefined profile of biological assay values. Visualization of hierarchical clusters as tree-maps and heatmaps provides simultaneous representation of cluster members along with their associated assay values. Tree-maps convey both the spatial relationship among cluster members and the value of a single property (activity) associated with each member. Heatmaps provide visualization of the cluster members across an activity profile. Unlike a tree-map, however, a heatmap does not convey the spatial relationship between cluster members. MPX seamlessly integrates tree-maps and heatmaps to represent multidimensional structure-activity data in a visually intuitive manner. In addition, MPX provides tools for clustering data on the basis of chemical structure or activity profile, displaying 2D chemical structures, and querying the data based over a specified activity range, or set of chemical structure criteria (e.g., Tanimoto similarity, substructure match, and "R-group" analysis).


Bioprinting endothelial cells with alginate for 3D tissue constructs.
Advanced solid freeform fabrication (SFF) techniques have been an interest for constructing tissue engineered polymeric scaffolds because of its repeatability and capability of high accuracy in fabrication resolution at the scaffold macro- and microscales. Among many important scaffold applications, hydrogel scaffolds have been utilized in tissue engineering as a technique to confide the desired proliferation of seeded cells in vitro and in vivo into its architecturally porous three-dimensional structures. Such fabrication techniques not only enable the reconstruction of scaffolds with accurate anatomical architectures but also enable the ability to incorporate bioactive species such as growth factors, proteins, and living cells. This paper presents a bioprinting system designed for the freeform fabrication of porous alginate scaffolds with encapsulated endothelial cells. The bioprinting fabrication system includes a multinozzle deposition system that utilizes SFF techniques and a computer-aided modeling system capable of creating heterogeneous tissue scaffolds. The manufacturing process is biologically compatible and is capable of functioning at room temperature and relatively low pressures to reduce the fluidic shear forces that could deteriorate biologically active species. The deposition system resolution is 10 microm in the three orthogonal directions XYZ and has minimum velocity of 100 microm/s. The ideal concentrations of sodium alginate and calcium chloride were investigated to determine a viable bioprinting process. The results indicated that the suitable fabrication parameters were 1.5% (w/v) sodium alginate and 0.5% (w/v) calcium chloride. Degradation studies via mechanical testing showed a decrease in the elastic modulus by 35% after 3 weeks. Cell viability studies were conducted on the cell encapsulated scaffolds for validating the bioprinting process and determining cell viability of 83%. This work exhibits the potential use of accurate cell placement for engineering complex tissue regeneration using computer-aided design systems.


Amyloid Goiter: A Case Report and Review of the Literature.
Amyloid goiter is a very rare manifestation of amyloidosis. Here, we describe the case of a 40-year-old male, who presented with upper airway obstructive symptoms including hoarseness and breathing difficulty, to highlight the clinical and pathological features of secondary amyloidosis of the thyroid gland and the difficulties in making a preoperative diagnosis. The patient had previously been wounded in the war in Bosnia, which resulted in the right kidney being surgically removed. Further, he had undergone two surgical interventions on both hips due to osteomyelitis and was on a chronic dialysis program due to a progressively poor left kidney function that had eventually resulted in complete loss of renal function. Thyroid function tests were normal, and the patient clinically was euthyroid; biochemical investigations were within normal limits. Results from sonography, computed tomography scan of the neck, scintigraphy and fine-needle aspiration cytology were nondiagnostic. Therefore, a thyroid biopsy was carried out, and amyloid deposits were found. After preoperative work-up, total thyroidectomy was performed with no complications. We conclude that amyloid goiter may have no major impact on thyroid function even when a substantial amount of amyloid has replaced the normal thyroid parenchyma, as was the case in our patient. Amyloid goiter should be suspected in all patients with a progressive, rapidly growing bilateral thyroid enlargement with concomitant inflammatory processes or in patients undergoing hemodialysis treatment.


Anticonvulsant activity of the ethanolic extract of Punica granatum L. seed.
Various morphological parts of pomegranate (Punica granatum L.) have extensively been used in the folk medicine to treat an array of human ailments. The aim of the present study is to demonstrate the anticonvulsant potential of the ethanolic extract of P. granatum L. seed in chemoconvulsant-induced seizures in mice. The anticonvulsant activity of the ethanolic extract was investigated in strychnine (STR)-induced and pentylenetetrazole (PTZ)-induced seizure models in mice. Diazepam was used as reference anticonvulsant drug. Ethanolic extract (150, 300, and 600 mg/kg per os, p.o.), diazepam (1 mg/kg intraperitoneally, i.p.), and distilled water (10 ml/kg, i.p.) were administered before induction of seizures by PTZ (60 mg/kg, i.p.) or STR (2.5 mg/kg, i.p.). The latent time before the onset of convulsions, the duration of convulsions, the percentage of seizure protection, and mortality rate were recorded. The seed ethanolic extract did not show any toxicity and did not protect the animals against seizures but demonstrated a significant increase in seizure latency at 300 and 600 mg/kg in both STR and PTZ seizure models (P < 0.001). It also showed a significant reduction in seizure duration at 300 mg/kg (P < 0.05) and 600 mg/kg (P < 0.001) in the STR seizure model and 600 mg/kg (P < 0.01) in the PTZ seizure model compared with the control group. Ethanol extract has dose-dependent anticonvulsant activity against STR- and PTZ-induced seizures. This activity might be due to its saponins, flavonoids, triterpenes, and alkaloids ingredients.


Down-regulation of estrogen receptor by the methylation of the estrogen receptor gene in endometrial carcinoma.
Human uterine endometrial carcinomas are composed of estrogen receptor (ER)-positve and ER-negative subgroups, though the mechanisms that down-regulate the ER expression are not understood. The present study was undertaken to examine the involvement of methylation of the ER gene on the ER status. DNA was extracted from 25 cases of endometrial carcinoma. Polymerase chain reaction (PCR), using the extracted DNA and methylation-sensitive restriction enzymes (Hpa II, Hha I), was performed to detect the methylation of a CpG island in the ER (alpha) gene. The results were compared with the ER expression by immunostaining. In the 25 endometrial carcinomas, methylation at the Hpa II site, or at both the Hpa II and Hha I sites, was found in 6 cases, while methylation was not found in the remaining 19 cases. Immunohistochemically, 5 of the 6 methylation-positive cases were negative for ER, whereas 14 of the 19 methylation-negative cases were ER-positive (p=0.02). Methylation of the CpG island of the ER gene is inversely correlated with ER expression in a subset of endometrial carcinomas.


Lichen nitidus: electron microscopic and immunofluorescence studies.
Skin biopsies from a patient suffering from lichen nitidus were studied by electron microscopy and immunofluorescence studies. Complete disintegration of the stratum basale in the central area of the lesion and signs of acantholysis in the border area were found. In the central part of the lesion the dermo-epidermal junction was severely damaged in most places. In the dermal infiltrate, macrophages and lymphocytes were found with a considerable representation of Sézary cells, not previously reported in lichen nitidus. The ultrastructural changes are identical with those found in lichen planus. No in vivo bound immunoglobulins, fibrinogen, or complement C3 were found.


Unraveling regulatory mechanisms of atrial remodeling of mitral regurgitation pigs by gene expression profiling analysis: role of type I angiotensin II receptor antagonist.
Left atrial enlargement associated with mitral regurgitation (MR) predicts a poor prognosis. However, the underlying regulatory mechanisms of atrial remodeling remain unclear. We used high-density oligonucleotide microarrays and enrichment analysis to identify the alteration of RNA expression pattern and biological processes involved in the atrial remodeling of pigs with and without MR. Gene arrays from left atria tissues were compared in 13 pigs (iatrogenic MR pigs [n = 6], iatrogenic MR pigs treated with valsartan [n = 4], and pigs without MR [n = 3]). A total of 22 genes were differentially upregulated by altered fold change >2.0 (Log2FC > 1), and 49 genes were differentially downregulated by altered fold change <0.5 (Log2FC < -1) in the left atria of the MR pigs compared with the pigs without MR. Enrichment analysis showed that renin-angiotensin system was identified in the Kyoto Encyclopedia of Genes and Genomes pathway. Notably, 12 of the 22 upregulated genes were identified to be downregulated by valsartan and 10 of the 49 downregulated genes were identified to be upregulated by valsartan. The tissue concentrations of angiotensin II and gene expression of hypertrophic gene, myosin regulatory light chain 2, ventricular isoforms, and fibrosis-related genes were significantly increased in the MR pigs compared with pigs without MR. In conclusion, differentially expressed transcriptome and related biological pathways have been identified in the left atria of the MR pigs compared with pigs without MR. Additionally, some of the differentially expressed genes could be regulated by type I angiotensin II receptor blocker.


Influence of humidity and temperature on the diel periodicity of oviposition of Toxorhynchites moctezuma (Diptera: Culicidae) in the field.
The diurnal pattern of oviposition by Toxorhynchites moctezuma (Dyar & Knab), ambient relative humidity, and ambient air temperature were monitored hourly between 0600 and 1800 hours for 46 consecutive d in a tropical rainforest in Trinidad, West Indies. The mean number of eggs per ovitrap per hour was correlated negatively with mean ambient relative humidity and positively with air temperature. Partial correlation coefficients among these variables and contingency table analysis indicated a stronger relationship between the oviposition rate and relative humidity than between oviposition rate and temperature. We suggest that this relationship is further evidence of the ability of female Tx. moctezuma to detect suitable oviposition sites using humidity gradients.


Effects of ulinastatin in experimental acute arterial occlusion in rats.
The effects of ulinastatin (human urinary trypsin inhibitor, UTI) were studied in experimental acute arterial occlusion in rats. The experimental model comprised concurrent cross-clamping of the abdominal aorta and bilateral femoral arteries for 4 hours. Blood was sampled for measurement of the enzymes 2 hours after release of the clamps. The rats were grouped according to method of infusing UTI and/or physiologic saline solution. When UTI was infused continuously from the start of clamping, the plasma creatine phosphokinase and plasma beta-glucuronidase levels were significantly lower than in the control rats (p less than 0.05). The results suggest that UTI prevents the destruction of the lysosomal membrane in acute arterial occlusion.


Chest X-rays findings in COVID 19 patients at a University Teaching Hospital - A descriptive study.
To analyze Chest X-ray findings in COVID 19 positive patients, presented at corona filtration center, Benazir Bhutto Hospital Rawalpindi, based on CXR classification of British Society of Thoracic Imaging (BSTI). In this study, all RT-PCR COVID-19 positive patients screened at corona filtration center, Benazir Bhutto hospital Rawalpindi from 20th March 2020 to 10th April 2020 were included. Mean age of the cohort with age range was calculated. Presenting complaints & Co-morbid were analyzed and tabulated in frequencies and percentages. Portable CXR findings were classified according to BSTI classification and documented in frequencies and percentages. Mean age of the patients was 44 years. Presenting complaints were cough 20 (67%), fever 18 (60%), shortness of breath 11 (37%), sore throat six (20%), loss of sense of taste and smell four(13%). Main co-morbid was hypertension six (20%). Two (7%) patients had normal and seven (23%) had classical COVID CXRs. 21 (70%) patients were in indeterminate group with only one (3%) having unilateral lung disease. Three (10%) patients had diffuse lung involvement and 18(60%) had peripheral lung involvement. Majority of patients 19 (63%), had bilateral middle and lower zonal involvement. In this study, COVID-19 CXRs generally manifested a spectrum of pure ground glass, mixed ground glass opacities to consolidation in bilateral peripheral middle and lower lung zones. BSTI CXR reporting classification of COVID-19 is valid in our patients with addition of middle zonal involvement in classical COVID-19 criteria as opposed to just lower zone involvement.


Helicobacter pylori and severe nausea and vomiting during pregnancy.
Helicobacter pylori is a bacterial infection of the stomach, which may aggravate nausea and vomiting in pregnancy. Studies have found conflicting evidence of the role of H. pylori in severe nausea and vomiting in pregnancy and hyperemesis gravidarum. Several women suffering from weight loss and experiencing continued nausea and vomiting were tested for H. pylori antibody during their pregnancy. This article reviews the outcomes of women with both positive and negative H. pylori tests, the treatment of H. pylori, and its controversial role in managing severe nausea and vomiting in pregnancy.


Inhibition of human lymphocyte natural cytotoxicity and antibody-dependent cell-mediated cytotoxicity by K-76 COONa, a reagent that blocks complement activity.
K-76 COONa is a 440 m.w. fungal product that can inhibit complement activity of C5 and Factor I. K-76 COONa abrogated both human natural killer (NK) cell activity and antibody-dependent cell-mediated cytotoxicity (ADCC) (ID50 approximately 1.5 mM). To be effective, K-76 COONa had to be present during the assay, because pretreatment of lymphocytes with highly inhibitory concentrations of K-76 COONa did not inhibit cytolysis. The monocarboxylic K-76 derivative was more inhibitory to NK than the dicarboxylic derivative. This relative efficacy is similar to that observed for inhibition of complement lysis. K-76 COONa inhibited NK when added before NK conjugate formation, but had little effect when added after conjugate formation. The compound also inhibited the formation of conjugates by NK and K cells. Therefore, this reagent selectively affected events that occurred between the initial effector-target cell interactions and the formation of stable conjugates. It had little influence on the post-binding "lethal hit" stage of cytolysis. These data imply a) that if any molecules similar to C5 are activated during the "lethal hit" stage of cytolysis, then they are inaccessible to K-76 COONa , and b) that C3bi-like molecules may be involved in lymphocyte binding.


Energy-dependent inactivation of citrate lyase in Enterobacter aerogenes.
Enterobacter aerogenes was grown in continous culture with ammonia as the growth-limiting substrate, and changes in citrate lyase and citrate synthase activities were monitored after growth shifts from anaerobic growth on citrate to aerobic growth on citrate, aerobic growth on glucose, anaerobic growth on glucose, and anaerobic growth on glucose plus nitrate. Citrate lyase was inactivated during aerobic growth on glucose and during anaerobic growth with glucose plus nitrate. Inactivation did not occur during anaerobic growth on glucose, and as a result of the simultaneous presence of citrate lyase and citrate synthase, growth difficulties were observed. Citrate lyase inactivation consisted of deacetylation of the enzyme. The corresponding deacetylase could not be demonstrated in cell extracts, and it is concluded that, as in a number of other inactivations, electron transport to oxygen or nitrate was required for inactivation.


Dapagliflozin exerts positive effects on beta cells, decreases glucagon and does not alter beta- to alpha-cell transdifferentiation in mouse models of diabetes and insulin resistance.
Loss of beta cell identity and subsequent transdifferentiation of beta-to-alpha cells is implicated in the pathogenesis of diabetes. In addition, sodium-glucose transport protein 2 (SGLT2) inhibition has been linked to altered alpha-cell function. To investigate these phenomenon, lineage tracing of beta-cells was examined following 10-12 days dapagliflozin (1 or 5 mg/kg, once daily, as appropriate) treatment in multiple low-dose streptozotocin (STZ), high fat fed (HFF) or hydrocortisone (HC) transgenic Ins1Cre/+/Rosa26-eYFP mouse models of diabetes and insulin resistance. As anticipated, STZ, HFF and HC treated mice developed characteristic features of insulin deficiency or resistance. Dapagliflozin elicited differing beneficial effects depending on the aetiology of syndrome studied. The SGLT2 inhibitor efficiently promoted (P < 0.001) weight loss in HFF and STZ mice, whilst in HC mice it reduced (P < 0.001) energy intake, without an impact on body weight. Despite lacking significant effects on glycaemia, 1 mg/kg dapagliflozin consistently decreased both plasma and pancreatic glucagon. This was associated with increased pancreatic insulin in STZ and HFF mice. In STZ and HFF mice, beta cell proliferation and Pdx1 expression were enhanced by dapagliflozin, with a further increase in overall glucagon staining in HFF islets. Islet, beta- and alpha-cell areas were increased in dapagliflozin treated HC mice, which appeared to be linked to decreased alpha- and beta-cell apoptosis. Although the diabetes-like syndromes induced clear alterations in islet cell transdifferentiation, treatment with dapagliflozin (1 mg/kg) had no significant impact on this process, with 5 mg/kg marginally decreasing loss of beta-cells identity in STZ mice. These data suggest that SGLT2 inhibitors have positive effects on beta cells and decrease plasma and pancreatic glucagon, independent of changes in ambient glucose levels. Our combined data indicate that SGLT2 inhibitors do not directly induce hyperglucagonaemia.


Laparoscopic surgery of the pancreas.
Diagnostic laparoscopy provides useful information in patients with pancreatic disease and is the most reliable technique for the staging of patients with pancreatic cancer. The advent of laparoscopic contact ultrasonography has enhanced the diagnostic and staging potential of laparoscopy. In addition to laparoscopic cholecystectomy for acute gallstone-associated pancreatitis, the following operations have been performed laparoscopically: bilio-enteric bypass and gastrojejunostomy in patients with advanced pancreatic cancer; internal drainage for pseudocysts; resection of insulinomas; distal resection for chronic pancreatitis; and pancreaticoduodenectomy for pancreatic cancer. Aside from cholecystectomy, there is as yet, insufficient information to conclude on the advantages of these laparoscopic approaches although the early results, particularly in the palliation of patients with malignant jaundice, are promising. Bilateral thoracoscopic splanchnicectomy for the relief of intractable pancreatic pain is also under current evaluation.


PAH transport and fluid absorption by isolated perfused frog proximal renal tubules.
Para-aminohippurate (PAH) transport and fluid absorption were studied in isolated perfused frog (Rana catesbeiana) proximal renal tubules. With 2 X 10(-5) M PAH in the bath, tubule fluid-to-bath (TF/B) concentration ratios averaged 3.0 and net secretion averaged 746 X 10(-15) mol min(-1) mm(-1) in the proximal tubule. Net PAH secretion did not vary with perfusion rate. During PAH secretion, cell water PAH concentration exceeded that in the tubular fluid or bath, suggesting active transport into cells and subsequent diffusion into lumen. In accordance with this concept, luminal membrane permeability (3.8 X 10(-5) cm s(-1) calculated from perfusion studies was about 6 times greater than peritubular membrane permeability (0.66 X 10(-5) cm s(-1)) determined from studies of PAH efflux from tubules with oil-filled lumens. Net transepithelial PAH transport saturated at bath concentration of about 6 X 10(-5) M. Addition of 20 mM urea to PAH bath concentration of 2 X 10(-5) M reduced net PAH secretion by 32%. Fluid absorption in proximal tubules averaged 0.34 nl min(-1) mm(-1). Ouabain (10(-4), 10(-5), or 10(-6) M) added to bath blocked fluid absorption. Fluid absorption was partially restored following removal of ouabain.


A Transcriptome Array-Based Approach Links Proteinuria and Distinct Molecular Signatures to Intrarenal Expression of Type I Interferon IFNA5 in Lupus Nephritis.
In systemic lupus erythematosus (SLE), the relevance of non-hematopoietic sources of type I interferon in human autoimmunity has recently been recognized. Particularly, type I interferon production precedes autoimmunity in early skin lesions related to SLE. However, the relevance of intrarenal type I interferon expression has not been shown in lupus nephritis. From transcriptome array datasets, median-centered log2 mRNA expression levels of IFNα (IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, and IFNA21), IFNω (IFNW1), and IFNβ (IFNB1) in lupus nephritis were extracted specifically from microdissected tubulointerstitial (n = 32) and glomerular compartments (n = 32). We found an association between proteinuria and tubulointerstitial expression of type I interferon IFNA5 (p = 0.0142), while all others were not significantly associated. By contrast, no such correlation was observed between proteinuria and any type I interferon expression in the glomerular compartment in lupus nephritis. Interestingly, there was no difference between female and male patients (p = 0.8237) and no association between type I interferon IFNA5 expression and kidney function or lupus nephritis progression. Finally, we identified distinct molecular signatures involved in transcriptional regulation (GLI protein-regulated transcription, IRF7 activation, and HSF1-dependent transactivation) and receptor signaling (BMP signaling and GPCR ligand binding) in association with tubulointerstitial expression of type I interferon IFNA5 in the kidney. In summary, this transcriptome array-based approach links proteinuria to the tubulointerstitial expression of type I interferon IFNA5 in lupus nephritis. Because type I interferon receptor subunit I antagonism has recently been investigated in active SLE, the current study further emphasizes the role of type I interferons in lupus nephritis and might also be of relevance for mechanistic studies.


Palladium-catalyzed C-H arylation of 2,5-substituted pyrroles.
The palladium-catalyzed direct arylation of 2,5-substituted pyrrole derivatives with diaryliodonium salts to generate tri-, tetra-, and penta-substituted pyrrole products is described. The scope and limitations of these transformations are also reported.


Diagnostic accuracy of various glomerular filtration rates estimating equations in patients with chronic kidney disease and diabetes.
The equations for estimating glomerular filtration rate (GFR) based on creatinine have been found to have limitations and have not been generalizable across all populations. Equations based on cystatin C provide an alternative method to estimate GFR. Whether the equation based on cystatin C alone or combined creatinine would improve GFR estimates has not been validated among Chinese patients with chronic kidney disease (CKD) and diabetes. The aim of this study was to compare the performance of the modification of diet in renal disease (MDRD) equation based on creatinine with the five cystatin C-based formulae for estimation of GFR in patients with CKD and diabetes. A total of 166 patients with CKD and 91 patients with type 2 diabetes were enrolled in this study. Cystatin C was measured by using the particle-enhanced immunonephelometric method and estimated formulae proposed by five different investigator teams (Stevens, Ma, Rule, Macisaac and Perkins). The plasma clearance of (99m)Tc-DTPA was determined as measured GFR (mGFR). For CKD patients, the bias and accuracy for the Ma and Macisaac equations were superior compared with the MDRD, and the mean results for the Ma formula were closer to mGFR than the other equations in CKD stages 2 - 5. The differences between Macisaac and mGFR in CKD stages 2 - 4 were significantly less than those in CKD stage 1 or 5. Stevens and Rule's formulae revealed a similar bias and accuracy compared with the MDRD equation. The MDRD formula had a higher accuracy in CKD stages 3 - 5 as compared with the results in other stages. For diabetic patients, the mean results between Macisaac and mGFR were closer than those of other equations in mGFR >or= 90 mlxmin(-1)x1.73 m(-2) stage. In GFR 60 - 89 mlxmin(-1)x1.73 m(-2) stage, the MDRD formula showed the smallest difference compared with other equations. All equations overestimated GFR in the cases with GFR < 60 mlxmin(-1)x1.73 m(-2) stages. The MDRD formula had a greater accuracy within 50% of mGFR than the equations based on cystatin C in diabetic patients. Perkins formula showed a large positive bias and low accuracy, therefore it may not be suitable for assessing GFR in patients with CKD and diabetes. The formulae for estimating GFR based on cystatin C or creatinine have different trends and accuracies in patients with CKD and diabetes, especially in patients with various GFR levels. The equations based on cystatin C provide less accurate results than MDRD formulae, at least in the diabetic patients. Therefore, whether the formulae based on cystatin C are superior to MDRD formula requires further investigation in large diverse populations.


The effect of lactic acid bacterial starter culture and chemical additives on wilted rice straw silage.
Lactic acid bacteria (LAB) are suitable for rice straw silage fermentation, but have been studied rarely, and rice straw as raw material for ensiling is difficult because of its disadvantages, such as low nutrition for microbial activities and low abundances of natural populations of LAB. So we investigated the effect of application of LAB and chemical additives on the fermentation quality and microbial community of wilted rice straw silage. Treatment with chemical additives increased the concentrations of crude protein (CP), water soluble carbohydrate (WSC), acetic acid and lactic acid, reduced the concentrations of acid detergent fiber (ADF) and neutral detergent fiber (NDF), but did not effectively inhibit the growth of spoilage organisms. Inoculation with LABs did not improve the nutritional value of the silage because of poor growth of LABs in wilted rice straw. Inoculation with LAB and addition of chemical materials improved the quality of silage similar to the effects of addition of chemical materials alone. Growth of aerobic and facultatively anaerobic bacteria was inhibited by this mixed treatment and the LAB gradually dominated the microbial community. In summary, the fermentation quality of wilted rice straw silage had improved by addition of LAB and chemical materials.


The negative regulator SMAX1 controls mycorrhizal symbiosis and strigolactone biosynthesis in rice.
Most plants associate with beneficial arbuscular mycorrhizal (AM) fungi that facilitate soil nutrient acquisition. Prior to contact, partner recognition triggers reciprocal genetic remodelling to enable colonisation. The plant Dwarf14-Like (D14L) receptor conditions pre-symbiotic perception of AM fungi, and also detects the smoke constituent karrikin. D14L-dependent signalling mechanisms, underpinning AM symbiosis are unknown. Here, we present the identification of a negative regulator from rice, which operates downstream of the D14L receptor, corresponding to the homologue of the Arabidopsis thaliana Suppressor of MAX2-1 (AtSMAX1) that functions in karrikin signalling. We demonstrate that rice SMAX1 is a suppressor of AM symbiosis, negatively regulating fungal colonisation and transcription of crucial signalling components and conserved symbiosis genes. Similarly, rice SMAX1 negatively controls strigolactone biosynthesis, demonstrating an unexpected crosstalk between the strigolactone and karrikin signalling pathways. We conclude that removal of SMAX1, resulting from D14L signalling activation, de-represses essential symbiotic programmes and increases strigolactone hormone production.


RINGdb: an integrated database for G protein-coupled receptors and regulators of G protein signaling.
Many marketed therapeutic agents have been developed to modulate the function of G protein-coupled receptors (GPCRs). The regulators of G-protein signaling (RGS proteins) are also being examined as potential drug targets. To facilitate clinical and pharmacological research, we have developed a novel integrated biological database called RINGdb to provide comprehensive and organized RGS protein and GPCR information. RINGdb contains information on mutations, tissue distributions, protein-protein interactions, diseases/disorders and other features, which has been automatically collected from the Internet and manually extracted from the literature. In addition, RINGdb offers various user-friendly query functions to answer different questions about RGS proteins and GPCRs such as their possible contribution to disease processes, the putative direct or indirect relationship between RGS proteins and GPCRs. RINGdb also integrates organized database cross-references to allow users direct access to detailed information. The database is now available at http://ringdb.csie.ncu.edu.tw/ringdb/. RINGdb is the only integrated database on the Internet to provide comprehensive RGS protein and GPCR information. This knowledge base will be useful for clinical research, drug discovery and GPCR signaling pathway research.


Subdural empyema due to Enterococcus faecalis.
Central nervous system infections due to Enterococcus species are uncommon. We report the first case of subdural empyema due to Enterococcus faecalis. Following partial treatment of a middle ear infection due to Enterococcus species and mixed coliforms, the patient developed signs of meningeal involvement. A lumbar puncture showed a raised polymorph cell count, but was sterile on culture; broad-spectrum antimicrobial therapy with cefotaxime, flucloxacillin and metronidazole was commenced. Following development of focal neurological signs, a CT scan revealed a subdural collection. Drainage and culture of the pus yielded a pure growth of Enterococcus faecalis. This case demonstrates the need to remain aware of the ability of the Enterococcus to cause serious infections and to direct specific antimicrobial therapy accordingly.


The venoneuroadipofascial pedicled distally based sural island myofasciocutaneous flap: case reports.
Complex soft-tissue defects of the lower third of the leg, the heel and the ankle still present a challenge for the reconstructive surgeon. In addition to skin replacement, many of these defects require muscle bulk, which promotes the healing of open bone fractures, effectively fills osteomyelitic cavities and deep three-dimensional defects, and helps to reconstruct the Achilles tendon. In an anatomical study, we developed a new flap based on the 'neuromuscular concept'. This flap consists of a paddle of gastrocnemius muscle and a skin paddle based distally on the sural venoneuroadipofascial pedicle supplied by the lower peroneal perforators. Three cases are presented to illustrate the versatile use of this flap.


A randomised phase II study of continuous versus stop-and-go S-1 plus oxaliplatin following disease stabilisation in first-line chemotherapy in patients with metastatic gastric cancer.
We compared continuous versus stop-and-go chemotherapy after disease stabilisation with induction chemotherapy in the first-line treatment of metastatic gastric cancer (MGC). MGC patients who achieved disease control after 6 cycles of S-1/oxaliplatin (SOX) were randomised to receive either continuous SOX until progression (continuous arm) or to have a chemotherapy-free interval followed by SOX reintroduction at progression (stop-and-go arm). The primary end-point was overall survival (OS). Of the 250 patients enrolled, 247 participated in the induction phase. Of these, 121 patients were randomised to the continuous arm (n = 59) or the stop-and-go arm (n = 62). Progression-free survival (PFS) was significantly longer in the continuous arm than in the stop-and-go arm (10.5 versus 7.2 months; hazard ratio [HR] 0.55, 95% CI, 0.37-0.81; P = 0.002). Duration of disease control (DDC) and OS, however, were comparable between the two arms: median DDC, 10.5 versus 11.3 months, HR 0.92 (95% CI, 0.62-1.36; P = 0.674); median OS, 22.6 versus 22.7 months, HR 0.78 (95% CI, 0.50-1.23; P = 0.284). Adverse events including grade ≥3 fatigue (28.8% versus 8.1%; P = 0.003) and sensory neuropathy (25.4% versus 9.7%; P = 0.022) occurred more frequently in the continuous arm than in the stop-and-go arm. Quality of life (QOL) including global health status, physical/role functioning and other symptom scores significantly favoured the stop-and-go arm. Compared with the stop-and-go strategy, maintenance chemotherapy improved PFS but not DDC and OS and had a negative impact on QOL, suggesting the stop-and-go strategy may be an appropriate option in MGC patients following induction chemotherapy.


OCTANE: Oncology Clinical Trial Annotation Engine.
Many targeted therapies are currently available only via clinical trials. Therefore, routine precision oncology using biomarker-based assignment to drug depends on matching patients to clinical trials. A comprehensive and up-to-date trial database is necessary for optimal patient-trial matching. We describe processes for establishing and maintaining a clinical trial database, focusing on genomically informed trials. Furthermore, we present OCTANE (Oncology Clinical Trial Annotation Engine), an informatics framework supporting these processes in a scalable fashion. To illustrate how the framework can be applied at an institution, we describe how we implemented an instance of OCTANE at a large cancer center. OCTANE consists of three modules. The data aggregation module automates retrieval, aggregation, and update of trial information. The annotation module establishes the database schema, implements data integration necessary for automation, and provides an annotation interface. The update module monitors trial change logs, identifies critical change events, and alerts the annotators when manual intervention may be needed. Using OCTANE, we annotated 5,439 oncology clinical trials (4,438 genomically informed trials) that collectively were associated with 1,453 drugs, 779 genes, and 252 cancer types. To date, we have used the database to screen 4,220 patients for trial eligibility. We compared the update module with expert review, and the module achieved 98.5% accuracy, 0% false-negative rate, and 2.3% false-positive rate. OCTANE is a general informatics framework that can be helpful for establishing and maintaining a comprehensive database necessary for automating patient-trial matching, which facilitates the successful delivery of personalized cancer care on a routine basis. Several OCTANE components are publically available and may be useful to other precision oncology programs.


Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise.
Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24-48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise.


Variability of serum reproductive hormones in cows presenting various reproductive conditions in semi-arid areas of the North West Province, South Africa.
Hormones play a significant role in supporting reproductive processes. Predisposition to metabolic disorders may result from biological alterations in the neurohormonal system, thus leading to impaired immune function and poor reproductive performance. The aim of this study was to determine the reproductive hormonal profile in cows with reproductive conditions in semi-arid areas of the North West Province, South Africa, to establish possible correlations between different conditions and the hormonal profile. Blood samples were collected from cows in different communal areas of Mafikeng. Convenience sampling was used to collect samples for the study. Blood samples were collected cows experiencing dystocia (n=50), retained placenta (n=13), downer cow syndrome (n=34), vaginal prolapse (n=16), and abortions (n=69), following cases reported at the Animal Health Hospital of the North-West University, Mafikeng Campus. Descriptive statistics, such as mean and standard deviations, were used to describe the distribution of hormone levels across reproductive conditions. p-value less than the significance level was set at 5% (p<0.05). Data obtained revealed significantly higher estradiol in abortion (1122.99±71.99 pg/ml), downer cow syndrome (781.32±135.7 pg/ml), and dystocia (862.09±123.44 pg/ml). Oxytocin (OT) differed significantly in cows with dystocia (370.50±71.66 pg/ml) and abortion (574.73±60.65 pg/ml). Significantly low progesterone (Pg) was observed in abortion (2.45±1.509 ng/ml) and dystocia (8.59±0.402 ng/ml) while increased prostaglandin alpha was observed in cows with vaginal prolapse and abortion. The findings highlight an increase in serum estradiol and OT in aborting cows. Low Pg and estradiol in cows with vaginal prolapses and retained placenta were noted. An association was seen between downer cow syndrome and high concentrations of estradiol and Pg. Prostaglandin alpha may increase in cases of vaginal prolapse and abortion. Hormonal alterations were observed and may contribute to the incidences of different reproductive conditions.


Myocardial injury and COVID-19: Possible mechanisms.
Coronavirus Disease 2019 (COVID-19) has quickly progressed to a global health emergency. Respiratory illness is the major cause of morbidity and mortality in these patients with the disease spectrum ranging from asymptomatic subclinical infection, to severe pneumonia progressing to acute respiratory distress syndrome. There is growing evidence describing pathophysiological resemblance of SARS-CoV-2 infection with other coronavirus infections such as Severe Acute Respiratory Syndrome coronavirus and Middle East Respiratory Syndrome coronavirus (MERS-CoV). Angiotensin Converting Enzyme-2 receptors play a pivotal role in the pathogenesis of the virus. Disruption of this receptor leads to cardiomyopathy, cardiac dysfunction, and heart failure. Patients with cardiovascular disease are more likely to be infected with SARS-CoV-2 and they are more likely to develop severe symptoms. Hypertension, arrhythmia, cardiomyopathy and coronary heart disease are amongst major cardiovascular disease comorbidities seen in severe cases of COVID-19. There is growing literature exploring cardiac involvement in SARS-CoV-2. Myocardial injury is one of the important pathogenic features of COVID-19. As a surrogate for myocardial injury, multiple studies have shown increased cardiac biomarkers mainly cardiac troponins I and T in the infected patients especially those with severe disease. Myocarditis is depicted as another cause of morbidity amongst COVID-19 patients. The exact mechanisms of how SARS-CoV-2 can cause myocardial injury are not clearly understood. The proposed mechanisms of myocardial injury are direct damage to the cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, interferon mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization, and hypoxia.


Management of achalasia with transabdominal esophagocardiomyotomy and partial posterior fundoplication.
In this article we present our experience in the management of achalasia. From May 1988 through August 2005, 71 patients with achalasia underwent transabdominal esophagocardiomyotomy and partial posterior fundoplication. Barium swallow, manometry, and 24-h pH studies were performed in all patients preoperatively. Manometry and 24-h pH monitoring were only carried out in 58 patients at the third post-operative week and in 43 patients during follow-up, even though 52 patients were included in the follow-up. There were no operative deaths or complications. All the 71 patients were able to eat semifluid or solid food without dysphagia and heartburn at discharge. Esophageal barium studies showed that the maximum esophageal diameter decreased 2.2 cm and the minimum gastroesophageal junction diameter increased 8.4 mm after operation. Manometry examination in 58 patients revealed that the lower esophageal sphincter resting pressure decreased 15.0 mmHg in the wake of the procedure. Twenty-four hour pH monitoring demonstrated that reflux events were within the normal post-operative range. Fifty-five of the 58 patients had normal DeMeester scores. Among the patients with a mean 90-month follow-up, 49 patients had normal intake of food without reflux, the remaining three had mild dysphagia without requiring treatment. All the patients resumed their preoperative work and social activities. The manometry and 24-h pH studies in the 43 patients showed there were no significant changes between the third post-operative week and during follow-up. Transabdominal esophagocardiomyotomy and posterior partial fundoplication are able to relieve the functional outflow obstruction of the lower esophageal sphincter, obviate the rehealing of the myotomy edge and prevent gastroesophageal reflux in patients who have undergone myotomy alone.


Expression of tumor necrosis factor-alpha and its mRNA in the endometrial mucosa during the menstrual cycle.
Endometrial biopsies, collected at various phases of the menstrual cycle, were examined for the presence of tumor necrosis factor-alpha (TNF-alpha) by histochemistry, and TNF-alpha mRNA by in situ hybridization and Northern blotting. During the proliferative phase, TNF-alpha and TNF-alpha mRNA were not detected or were at low levels. During the secretory phase, the TNF-alpha mRNA level was increased and observed in the wall of coiled arteries. TNF-alpha was detected both in the wall of the coiled arteries and, in highest concentration, within the epithelial cells. In regard to the capacity of TNF-alpha to induce a hemorrhagic necrosis in various tissues, this study suggests that an overproduction of TNF-alpha within the small arteries of the endometrial mucosa might be responsible for menstruation.


Molecular analysis of neurolysin expression in the rat and bovine ciliary body.
This paper deals with the capability of the ciliary epithelium to express neurolysin, involved in the inactivation of numerous neuropeptides. Total RNAs from ciliary body (CB) were processed for RT-PCR, and the amplification products were sequenced. The whole-protein extracts of CBs were analyzed using the Western blot. The CBs were processed for neurolysin immunolocalization. The RT-PCR detected the presence of neurolysin mRNA in the ciliary body. The Western blot assays demonstrated immunochemical cross-reactivity with neurolysin. The immunoreactivity to neurolysin was observed in ciliary epithelium. These results indicate that the ciliary epithelium expresses neurolysin.


A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer.
Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.


[The usefulness of preoperative exercise stress myocardial single photon emission CT with thallium-201 to predict the responses to coronary revascularization].
To evaluate the usefulness of preoperative exercise stress (Ex) myocardial single photon emission CT (SPECT) with thallium-201 to predict the responses to coronary revascularization (CRV), Ex-SPECT's were obtained in 42 patients with coronary artery disease (CAD). In 34 patients angioplasty was performed and in 18 patients coronary bypass surgery was undergone. Before and after CVR, Ex-SPECT's were obtained both at immediately after Ex (Initial) and 3 hours later (RD) by the rotating gamma camera. Initial images before CRV showed definite perfusion defects (+3) in 76 myocardial segments. Perfusion abnormalities at RD images were graded into 4 (+3 to 0) by visual interpretation. "+3" indicated fixed defect and "0" indicated no perfusion abnormality. At RD images 17 segments showed fixed defect and 59 segments showed improved perfusion more than one grade. After CRV, all 59 segments with improved perfusion at RD images showed improvement of perfusion in comparison with initial images before CRV. Out of 17 segments with fixed defect before CRV, 14 segments showed perfusion defect with +3, while 3 segments showed improved perfusion after CRV. These 3 segments had ECG evidence of myocardial infarction. In these 3 segments, Ex-SPECT's before CRV showed abnormally low myocardial T1 washout rate (WOR) despite they indicated fixed defect visually. On the contrary, other 14 segments with fixed defect showed normal WOR before CRV. In conclusion, visually interpreted Ex-SPECT's before CRV predict the myocardial perfusion after CRV in most of cases.2+n a small


Validation of the Practice Environment Scale to the Brazilian culture.
To validate the Brazilian version of the Practice Environment Scale. The Practice Environment Scale is a tool that evaluates the presence of characteristics that are favourable for professional nursing practice because a better work environment contributes to positive results for patients, professionals and institutions. Methodological study including 209 nurses. Validity was assessed via a confirmatory factor analysis using structural equation modelling, in which the correlations between the instrument and the following variables were tested: burnout, job satisfaction, safety climate, perception of quality of care and intention to leave the job. Subgroups were compared and the reliability was assessed using Cronbach's alpha and the composite reliability. Factor analysis resulted in exclusion of seven items. Significant correlations were obtained between the subscales and all variables in the study. The reliability was considered acceptable. The Brazilian version of the Practice Environment Scale is a valid and reliable tool used to assess the characteristics that promote professional nursing practice. Use of this tool in Brazilian culture should allow managers to implement changes that contribute to the achievement of better results, in addition to identifying and comparing the environments of health institutions.


Evaluation of medication use in Malaysian predialysis patients.
Chronic kidney disease (CKD) patients suffer from multiple comorbidities and complications as a cause or consequence of kidney disease. Information regarding medication- prescribing patterns in predialysis patients is sparse. We conducted a retrospective study to evaluate the medication prescription patterns among predialysis patients. Medical records (both paper based and computerized) of patients at CKD Resource Centre, Hospital Universiti Sains Malaysia, were reviewed. A total of 615 eligible cases were included in the study. The mean number of medications prescribed per patient was 8.22 ± 2.81, and medication use was correlated to the renal function (stage 3a < stage 3b < stage 4 < stage 5; P <0.001). The top three prescribed medication groups were found to be lipid-lowering agents, calcium channel blockers, and antiplatelet agents. Some medication classes such as nonaluminum/noncalcium phosphate binders, erythropoietin-stimulating agents, and renin-angiotensin-aldosterone system blockers, particularly in advanced stage, were found to be underutilized. In conclusion, predialysis patients are prescribed a large number of medications. Our findings highlight the need for assessing the impact of current medication-prescribing patterns on morbidity and mortality rates in Malaysian predialysis population.


Coexistence of Two Prothrombotic Mutations, Factor V 1691 G-A and Prothrombin 20210 G-A, and the Risk of Thrombosis in Turkish Population.
This report summarizes the coexistence of two mutations; Factor V 1691 G-A and prothrombin 20210 G-A in Turkish population and emphasises on the point that, this coexistence increases the risk of thrombosis in such patients. In thrombophilia screening programs, these two variants should be included, particularly in Turkish population.


Adrenocortical hyperfunction associated with bronchogenic carcinoma: report of five cases.
Five patients with bronchogenic carcinoma associated with adrenocortical hyperfunction are described. The clinical features, laboratory studies and autopsy findings are discussed and compared with previously reported cases. Four patients presented most of the typical features of this disorder as previously described, whereas the fifth was atypical in some respects. Typical features included: acute onset of adrenocortical hyperfunction in a middle-aged male, rapid downhill course, slight or absent physical signs of Cushing's syndrome, frequently impaired glucose tolerance, markedly elevated plasma and urinary 17-hydroxycorticosteroids not suppressed by exogenous steroids, absent diurnal variation of plasma corticoids, hypokalemic alkalosis with normal aldosterone excretion, and tumour histology of the oat cell variety. The adrenal glands of two patients were of normal or slightly increased weight, and mean 17-ketosteroid excretion values were normal in three; this contrasts with the marked increase in adrenal weight and 17-ketosteroid excretion in most reported cases.


Differential effects of doxorubicin treatment on cell cycle arrest and Skp2 expression in breast cancer cells.
Overexpression of Skp2, the ubiquitin ligase subunit that targets p27 for degradation, is often observed in cancers, and is associated with aggressive tumor proliferation and poor prognosis. As there is no drug at present that specifically targets Skp2, studies were undertaken to examine the effects of commonly used drugs on Skp2 regulation. Doxorubicin is among the most effective antitumor agents used for the management of breast cancer, but its effect on Skp2 expression is unknown. The objective of this study was to examine the effect of doxorubicin on Skp2 expression regulation in breast cancer cell lines. The expression of Skp2 mRNA and the protein levels of Skp2, p27, p21 and cyclin B were examined in doxorubicin-treated MCF-7 and MDA-MB-231 breast cancer cells. The effect of doxorubicin on the cell cycle profile was assessed by fluorescence-activated cell sorting analysis. Doxorubicin decreased Skp2 mRNA and protein levels in MCF-7 cells, but had the opposite effect in MDA-MB-231 cells. p27 levels were slightly decreased, whereas p53 and p21 levels were significantly upregulated in doxorubicin-treated MCF-7 cells. In contrast, p27 levels were unaffected by doxorubicin treatment in MDA-MB-231 cells, but cyclin B levels were markedly increased. Doxorubicin arrested MCF-7 cells at G1/S and G2/M checkpoints, whereas MDA-MB-231 cells were arrested at G2/M only. The differential effects of doxorubicin on Skp2 expression in breast cancer cells depend upon the specific cell cycle checkpoints activated by the drug. These changes induced by doxorubicin, however, do not significantly affect p27 expression in these cell lines, suggesting that the potential of a given drug to alter p27 expression through Skp2 modulation might depend on its specific action on cell cycle arrest.


Recommended prophylactic and management strategies for severe acute respiratory syndrome coronavirus 2 infection in transplant recipients.
Since December 2019, increasing attention has been paid to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic in Wuhan, China. SARS-CoV-2 primarily invades the respiratory tract and lungs, leading to pneumonia and other systemic disorders. The effect of SARS-CoV-2 in transplant recipients has raised significant concerns, especially because there is a large population of transplant recipients in China. Based on the current epidemic situation, this study reviewed publications on this virus and coronavirus disease 2019 (COVID-19), analyzed common features of respiratory viral pneumonias, and presented the currently reported clinical characteristics of COVID-19 in transplant recipients to improve strategies regarding the diagnosis and treatment of COVID-19 in this special population.


Patient-reported long-term outcome following allogeneic hematopoietic stem cell transplantation in pediatric chronic myeloid leukemia.
Pediatric CML is very rare. Before the introduction of tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation (HSCT) from a donor -if available- was the standard cure attempt. Data on the long-term outcome and health-related quality of life (HRQOL) in former pediatric CML patients undergoing HSCT are lacking. We investigated long-term survivors' self-reporting to a questionnaire sent out to patients formerly enrolled in pediatric CML-HSCT trials. Individuals with CML transplanted at age <18 years were identified from the German Childhood Cancer Registry database. Long-term survivors received a questionnaire based on the SF-36 and FACT-BMT asking them to self-report HRQOL issues. (Ethical vote #541_20 B, Medical Faculty, University of Erlangen-Nürnberg). 111/171 (64.9%) individuals survived HSCT long-term and 86/111 (77.5%) fulfilled all inclusion criteria and received the questionnaire. 37/86 (43%) participants (24 female, 13 male, median age at HSCT 12 years [range 2-18], median age at the time of the survey 29 years [range 18-43]) responded after a median follow-up period of 19 years (range 4-27) after HSCT. 10/37 (27%) participants underwent no regular medical follow-up examinations. Self-reported symptoms like chronic graft-versus-host disease (cGvHD)-associated organ impairments and conditioning regimen consequences could causatively not sharply be separated in each case. Complains comprised hypothyroidism (N=11, 30%), infertility (N=9, 24%), lung problems, dry eyes (each N=7, 19%), skin alterations (N=6, 17%), hair problems (N=4, 11%), and sexual dysfunction (N=3, 9%). 10 (27%) participants experienced 13 CML relapses after a median interval from HSCT of 31 months (range 2-93). Only one patient underwent 2nd SCT after failure of relapse treatment with TKIs. Six secondary malignancies (dysplastic melanocytic nevus and ALL, basal cell carcinoma (N=2), rhabdomyosarcoma, and thyroid carcinoma developed in 5 (13%) participants. As assessed by the SF-36 questionnaire, impaired physical health was mainly associated with cGvHD. The mental component summary score showed that also participants without cGvHD scored significantly lower than the general population. When assessed by the FACT-BMT, participants with cGvHD scored significantly lower while participants without cGvHD scored even 5 points higher than the data from controls. 18 (49%) participants considered the sequelae of HSCT an obstacle to education. Out of the total cohort, N=20 (54%), N=7 (19%), N=5 (14%), and N=4 (11%) participants worked full time, part-time, were unemployed, or had not yet finalized their education, respectively. 20 (54%) participants lived as singles, 8 (22%) lived in a partnership, 6 (16%) were married, and 3 (8%) had been divorced. Four (11%) participants reported a total number of 7 children. This first assessment of HRQOL in former pediatric patients with CML surviving HSCT for more than two decades demonstrates self-reported satisfactory well-being only in the absence of cGvHD. Research-based on self-reported outcomes sheds light on former patients' perspectives and provides an additional layer of valuable knowledge for pediatric and adult hematologists. Regular follow-up examinations are mandatory helping to avoid that late secondary neoplasias, CML-relapse, and disorders forming the broad range of possible long-term consequences of HSCT are not detected too late.


Graphene-Mesoporous Si Nanocomposite as a Compliant Substrate for Heteroepitaxy.
The ultimate performance of a solid state device is limited by the restricted number of crystalline substrates that are available for epitaxial growth. As a result, only a small fraction of semiconductors are usable. This study describes a novel concept for a tunable compliant substrate for epitaxy, based on a graphene-porous silicon nanocomposite, which extends the range of available lattice constants for epitaxial semiconductor alloys. The presence of graphene and its effect on the strain of the porous layer lattice parameter are discussed in detail and new remarkable properties are demonstrated. These include thermal stability up to 900 °C, lattice tuning up to 0.9 % mismatch, and compliance under stress for virtual substrate thicknesses of several micrometers. A theoretical model is proposed to define the compliant substrate design rules. These advances lay the foundation for the fabrication of a compliant substrate that could unlock the lattice constant restrictions for defect-free new epitaxial semiconductor alloys and devices.


Alcohol-related relationship dissatisfaction: A putative mechanism for intimate partner aggression.
Decades of research has identified alcohol use as a contributing cause of intimate partner aggression (IPA) perpetration; however, there have been fewer studies that seek to identify mediators of the relation between alcohol use and IPA perpetration. Building on research showing a positive association between problematic drinking and relationship dissatisfaction and relationship dissatisfaction and IPA, we examined whether relationship dissatisfaction accounted for the relation between problematic drinking and IPA perpetration in couples using statistical modeling that accounted for the interdependence between partners. Our results showed that (a) actor problematic drinking was related to actor psychological and physical IPA perpetration and that this relation was partially explained by actor relationship dissatisfaction, (b) partner problematic drinking was related to actor physical and psychological IPA perpetration and that this relation was partially explained by actor relationship dissatisfaction, and (c) partner problematic drinking was related to actor psychological IPA perpetration and that this relation was partially explained by partner relationship dissatisfaction. Together, our results highlight that when partner interdependence is considered, relationship dissatisfaction could be a potential mechanism of the alcohol-IPA association and provide some evidence for different pathways for psychological and physical aggression. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


The assessment of pain sensation during local anesthesia using a computerized local anesthesia (Wand) and a conventional syringe.
The purpose of this study was to compare the behavior reaction of children who received local anesthesia with a conventional syringe injection and a computerized device (Wand). One hundred and two children ages 3 to 10 years were selected for this study. In 1 group there were 55 children between the ages of 3 to 5 years old, and in the other group there were 47 children ages 6 to 10 years old. They all needed at least 2 clinical sessions of operative procedures, preceded by a local anesthetic injection, 1 on either side of the same jaw. The local anesthesia was delivered using either the Wand or the traditional syringe. A random crossover design was used so that each child served as his/her own control. There were 25 girls and 30 boys in group A (mean 4.1 +/- 0.6 years), and 26 boys and 21 girls in group B (mean 7.2 +/- 1.3 years). Most of the children had a good reaction to both techniques of local anesthesia. No significant difference in either group was found between boys and girls. The children's reactions to injection in the mandible or the maxilla with the Wand or the conventional technique, regarding crying, facial expression, hands, legs and torso movements were similar with no statistically significant difference. There was no statistical difference when the maxillary infiltration was delivered to 1 or multiple teeth. No significant difference was found when the Wand was delivered during the first or second visit. The results suggested there was no difference in the pain behavior of children during the administration of local anesthesia with a conventional injection or a computerized device when the operator was an experienced pediatric dentist. This was true for maxillary infiltration and mandibular block. For other techniques, such as palatal injection and periodontal ligament injection, more studies should be conducted.


Temporal Patterns in Seawater Quality from Dredging in Tropical Environments.
Maintenance and capital dredging represents a potential risk to tropical environments, especially in turbidity-sensitive environments such as coral reefs. There is little detailed, published observational time-series data that quantifies how dredging affects seawater quality conditions temporally and spatially. This information is needed to test realistic exposure scenarios to better understand the seawater-quality implications of dredging and ultimately to better predict and manage impacts of future projects. Using data from three recent major capital dredging programs in North Western Australia, the extent and duration of natural (baseline) and dredging-related turbidity events are described over periods ranging from hours to weeks. Very close to dredging i.e. <500 m distance, a characteristic features of these particular case studies was high temporal variability. Over several hours suspended sediment concentrations (SSCs) can range from 100-500 mg L-1. Less turbid conditions (10-80 mg L-1) can persist over several days but over longer periods (weeks to months) averages were <10 mg L-1. During turbidity events all benthic light was sometimes extinguished, even in the shallow reefal environment, however a much more common feature was very low light 'caliginous' or daytime twilight periods. Compared to pre-dredging conditions, dredging increased the intensity, duration and frequency of the turbidity events by 10-, 5- and 3-fold respectively (at sites <500 m from dredging). However, when averaged across the entire dredging period of 80-180 weeks, turbidity values only increased by 2-3 fold above pre-dredging levels. Similarly, the upper percentile values (e.g., P99, P95) of seawater quality parameters can be highly elevated over short periods, but converge to values only marginally above baseline states over longer periods. Dredging in these studies altered the overall probability density distribution, increasing the frequency of extreme values. As such, attempts to understand the potential biological impacts must consider impacts across telescoping-time frames and changes to extreme conditions in addition to comparing central tendency (mean/median). An analysis technique to capture the entire range of likely conditions over time-frames from hours to weeks is described using a running means/percentile approach.


Comparative analysis of the packing topology of structurally important residues in helical membrane and soluble proteins.
Elucidating the distinct topology of residue packing in transmembrane proteins is essential for developing high-quality computational tools for their structure prediction. Network approaches transforming a protein's three-dimensional structure into a network have proven useful in analyzing various aspects of protein structures. Residues with high degree of connectivity as identified through network analysis are considered to be important for the stability of a protein's folded structure. It is thus of interest to study the packing topology of these structurally important residues in membrane proteins. In this work, we systematically characterized the importance and the spatial topology of these highly connected residues in helical membrane and helical soluble proteins from several aspects. A representative helical membrane protein and two helical soluble protein structure data sets were compiled and analyzed. Results of analyses indicate that the highly connected amino acid residues in membrane proteins are more scattered peripherally and more exposed to the membrane than in soluble proteins. Accordingly, they are less densely connected with each other in membrane proteins than in soluble proteins. Together with the knowledge of a centralized function site for many membrane proteins, these findings suggest a structure-function model that is distinguishable from soluble proteins.


[Changing susceptibility patterns of surgical site infection pathogens after the introduction of modern perioperative chemotherapy in the emergency surgery clinic].
993 surgical site infection aerobic pathogens are isolated over a six-year period (I.1994-I.2000) by the Microbiology Laboratory at University Hospital "Tzaritza Joana". 224 (22.6%) of them are isolated from patients undergoing abdominal surgery in the Emergency Surgery Clinic. The period covers 3 years before the introduction of current single-dose perioperative prophylaxis (i.e. under the conditions of long-term one) as well as the next 3 years following its introduction in the Emergency Surgery Clinic. The changes of pathogens susceptibility patterns to single-dose drug schemes in both hospital elective abdominal surgery and emergency surgery clinics are followed during the whole period. Our microbial susceptibility data support the ecological expedience of single-dose approach categorically.