Differential effects of hemorrhage on Kupffer cells: decreased antigen presentation despite increased inflammatory cytokine (IL-1, IL-6 and TNF) release.
Although studies indicate that simple hemorrhage induces profound depression of cell-mediated immunity and enhances the host's susceptibility to sepsis, the mechanism for this remains unknown. Since the Kupffer cells (KC) are positioned to have constant exposure to various immunomodulators and antigens released during hypotension, we have examined whether antigen presentation by KC, a critical component in eliciting an antigen specific immune response or those processes associated with it, are depressed following hemorrhage. C3H/HeN mice were bled to and maintained at a mean BP of 35 mmHg for 60 min, and then resuscitated with their own blood and adequate fluids. The mice were killed at varying periods of time after hemorrhage to obtain KC from the liver, and assessed for their capacity to present antigen to a sensitized clone Th/cell line (D10.G4.1). Hemorrhaged mice exhibited a marked decrease in antigen presenting capacity beginning as little as 2 h and lasting up to 3-5 days post-hemorrhage. The ability of KC to express mouse interleukin 1 (mIL-1) showed a significant decline at 2 h following hemorrhage, but this effect was not apparent at 24 h post-hemorrhage. In contrast, KC capacity to produce IL-1, IL-6 and tumour necrosis factor (TNF) (cytokines which can co-stimulate T cell antigen presentation) was markedly enhanced during the first 24 h following hemorrhage. A marked decrease was observed in both the mean of the average fluorescence per KC and the percent of Ia antigen-positive KC which persisted for at least 3 days after hemorrhage. The ability of ibuprofen (a cyclooxygenase blocker) to partially restore the antigen presenting capacity of KC from hemorrhaged mice in vitro indicates that prostaglandins are involved in this dysfunction. Thus, the depression of KC antigen presentation, as well as the enhanced capacity of these cells to release inflammatory mediators (TNF, IL-1, IL-6 and prostanoids) which may produce cell and organ dysfunction, could contribute to the host's enhanced susceptibility to sepsis following hemorrhage.


Mechanical circulatory support with the Impella® LP5.0 pump and an intra-aortic balloon pump for cardiogenic shock in acute myocardial infarction: The IMPELLA-STIC randomized study.
Percutaneous assist devices may be used as a bridge to recovery in patients with acute myocardial infarction complicated by cardiogenic shock (CS-AMI). To test the hypothesis that the Impella® LP5.0 pump (Abiomed Europe GmbH, Aachen, Germany) provides haemodynamic benefits and improves left ventricular ejection fraction (LVEF) in patients with CS-AMI already managed with an intra-aortic balloon pump (IABP). This was a prospective randomized study. The primary endpoint was change in cardiac power index (CPI) from baseline to 12hours after implantation, measured with a Swan-Ganz catheter. Secondary endpoints included LVEF at 30 days. Fifteen patients with CS-AMI were randomized; 12 were available for primary endpoint analysis (IABP group, n=6; Impella LP5.0+IABP group, n=6). Baseline characteristics were similar in both groups. Change in CPI after 12hours was not significantly different between the two groups (IABP group: ΔCPI=0.08±0.08W/m2; Impella LP5.0+IABP group: ΔCPI=-0.02±0.25W/m2; P=0.4). There was no significant change from baseline CPI in either group over 96hours, and no difference in CPI between groups at each timepoint. In the Impella LP5.0+IABP group, the part of the CPI provided by the native heart decreased from 0.37±0.10 to 0.10±0.20 (P=0.01). LVEF was similar at baseline (29.7%±8.4% and 29.3%±6.7%) and 1 month (40.6%±12.5% and 38.6%±14.4%) in the IABP and Impella LP5.0+IABP groups, respectively. Adverse events, especially major bleeding, were common, and occurred mainly in the Impella LP5.0+IABP group. In patients with CS-AMI stabilized by initial treatment with inotropes and an IABP, the Impella LP5.0 did not provide additional haemodynamic support or improvement in LVEF at 1 month; its use in this setting might be futile and possibly harmful.


Gepirone and 1-(2-pyrimidinyl)-piperazine in vitro: human cytochromes mediating transformation and cytochrome inhibitory effects.
Biotransformation of gepirone to its principal metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), was studied in human liver microsomes and in microsomes from cDNA-transfected human lymphoblastoid cells. Formation of 1-PP from gepirone in liver microsomes proceeded with a mean apparent Km ranging from 335 to 677 microM. Coincubation with 1 microM ketoconazole reduced reaction velocity to less than 5% of control values at a gepirone concentration of 250 microM. Three other metabolites, presumed to be hydroxylated products, were also formed from gepirone. Formation of all three products was reduced to approximately 20% of control values by 1 microM ketoconazole; quinidine at 1 microM produced a small reduction in formation (91-94% of control) of two of the metabolites. 1-PP was formed from gepirone exclusively by pure P450-3A4 with a Km of 849 microM; Km values for the other metabolites were 245, 240, and 415 microM. Two of the products were also formed by P450-2D6. The results indicate that 3A4 is the principal cytochrome mediating 1-PP formation, as well as formation of the other metabolites. The properties of gepirone and 1-PP themselves as cytochrome inhibitors were tested in human liver microsomes using index reactions representing activity of P450-1A2, -2C9, -2C19, -2D6, -2E1 and -3A. Gepirone and 1-PP produced negligible inhibition of all these reactions. Thus gepirone at therapeutic doses in humans has a low likelihood of inhibiting P450-mediated drug metabolism involving these cytochromes.


Electrophysiological effects of adenosine and adenosine triphosphate on sheep Purkinje fibres under normal and simulated ischaemic conditions.
1. The electrophysiological effects of adenosine and adenosine triphosphate (ATP) were examined in sheep Purkinje fibres, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). The ability of adenosine to modify the effects of noradrenaline on action potential characteristics was also investigated. 2. The only statistically significant effects of adenosine (10(-6)-10(4) M) and of ATP (10(-6)-10(-4) M) on normal action potential characteristics were a slight dose-dependent shortening of the action potential by adenosine and a depolarization by ATP, 10(-4) M. 3. Superfusion with a hypoxic, hyperkalaemic and acidotic PSS caused marked reductions in resting membrane potential, upstroke and duration of the action potential. 4. Both adenosine and ATP attenuated the reduction in the rate of rise of the upstroke and the amplitude of the action potential caused by the modified PSS. 5. Adenosine did not alter the noradrenaline-induced effects on automaticity or on action potentials of normal or depressed Purkinje fibres. 6. Adenosine and ATP had electrophysiological effects on Purkinje fibres, exposed to conditions in vitro that mimic mild myocardial ischaemia, that were different from those observed on normally polarized fibres.


Pacemaker implantation after TAVI: predictors of AV block persistence.
Approximately every fifth patient undergoing transcatheter aortic valve implantation (TAVI) requires a permanent pacemaker (PPM) after the procedure. The aim of this study was to analyse predictors of atrioventricular block III° (AVBIII) persistence with concurrent PPM dependency after TAVI. Between 2010 and 2015 a total of 1198 patients underwent TAVI at the Kerckhoff Heart and Thorax Center, Germany. After exclusion of patients with prior PPM (n = 173) 14.7% (n = 176) of the patients underwent PPM implantation after the procedure. Independent predictors of PPM implantation were pre-existing right bundle branch block (RBBB, p < 0.001) and implantation of a CoreValve prosthesis (p < 0.001). A subgroup of patients with a newly implanted PPM (n = 102) were followed-up for a median of 73 (IQR 62-85) days. The leading indication for PPM implantation was AVBIII in 74.5% (76/102). Of these patients only 22.4% (17/76) had persistent AVBIII at follow-up. Predictors of AVBIII persistence were prior RBBB (p = 0.04), postdilatation (p = 0.006) and higher mean aortic valve gradient prior to implantation (p = 0.013). PPMs were implanted earlier in patients with persisting AVBIII [1 day (IQR0-2.5) vs. 4 days (IQR2-7); p < 0.001]. Early PPM implantation after TAVI was the only independent predictor of persistent AVBIII [OR 1.36 (95% 1.05-1.75); p = 0.02]. The long-term persistence of AVBIII is generally low after TAVI. Therefore, it may be wise to postpone the indication for PPM implantation for a couple of days. The only predictors of a lack of recovery of the AVB are prior RBBB, higher mean aortic valve gradients and postdilatation of the prosthesis.


C-C motif chemokine CCL11 is a novel regulator and a potential therapeutic target in non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) is characterised by accelerated lipid deposition, aberrant inflammation, and excessive extracellular matrix production in the liver. Short of effective intervention, NAFLD can progress to cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of the C-C motif ligand 11 (CCL11) in NAFLD pathogenesis. NAFLD was induced by feeding mice with a high-fat high-carbohydrate diet. CCL11 targeting was achieved by genetic deletion or pharmaceutical inhibition. The transcriptome was analysed using RNA-seq. We report that CCL11 expression was activated at the transcription level by free fatty acids (palmitate) in hepatocytes. CCL11 knockdown attenuated whereas CCL11 treatment directly promoted production of pro-inflammatory/pro-lipogenic mediators in hepatocytes. Compared with wild-type littermates, CCL11 knockout mice displayed an ameliorated phenotype of NAFLD when fed a high-fat high-carbohydrate diet as evidenced by decelerated body weight gain, improved insulin sensitivity, dampened lipid accumulation, reduced immune cell infiltration, and weakened liver fibrosis. RNA-seq revealed that interferon regulatory factor 1 as a mediator of CCL11 induced changes in hepatocytes. Importantly, CCL11 neutralisation or antagonism mitigated NAFLD pathogenesis in mice. Finally, a positive correlation between CCL11 expression and NAFLD parameters was identified in human patients. Our data suggest that CCL11 is a novel regulator of NAFLD and can be effectively targeted for NAFLD intervention. Non-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper we describe the regulatory role of CCL11, a C-C motif ligand chemokine, in NAFLD pathogenesis. Our data provide novel insights and translational potential for NAFLD intervention.


SWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress.
Enduring behavioral changes upon stress exposure involve changes in gene expression sustained by epigenetic modifications in brain circuits, including the mesocorticolimbic pathway. Brahma (BRM) and Brahma Related Gene 1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that in mice, social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons, Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.


[Identification of lung architecture using HRCT].
The pulmonary interstitium is divided into different compartments, with the secondary pulmonary lobule representing the smallest subunit surrounded by connective tissue. Identification of the lobular architecture is a prerequisite for categorizing the broad spectrum of pulmonary interstitial diseases into distinct patterns. High-resolution computed tomography (HRCT) patterns comprise reticular and nodular opacities, ground-glass opacities, and consolidation. Air trapping and emphysema are associated with decreased pulmonary attenuation. The features of these patterns are derived from the anatomic basis and are linked with typical differential diagnoses, although the nonspecificity of the different patterns should be kept in mind. A main objective is to focus on mixed patterns.


Biochanin A affects steroidogenesis and estrogen receptor-β expression in porcine granulosa cells.
Biochanin A, similar to other isoflavones, is present in soy and soy-based food, but predominantly in red clover. Red clover extract and biochanin A were reported to affect reproductive processes as well as to demonstrate menopause relief and anticancerogenic properties. Because porcine granulosa cells provide a suitable in vitro model for studying the intracellular mechanism of phytoestrogen action in the ovary, the objective of the study was to evaluate the in vitro effects of biochanin A on the following: (1) progesterone (P4) and estradiol (E2) secretion by granulosa cells, (2) viability of the granulosa cells, and (3) mRNA and protein expression of estrogen receptors α (ERα) and β (ERβ) in the granulosa cells harvested from both medium (3-6 mm) and large (≥8 mm) porcine ovarian follicles. RIA, alamarBlue assay, reverse transcriptase-polymerase chain reaction, and immunocytochemistry were used in the study to address the objectives. Biochanin A significantly inhibited P4 and did not affect E2 secretion by porcine granulosa cells regardless of the size of follicles that served as the source of the cells. Cell viability was not affected by the treatment. Biochanin A did not alter ERα and ERβ mRNA levels in the cultured porcine granulosa cells. In contrast, this isoflavone increased (P < 0.05) the immunoexpression of ERβ in the cells from both follicle types. In summary, biochanin A, similar to genistein and daidzein, affects follicular steroidogenesis and ER expression. Its effect on ERβ protein was more intense compared with other previously examined phytoestrogens.


Analysis of the predictable variables for placenta accreta without placenta previa.
To clarify the predictive variables for adherence of the placenta (AP) in cases without placenta previa. A prospective cohort study was conducted between 2008 and 2010. Patients without placenta previa who delivered singleton babies after 36 weeks' gestation were enrolled. The maternal and ultrasonographic variables associated with AP were evaluated at the time of admission for delivery. A total of 2834 consecutive subjects were included. Placenta accreta without placenta previa was observed in six cases (0.2 %). Two cases in which the placenta was located on the previous uterine scar had AP, but AP was found only in 0.1 % of cases in which the placenta was not on the previous scar (p < 0.001). AP was frequently observed in cases with a history of previous uterine surgery compared to cases without a history [(1.9 vs. 0.1 %) p < 0.001]. AP was observed in 33 % of cases in which no retroplacental clear zone was detected, whereas AP was observed in only 0.1 % of cases with a clear zone (p < 0.001). A past history of uterine surgery, ultrasonographic findings of no retroplacental clear zone, and a placenta on the uterine scar were associated with AP in cases without placenta previa.


Therapeutic uses of FGFs.
Fibroblast growth factors and their receptors regulate a wide range of biological functions from developmental processes during embryogenesis to diverse physiological roles in the adult state, including the regulation of angiogenesis, wound healing, and metabolism. Genetic defects, or dysregulated FGF signaling, result in a variety of human conditions, which in turn provides a myriad of potential opportunities for FGF-targeted therapies to treat diseases such as cancer, impaired wound healing, metabolic syndrome, chronic kidney disease, and cardiovascular diseases. This review summarizes some of these approaches, focusing on recombinant FGFs or FGFR fragments, small molecule inhibitors, agonistic and antagonistic antibodies, and nucleic acid based therapeutics.


Vibration-induced hyperresponsiveness of arterial smooth muscle to noradrenaline with special reference to Raynaud's phenomenon in vibration disease.
Effects of in vitro and in vivo vibratory stimulations were studied on dose-response relationships of noradrenaline in excised femoral arteries of dogs and rats. The responsiveness of these arteries were enhanced after the application of the stimulation. The degree of the hyperresponsiveness was dependent upon frequency, amplitude, and duration of the stimulation. Based on the experimental results, a possible explanation was offered for Raynaud's phenomenon in vibration disease.


Prevalence and clinical significance of the Sg6/Sg7 intersegmental veins based on re-evaluation of the Couinaud classification for the right posterior portal vein.
Although Segment 6(Sg6) and Segment 7(Sg7) are two independent units, there are currently no clear anatomical boundary markers between Sg6 and Sg7. This study aimed to identify intersegmental veins (ISV) in the intersegmental plane of Sg6 and Sg7, and evaluate the prevalence of ISV, and its clinical significance in anatomical hepatectomy. We analyzed data from 180 patients undergoing abdominal computed tomography (CT) examination, and simultaneously performed 3D reconstruction models of the liver for each patient. The right posterior portal vein was analyzed and re-typed. Furthermore, the existence of ISV was defined, and prevalence and confluence patterns of ISV were analyzed. The author attempted to apply ISV to laparoscopic S6/S7 segmentectomy. We sorted data from the right posterior portal vein and divided it into six types. The ISV could be identified in 82.2% (148/180) of the patients, which were derived from the right hepatic vein (RHV) (91.9%) and right posterior inferior vein (IRHV) (8.1%). Ten ISV-guided laparoscopic Sg6/Sg7 segmentectomy were successfully carried out, seven patients underwent Sg6 segmentectomy, and three patients underwent Sg7 segmentectomy. There was no perioperative mortality. The median operative time was 223 min (range 181-260 min). The median blood loss was 200 ml (range 150-310 ml). The R0 resection rate was 100%. The ISV may be a candidate vessel to distinguish the boundary of the right posterior sector; it is expected to be a landmark in the liver parenchyma of anatomical hepatectomy.


The computational capabilities of many-to-many protein interaction networks.
Many biological circuits comprise sets of protein variants that interact with one another in a many-to-many, or promiscuous, fashion. These architectures can provide powerful computational capabilities that are especially critical in multicellular organisms. Understanding the principles of biochemical computations in these circuits could allow more precise control of cellular behaviors. However, these systems are inherently difficult to analyze, due to their large number of interacting molecular components, partial redundancies, and cell context dependence. Here, we discuss recent experimental and theoretical advances that are beginning to reveal how promiscuous circuits compute, what roles those computations play in natural biological contexts, and how promiscuous architectures can be applied for the design of synthetic multicellular behaviors.


Dietary intakes of total, nonheme, and heme iron and hypertension risk: a longitudinal study from the China Health and Nutrition Survey.
Evidence is limited regarding the long-term impact of dietary iron intake on the development of hypertension. We investigated the association between dietary intakes of total, nonheme, and heme iron and hypertension risk in a large prospective cohort of Chinese populations over 26 years. A total of 16,122 adults (7810 men and 8312 women) who participated in the China Health and Nutrition Survey (1989-2015) were included. Dietary intake was repeatedly assessed by combining three consecutive 24‑h individual dietary recalls with household food inventory weighing at each survey round. Incident hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, diagnosis by physicians, or current use of anti-hypertensive drugs. During a median follow‑up of 11.1 years, 2863 men and 2532 women developed hypertension. After adjustment for non-dietary and dietary factors, a lower risk of hypertension was found in men and women with higher intakes of total, nonheme, or heme iron. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the highest vs. lowest quartiles were 0.76 (0.67, 0.87) in men and 0.85 (0.74, 0.97) in women for total iron intake, 0.77 (0.67, 0.87) in men and 0.85 (0.74, 0.98) in women for nonheme iron intake, and 0.73 (0.62, 0.87) in men and 0.69 (0.58, 0.82) in women for heme iron intake. Dose-response analyses further revealed a U-shaped association of total and nonheme iron intake and an L-shaped association of heme iron intake with hypertension risk in both men and women (all P for non-linearity < 0.001). Our findings emphasize the importance of maintaining moderate iron intake in the prevention of hypertension. Both insufficient and excess intake of iron might increase the risk of hypertension.


Injury factors and pathological features of toxic milk mice during different disease stages.
To evaluate different injury factors and pathological characteristics of the brain at different disease stages in toxic milk (TX) mice, an animal model of Wilson's disease (WD). Thirty TX mice (10 each at 3, 6 and 12 months old) and 30 age-matched C57 mice were used in this study. Corrected phase (CP) values were determined from susceptibility-weighted images. Myelin content was determined by measuring inhibition optical density values of Luxol fast blue-stained sections. Neurofilament protein 68 kDa (NF68), β-amyloid precursor protein (β-APP), and myelin basic protein (MBP) levels, as well as copper and iron content, in brain nuclei of the TX mouse were evaluated. Gene amplification ratios for catalase (CAT), GSH peroxidase (GSH-PX), nitric oxide synthase (NOS), and superoxide dismutase (SOD) in mouse brain were also determined. Compared with C57 mice, neuronal cell counts were decreased in 12-months-old TX mice (p = .011). Myelin content was decreased in the lenticular nucleus (p = .029), thalamus (p = .030), and brainstem (p = .034) of 6-months-old TX mice; decreases in the corresponding nuclei (p = .044, .037, and .032, respectively) were also found in 12-months-old TX mice. MBP values were lower in the lenticular nucleus and thalamus (p = .027 and .016, respectively) of 6-months-old TX mice and in the corresponding nuclei (p = .24 and .040) of 12-months-old TX mice. NF-68 values were lower in the lenticular nucleus and thalamus (p = .034 and .037, respectively) of 6-months-old TX mice and in the corresponding nuclei (p = .006 and .012) of 12-months-old TX mice. β-APP values were higher in the thalamus of 6-months-old (p = .037) and 12-months-old (p = .012) TX mice. Iron content was higher in the lenticular nucleus, thalamus, and cerebellum (p = .044, .038, and .029, respectively) of 6-months-old TX mice and in the corresponding nuclei (p = .017, .024, and .029) of 12-months-old TX mice. The NOS gene amplification multiple was higher (p = .039), whereas the SOD1 gene amplification multiple was lower (p = .041) in 12-months-old TX mice. There was no correlation between metal content or oxidation index and pathological index. The pathological characteristics of the brains of TX mice may differ at different ages. Different pathogenic factors, including copper and iron deposition and abnormal oxidative stress, are present at different stages.


A U4-like small nuclear RNA is dispensable in yeast.
We have cloned a single copy gene that encodes a small nuclear RNA, designated snR3, from the yeast Saccharomyces cerevisiae. This RNA is highly conserved among fungi, and sequence and secondary structure analyses suggest that snR3 is analogous to mammalian U4 snRNA. To determine whether snR3 has an essential function in yeast, the gene (designated SNR3), was disrupted by replacing 35 nucleotides of coding sequences with 2.2 kb of yeast DNA containing the LEU2 gene. Since cells entirely lacking snR3 were expected to be inviable, the nonfunctional gene was used to replace one chromosomal copy in a diploid cell, and the diploid transformants were sporulated. Surprisingly, virtually all tetrads gave rise to four viable spores. Moreover, these haploid strains, which have been shown by DNA blot hybridization to lack an intact copy of the SNR3 gene, and which contain no detectable snR3 transcripts, are indistinguishable from their SNR3+ sister spores under a variety of growth conditions.


In vivo apoptosis induction and reduction of infectivity by an Autographa californica multiple nucleopolyhedrovirus p35(-) recombinant in hemocytes from the velvet bean caterpillar Anticarsia gemmatalis (Hübner) (Lepidoptera: Noctuidae).
Baculoviruses have long been shown to regulate apoptosis in cultured insect cells. Recently, this phenomenon was also reported to occur in vivo, reinforcing the importance of apoptosis in insect immunity against viruses. The vP35del virus, an Autographa californica multiple nucleopolyhedrovirus (AcMNPV) recombinant, was previously shown to induce apoptosis in Anticarsia gemmatalis cultured cells. In order to verify the AcMNPV interaction with hemocytes, apoptosis induction in vivo and its effects upon infectivity, we studied the course of intrahemocoelic infection of recombinant viruses (vHSGFP and vHSGFP/P35del) in A. gemmatalis larvae. Insect development and mortality were monitored and infection progress was followed by light, fluorescence and electron microscopy. For all doses tested, vHSGFP/P35del caused lower mortality than vHSGFP. Mortality of 95% occurred with a dose of 4x10(6) PFUs of vHSGFP, which was reduced to 60% for vHSGFP/P35del. GFP expression was first observed at 3 h p.i. for the two viruses, increasing for vHSGFP (40% at 120 h p.i.) and decreasing for vHSGFP/P35del (0% at 120 h p.i.). The virus vHSGFP/P35del induced apoptosis in hemocytes, with some budded virus being produced, and fragmented cells were observed between 24 and 72 h p.i. The recombinant vHSGFP induced typical wild-type cytopathic effects, with low production of occluded viruses until 120 h p.i. Plasmatocytes and granular hemocytes type 1 were the hemocytes most susceptible to both viruses. For these experimental conditions, we concluded that A. gemmatalis is a semi-permissive host to AcMNPV; moreover, apoptosis reduces AcMNPV infectivity and the p35 gene is essential for blocking apoptosis in this system.


Inhibitory effect of potassium channel openers on proliferation of cultured rabbit aortic smooth muscle cells.
To study the effects of pinacidil (Pin), nicorandil (Nic), RP 49356 (RP), and lemakalim (Lem) on phenylephrine (PE)-induced proliferation of cultured rabbit aortic smooth muscle cells (ASMC). The [3H]thymidine incorporation into DNA and number of ASMC were measured. [3H]Thymidine uptake induced by PE was markedly inhibited by Pin, Nic, RP, and Lem (0.1-10 mumol.L-1). Only RP inhibited [3H]thymidine uptake without PE-pretreatment. Cell growth induced by PE was completely inhibited by Pin. Pin, Nic, RP, and Lem showed potent antiproliferation of ASMC.


A data-driven reduced-order surrogate model for entire elastoplastic simulations applied to representative volume elements.
This contribution discusses surrogate models that emulate the solution field(s) in the entire simulation domain. The surrogate uses the most characteristic modes of the solution field(s), in combination with neural networks to emulate the coefficients of each mode. This type of surrogate is well known to rapidly emulate flow simulations, but rather new for simulations of elastoplastic solids. The surrogate avoids the iterative process of constructing and solving the linearized governing equations of rate-independent elastoplasticity, as necessary for direct numerical simulations or (hyper-)reduced-order-models. Instead, the new plastic variables are computed only once per increment, resulting in substantial time savings. The surrogate uses a recurrent neural network to treat the path dependency of rate-independent elastoplasticity within the neural network itself. Because only a few of these surrogates have been developed for elastoplastic simulations, their potential and limitations are not yet well studied. The aim of this contribution is to shed more light on their numerical capabilities in the context of elastoplasticity. Although more widely applicable, the investigation focuses on a representative volume element, because these surrogates have the ability to both emulate the macroscale stress-deformation relation (which drives the multiscale simulation), as well as to recover all microstructural quantities within each representative volume element.


Deletion of SIP1 promotes liver regeneration and lipid accumulation.
The function of Smad interacting protein-1 (SIP1) in liver regeneration is not yet known. As it is a key factor linked to the TGF-β, BMP and Wnt signaling pathways, which are important for liver regeneration, we tested whether SIP1 might also have a critical role in liver regeneration after liver injury. In this study, the 2/3 partial hepatectomy (2/3 PH) animal model was used to assess wild-type and SIP1 tissue-specific knockout mice. We collected the blood and liver tissue at selected time points after inducing injury. The level of liver regeneration was monitored using several methods, including H&E staining, immunohistochemistry (IHC), Western blotting, and qPCR. There was no difference between adult SIP1 knockout and wild-type mice in morphological appearance or liver tissue sections. The peak level of BrdU- and Ki67-positive cells was observed at 36h after PH in both SIP1 knockout and wild-type mice. However, the peak level of BrdU- and Ki67-positivity was higher in SIP1 knockout mice than in wild-type mice (P<0.05). A higher amount of peak cyclin protein expression was also observed in SIP1 knockout mice. Furthermore, lipid accumulation was observed in SIP1 knockout mice during the liver regeneration process. Expression of Plin2, which plays an essential role in adipose differentiation, was found to be significantly higher in SIP1 knockout mice than in wild-type mice after 2/3 PH (P<0.05). SIP1 plays an essential role in lipid metabolism during the liver regeneration process and might be a regulator of liver regeneration following PH injury.


Utilization of ferroproteins by Candida albicans during candidastasis by apotransferrin.
Many reports have stated that some of the pathogenic bacteria can obtain iron from ferroproteins, such as cytochrome C, ferritin, hemin, hemoglobin, and myoglobin. These reports prompted us to determine if an opportunistic pathogenic fungus, Candida albicans, can utilize ferroproteins to circumvent the iron-regulatory effect of transferrin. The following assays were carried out to measure in vitro growth stimulation by the ferroproteins: as an initial step, C. albicans was cultured in iron-free (pretreated with apotransferrin for 24 h) culture medium. Once Candida albicans yeast cell growth reached stasis from iron starvation, individual ferroproteins were added to the culture media. Results showed that hemin, hemoglobin, and myoglobin supported a partial growth recovery. Additional studies with haptoglobin, a serum protein that interacts with the globin moiety of certain ferroproteins, established that C. albicans could obtain iron from the haptoglobin-ferroprotein complexes. These data indicate that the heme part of the ferroproteins is the source of iron. This implies that heme oxygenase, CaHMX1 might be involved in bringing about dissociation of heme-containing protein for iron-acquisition. In addition, anticandidal activity of transferrin takes place not only by the process of iron regulation, but also by direct interaction with the yeast cells.


[Early reoperations in urgent surgery of the abdomen, after interventions on stomach and duodenum (author's transl)].
The problem of early re-operations in urgent surgery of the abdomen is taken into account in the light of a wide range of cases admitted into the urgent surgical ward of the Ospedale Maggiore "Cà Granda" in Milan. These cases refer to the 1950-1975 period necessitating repeated operations. The Author, after analysing the different and most important pathogenetic mechanisms, examines each case tabulating them. In the cases reported, the percentage of the re-operations is less than 20% with a total mortality rate of 33,3%, values which do coincide with the observations of other Authors.


Y-box factor YB1 controls p53 apoptotic function.
Nuclear localization and high levels of the Y-box-binding protein YB1 appear to be important indicators of drug resistance and tumor prognosis. YB1 also interacts with the p53 tumor suppressor protein. In this paper, we have continued to explore YB1/p53 interactions. We report that transcriptionally active p53 is required for nuclear localization of YB1. We go on to show that nuclear YB1 regulates p53 function. Our data demonstrate that YB1 inhibits the ability of p53 to cause cell death and to transactivate cell death genes, but does not interfere with the ability of p53 to transactivate the CDKN1A gene, encoding the kinase p21(WAF1/CIP1) required for cell cycle arrest, nor the MDM2 gene. We also show that nuclear YB1 is associated with a failure to increase the level of the Bax protein in normal mammary epithelial cells after stress activation of p53. Together these data suggest that (nuclear) YB1 selectively alters p53 activity, which may in part provide an explanation for the correlation of nuclear YB1 with drug resistance and poor tumor prognosis.


Geothermal industry waste-derived catalyst for enhanced biohydrogen production.
The main aim of this work was to develop sustainable catalyst from geothermal waste by hydrothermal process for enhanced biohydrogen production. The effects of Si/Al ratio and pH neutralization on the catalyst were also investigated to provide further insight into the hydrogen production capability. Results have shown with increasing Si/Al ratio, a lower amount of catalyst was synthesized and smaller particle size was obtained. pH neutralization treatment resulted in higher conversion compared to non-neutralized ones. Meanwhile, the highest conversion of biohydrogen from ethanol through steam reforming process (95.19%) was obtained from catalyst with pH neutralization treatment and Si/Al ratio of 10. The catalyst developed in this study was concluded to be suitable for framework/supporting catalyst due to relatively low selectivity.


Comparison of a commercial Varicella Zoster glycoprotein IgG enzyme immunoassay with a reference time resolved fluorescence immunoassay (VZV TRFIA) for measuring VZV IgG in sera from pregnant women, sera sent for confirmatory testing and pre and post vOka vaccination sera from healthcare workers.
Recently, a commercial, standardised VZV IgG glycoprotein EIA, Binding Site VaccZyme™VZV glycoprotein IgG low level EIA (VaccZyme™EIA) has become available. The VaccZyme™EIA is more robust and user friendly than the reference VZV time-resolved fluorescence immunoassay (VZV TRFIA). To assess the usefulness of the VaccZyme™EIA in the diagnostic laboratory by comparing VZV IgG levels generated by both assays on serum panels representing, non-vaccinated, and vOka vaccinated populations. Sera from non-vaccinated individuals were tested; 248 from pregnant women, 117 from various patient groups referred to the Virus Reference Department for confirmatory VZV IgG testing and 102 from healthcare workers enrolled in a study (ROVE) of antibody/IgG response to vOka. From the ROVE study, 282 post vaccination sera were tested; 108 and 101 collected at six weeks post first and second doses of vOka, respectively, and 73 collected at 18 month follow-up. Sensitivities and specificities (equivocals treated as negatives) of the VaccZyme™EIA for sera from pregnant women were 97.8% (95% CI: [94.6%, 99.4%]) and 96.8% (95% CI: [89.0%, 99.6%]), respectively, and for sera referred for confirmatory testing were 81.2% (95% CI: [71.2%, 88.8%]) and 96.9% (95% CI: [83.8%, 99.9%]), respectively, and for ROVE baseline sera were 54.2% (95% CI: [32.8%, 74.4%]) and 100% (95% CI: [95.4%, 100.0%]), respectively. For the post vOka serum panels sensitivities of the VaccZyme™EIA ranged from 65.3% (95% CI: [50.4%, 78.3%]) to 80.4% (95% CI: [71.1%, 87.8%]). Specificities were all 100%. Correlation with VZV TRFIA was high and agreement varied between the serum panels tested. VaccZyme™EIA is recommended for detecting VZV IgG in sera from non-vaccinated populations; however, caution is advised when measuring post vOka VZV IgG levels.


Simple algorithm to narrow down the candidates to receive echocardiography in patients with chronic liver disease for suspected pulmonary hypertension.
Portopulmonary hypertension (PoPH) is a subtype of pulmonary arterial hypertension related to portal hypertension. The definitive diagnosis of PoPH is made by invasive right heart catheterization. Alternatively, pulmonary arterial hypertension may be recognized noninvasively from the tricuspid regurgitant pressure gradient (TRPG), measured by echocardiography. In this study, we aimed to establish a simple algorithm to identify chronic liver disease patients with a high TRPG value in order to narrow down the candidates to receive echocardiography. TRPG was measured by echocardiography in 152 patients with chronic liver disease. Factors predictive of TRPG >30 mmHg were investigated. There were 28 (18%) cases with TRPG >30 mmHg. Independent factors associated with a high TRPG were the presence of shortness of breath, high serum brain natriuretic peptide (BNP), and low serum albumin. Child-Pugh class or the presence of ascites, varices, or encephalopathy was not associated with TRPG. There was a correlation between the serum BNP and TRPG, and the optimal cutoff value of BNP by the Youden index was 122 pg/mL, and by 100% sensitivity was 50 pg/mL. A combination of these factors identified patients with a high probability of TRPG >30 mmHg (n = 12, positive predictive value [PPV] of 83%), no probability (n = 80, PPV 0%), and intermediate probability (n = 60, PPV 25-34%). This algorithm has reduced the number of patients needing echocardiography by 53%. A simple algorithm using the presence of shortness of breath, serum BNP, and albumin levels can narrow down the candidates to receive echocardiography.


Splenic cysts in the differential diagnosis of suprarenal masses.
Splenic cysts are uncommon and their preoperative diagnosis is suspected rarely from the clinical presentation. The urologist should be aware that on an excretory urogram these cysts appear as suprarenal masses, suggesting adrenal enlargement. Two recent cases are presented, with a discussion of their classification, incidence, diagnostic evaluation and therapy.


Targeting in linear DNA duplexes with two complementary probe strands for hybrid stability.
A new in vitro hybridization reaction targets two short complementary RecA protein-coated DNA probes to homologous sequences at any position in a linear duplex DNA molecule. Stable hybrids are obtained after RecA protein removal when both complementary probe strands are present in a four-stranded hybrid, but not when one probe strand is present in a three-stranded hybrid. In four-stranded hybrids with one probe strand biotinylated and the other radiolabelled, the deproteinized hybrids can be isolated and detected by affinity capture on streptavidin-coated magnetic beads. RecA-mediated targeting of complementary biotinylated DNA probe strands allows the affinity capture of 48.5-kilobase duplex lambda genomic DNA. These reactions provide a means of isolating any desired duplex gene or chromosomal DNA fragment.


Multicultural presentation of chest pain at an emergency department in Australia.
To investigate differences in presenting patient characteristics, investigation, management and related outcomes between culturally and linguistically diverse (CALD) and non-CALD chest pain (CP) patients presenting to the ED. A cohort study of 258 patients was enrolled on presentation to Liverpool Hospital ED with a complaint of CP over a 2-week period. Main outcomes included frequency and timeliness of diagnostic and radiological investigations, medication administered and ED length of stay. Administrative and clinical data were extracted and linked from Cerner EMR FirstNet®, PowerChart® and paper records. There were 155 (60%) CALD and 103 (40%) non-CALD patients. CALD patients were older by 10 years (95% CI 4, 15; P < 0.0001). There were no significant differences in the number of pathology and imaging investigations carried out in each group, and similarly there were no significant differences in the number of patients administered analgesia or cardiac-specific medications. Neither group differed in their ED length of stay (median 280 vs 259.5 min; P = 0.79) or hospital admission rate (median 56% vs 55%, P = 0.8). Both CALD and non-CALD ED CP patients had similar test ordering, medication administration and clinical outcomes, but this was in the context of CALD patients being 10 years older together with a small study sample size. A larger cohort, matched for age, would provide further insights into potentially important differences.


Coping in the Emergency Medical Services: Associations With the Personnel's Stress, Self-Efficacy, Job Satisfaction, and Health.
Emergency Medical Services personnel (EMSP) are recurrently exposed to chronic and traumatic stressors in their occupation. Effective coping with occupational stressors plays a key role in enabling their health and overall well-being. In this study, we examined the habitual use of coping strategies in EMSP and analyzed associations of coping with the personnel's health and well-being. A total of N = 106 German Red Cross EMSP participated in a cross-sectional survey involving standardized questionnaires to report habitual use of different coping strategies (using the Brief-COPE), their work-related stress, work-related self-efficacy, job satisfaction, as well as mental and physical stress symptoms. A confirmatory factor analysis corroborated seven coping factors which have been identified in a previous study among Italian emergency workers. Correlation analyses indicated the coping factor "self-criticism" is associated with more work-related stress, lower job satisfaction, and higher depressive, posttraumatic, and physical stress symptoms. Although commonly viewed as adaptive coping, the coping factors "support/venting", "active coping/planning", "humor", "religion", and "positive reappraisal" were not related to health and well-being in EMSP. Exploratory correlation analyses suggested that only "acceptance" was linked to better well-being and self-efficacy in EMSP. Our results emphasize the need for in-depth investigation of adaptive coping in EMSP to advance occupation-specific prevention measures.


Immunoblotting analysis of the reaction of wildebeest, sheep and cattle sera with the structural antigens of alcelaphine herpesvirus-1 (malignant catarrhal fever virus).
Malignant catarrhal fever (MCF) is a disease of cattle and some other ruminants caused by alcelaphine herpesvirus-1 (AHV-1), a virus of wildebeest. The disease also occurs in the absence of wildebeest and is then thought to be caused by a viral agent harboured by the sheep. The structural proteins of AHV-1 have been used as antigens for the immunoblotting analysis of sera from wildebeest, sheep and cattle infected by either AHV-1 or the "sheep-associated" form of the disease. Wildebeest sera showed a uniform response reacting strongly with six polypeptides. Sheep sera also gave positive results but individual sera reacted with varying subsets of the antigens recognized by wildebeest. These results support the earlier suggestion that sheep harbour a herpesvirus related to AHV-1. A bovine serum from a case of MCF caused by AHV-1 also reacted only with a subset of the six wildebeest-reactive polypeptides. Sera from cattle affected with the "sheep-associated" form of the disease gave reactions in only two of the eight cases tested; both positive sera reacted to a few polypeptides only.


Modelling the vertical gradient of nitrogen dioxide in an urban area.
Land use regression models environmental predictors to estimate ground-floor air pollution concentration surfaces of a study area. While many cities are expanding vertically, such models typically ignore the vertical dimension. We took integrated measurements of NO2 at up to three different floors on the facades of 25 buildings in the mid-sized European city of Basel, Switzerland. We quantified the decrease in NO2 concentration with increasing height at each facade over two 14-day periods in different seasons. Using predictors of traffic load, population density and street configuration, we built conventional land use regression (LUR) models which predicted ground floor concentrations. We further evaluated which predictors best explained the vertical decay rate. Ultimately, we combined ground floor and decay models to explain the measured concentrations at all heights. We found a clear decrease in mean nitrogen dioxide concentrations between measurements at ground level and those at higher floors for both seasons. The median concentration decrease was 8.1% at 10 m above street level in winter and 10.4% in summer. The decrease with height was sharper at buildings where high concentrations were measured on the ground and in canyon-like street configurations. While the conventional ground floor model was able to explain ground floor concentrations with a model R2 of 0.84 (RMSE 4.1 μg/m3), it predicted measured concentrations at all heights with an R2 of 0.79 (RMSE 4.5 μg/m3), systematically overpredicting concentrations at higher floors. The LUR model considering vertical decay was able to predict ground floor and higher floor concentrations with a model R2 of 0.84 (RMSE 3.8 μg/m3) and without systematic bias. Height above the ground is a relevant determinant of outdoor residential exposure, even in medium-sized European cities without much high-rise. It is likely that conventional LUR models overestimate exposure for residences at higher floors near major roads. This overestimation can be minimized by considering decay with height.


Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing.
Ageing brings about the gradual deterioration of the immune system, also known as immunosenescence. The role of non-coding circular RNA in immunosenescence is under studied. Using circular RNA microarray data, we assembled Comparison groups (C1, C2, C3 and C4) that allowed us to compare the circular RNA expression profiles between CD28(+)CD8(+) T cells and CD28(-)CD8(+) T cells isolated from healthy elderly or adult control subjects. Using a step-wise biomathematical strategy, the differentially-expressed circRNAs were identified in C1 (CD28(+)CD8(+) vs CD28(-)CD8(+)T cells in the elderly) and C4 (CD28(-)CD8(+)T cells in the elderly vs in the adult), and the commonly-expressed circRNA species from these profiles were optimized as immunosenescence biomarkers. Four overlapping upregulated circular RNAs (100550, 100783, 101328 and 102592) expressed in cross-comparison between C1 and C4 were validated using quantitative polymerase chain reaction. Of these, only circular RNA100783 exhibited significant validation. None of the down-regulated circular RNAs were expressed in the C1 and the C4 cross-comparisons. Therefore, we further predicted circular RNA100783-targeted miRNA-gene interactions using online DAVID annotation. The analysis revealed that a circular RNA100783-targeted miRNA-mRNA network may be involved in alternative splicing, the production of splice variants, and in the regulation of phosphoprotein expression. Considering the hypothesis of splicing-related biogenesis of circRNAs, we propose that circular RNA100783 may play a role in phosphoprotein-associated functions duringCD28-related CD8(+) T cell ageing. This study is the first to employ circular RNA profiling to investigate circular RNA-micro RNA interactions in ageing human CD8(+)T cell populations and the accompanying loss of CD28 expression. The overlapping expression of circular RNA100783 may represent a novel biomarker for the longitudinal tracking ofCD28-related CD8(+) T cell ageing and global immunosenescence.


Key diagnostic characteristics of fever of unknown origin in Japanese patients: a prospective multicentre study.
To identify the key diagnostic features and causes of fever of unknown origin (FUO) in Japanese patients. Multicentre prospective study. Sixteen hospitals affiliated with the Japanese Society of Hospital General Medicine, covering the East and West regions of Japan. Patient aged ≥20 years diagnosed with classic FUO (axillary temperature≥38.0°C at least twice within a 3-week period, cause unknown after three outpatient visits or 3 days of hospitalisation). A total of 141 cases met the criteria and were recruited from January 2016 to December 2017. Japanese standard diagnostic examinations. Data collected include usual biochemical blood tests, inflammatory markers (erythrocyte sedimentation rate (ESR), C reactive (CRP) protein level, procalcitonin level), imaging results, autopsy findings (if performed) and final diagnosis. The most frequent age group was 65-79 years old (mean: 58.6±9.1 years). The most frequent cause of FUO was non-infectious inflammatory disease. After a 6-month follow-up period, 21.3% of cases remained undiagnosed. The types of diseases causing FUO were significantly correlated with age and prognosis. Between patients with and without a final diagnosis, there was no difference in CRP level between patients with and without a final diagnosis (p=0.121). A significant difference in diagnosis of a causative disease was found between patients who did or did not receive an ESR test (p=0.041). Of the 35 patients with an abnormal ESR value, 28 (80%) had causative disease identified. Age may be a key factor in the differential diagnosis of FUO; the ESR test may be of value in the FUO evaluation process. These results may provide clinicians with insight into the management of FUO to allow adequate treatment according to the cause of the disease.


CuO and Ag2O/CuO catalyzed oxidation of aldehydes to the corresponding carboxylic acids by molecular oxygen.
Furfural was oxidized to furoic acid by molecular oxygen under catalysis by 150 nm-sized Ag(2)O/CuO (92%) or simply CuO (86.6%). When 30 nm-size catalyst was used,the main product was a furfural Diels-Alder adduct. Detailed reaction conditions and regeneration of catalysts were investigated. Under optimal conditions, a series of aromatic and aliphatic aldehydes were oxidized to the corresponding acids in good yields.


Neutrophil and T lymphocyte characteristics of two patients with hyper-IgE syndrome.
Immunologic parameters including quantitative and qualitative immunoglobulin studies, various T cell functions and neutrophil chemotaxis were evaluated in two patients with the Hyper-IgE syndrome. Both exhibited pruritic dermatitis in locations atypical for atopic dermatitis, marked elevations in serum IgE levels (to 40,000 IU/ml), recurrent staphylococcal abscesses, coarse facial features and variable chemotactic defects characteristic of this syndrome. Both patients responded favorably to courses of trimethoprim-sulfamethoxazole, particularly in helping control the cutaneous infections. We believe that this is a useful therapeutic alternative to anti-staphylococcal antibiotics and prophylactic treatment has permitted therapeutic response. Serum IgG, IgG subclasses, IgM, and IgA were normal for age. Serum IgD was markedly deficient in one patient. Functional IgM was normal with positive isohemagglutinin titers. IgG poliovirus titers were present in both patients; however, tetanus titers were not detectable in either patient, despite repeated immunizations. Despite normal E rosette numbers, subtle T cell abnormalities were noted with variable responses to both in vivo SK-SD, candida, and mumps skin tests and in vitro PHA-, Con A-tetanus-induced lymphocyte proliferation. Lymphocyte production of macrophage inhibitory factor and interferon and responsiveness in a mixed lymphocyte culture were normal in both patients. Considerable Con-A-induced suppressor cell activity was present in one patient, but diminished in the other. In vivo chemotaxis determined by a Rebuck skin window, revealed a markedly delayed PMN migration in both patients during a time when both patients were clinically free of furunculosis or dermatitis.(ABSTRACT TRUNCATED AT 250 WORDS)


Media for cultivation of animal cells: an overview.
The increasing interest in products from animal cells has caused an extensive research effort towards development of media for cell cultivation.The basic components in the media used for cultivation of animal cells vary depending upon the characters of the cells and the cultivation method. Basic components consist of an energy source, nitrogen source, vitamins, fats and fatty soluble components, inorganic salts, nucleic acid precursors, antibiotics, oxygen, pH buffering systems, hormones, growth factors and serum. Extensive efforts are directed towards developing serum-free or chemically defined media. Among the serum substitutes is a long list of hormones and growth factors.


Diffuse and localized tenosynovial giant cell tumor and pigmented villonodular synovitis: a clinicopathologic and flow cytometric DNA analysis.
The DNA content and proliferative indexes of seven cases of tenosynovial giant cell tumor of tendon sheath, diffuse type (TGCT-D); 11 cases of tenosynovial giant cell tumor of tendon sheath, localized type (TGCT-L); and seven cases of pigmented villonodular synovitis (PVNS) were analyzed by flow cytometry in an attempt to assess objectively their biologic differences. Three cases of TGCT-D manifested an aneuploid DNA content and four had a diploid DNA pattern. All cases of TGCT-L and PVNS showed a diploid DNA content. The proliferative indexes for TGCT-D were significantly higher than those found in the other two groups. There was no histopathologic feature that correlated with the aneuploid DNA pattern found in two of the three cases of TGCT-D. Only one of the three aneuploid DNA content TGCT-D cases displayed marked cellular pleomorphism with dense fibrous stroma; in that case there was recurrence 4 years after initial excision. Our data further support that TGCT-D, TGCT-L, and PVNS are histopathologically similar but clinically distinct lesions. The high proliferative indexes of TGCT-D may reflect a rapid, uncontrolled growth that may explain its aggressive biologic behavior. The presence of an aneuploid DNA pattern in some cases of TGCT-D in this study, coupled with the reported chromosomal abnormalities and occurrence of malignant transformation in these lesions, clearly supports their neoplastic nature.


Biotransformations of 20-hydroxyecdysone and analogues by Curvularia lunata NRRL 2178.
20-Hydroxyecdysone, the arthropod moulting hormone, was biotransformed by the fungus Curvularia lunata NRRL 2178 to the rare ecdysteroid, 2-dehydro-3-epi-20-hydroxyecdysone, and the novel 3alpha,9alpha-cyclo ecdysteroid analogue, (20R,22R)-3beta,14alpha,20,22,25-pentahydroxy-3alpha,9alpha-cyclo-5beta-cholest-7-en-2,6-dione in 14 and 44% yields, respectively. Ponasterone A and pterosterone were similarly biotransformed to the corresponding 2-dehydro-3-epi- and 3alpha,9alpha-cyclo-analogues.


Plant-Specific Features of Ribosome Biogenesis.
The biogenesis of eukaryotic ribosomes is a fundamental process involving hundreds of ribosome biogenesis factors (RBFs) in three compartments of the cell, namely the nucleolus, nucleus, and cytoplasm. Many RBFs are involved in the processing of the primary ribosomal (r)RNA transcript, in which three of the four rRNAs are imbedded. While pre-rRNA processing is well described for yeast and mammals, a detailed processing scheme for plants is lacking. Here, we discuss the emerging scheme of pre-rRNA processing in Arabidopsis thaliana in comparison to other eukaryotes, with a focus on plant characteristics. In addition, we highlight the impact of the ribosome and its biogenesis on developmental processes because common phenotypes can be observed for ribosomal protein and RBF mutants.


Mesenchymal stem cells attenuate adriamycin-induced nephropathy by diminishing oxidative stress and inflammation via downregulation of the NF-kB.
This study aimed to evaluate the molecular mechanism mitigating progress of chronic nephropathy by mesenchymal stem cells (MSCs). Rats were divided into normal control (Normal), adriamycin (ADR)+vehicle (CON), and ADR+MSC (MSC) groups. Nephropathy was induced by ADR (4 mg/kg) and MSCs (2 × 106 ) were injected. Rats were euthanized 1 or 6 weeks after ADR injection. NF-kB, MAPKs, inflammation, oxidative stress, profibrotic molecules, and nephrin expression were evaluated. Electron and light microscopy were used for structural analysis. MSCs were co-cultured with renal tubular epithelial cells or splenocytes to evaluate relation with oxidative stress and inflammatory molecules RESULTS: Adriamycin treatment upregulated inflammation, oxidative stress, and profibrotic molecules; this was mitigated by MSCs. Glomerulosclerosis and interstitial fibrosis were observed in ADR-treated groups, and were more prominent in the CON group than in the MSC group. Fusion of foot processes and loss of slit diaphragms were also more prominent in the CON group than in the MSC group. In vitro, MSCs reduced oxidative stress related molecules, inflammatory cytokines, and NF-kB transcription. MSC- or ADR-induced regulation of NF-kB transcriptional activity was confirmed by a luciferase reporter assay. Mesenchymal stem cells attenuate ADR-induced nephropathy by diminishing oxidative stress and inflammation via downregulation of NF-kB.


CSF levels of dopamine and serotonin, but not norepinephrine, metabolites are influenced by the ketogenic diet in children with epilepsy.
The ketogenic diet (KD) is a non-pharmacological treatment of medically refractory epilepsy in children. Its mechanisms of action are still unclear but monoamine neurotransmitters have been proposed to be involved. Norepinephrine, dopamine, and serotonin are known to modulate seizure susceptibility in many animal models. We examined whether the concentrations of norepinephrine, dopamine, and serotonin metabolites were affected by the KD in children with pharmacoresistant epilepsy. The metabolites of norepinephrine, HMPG, of dopamine, HVA, and of serotonin, 5-HIAA, were analyzed in cerebrospinal fluid (CSF) before and 3 months after starting the KD. Twenty-six children (mean age 5.9 years) participated. Twenty-one children had generalized epilepsy and five partial. CSF was sampled by lumbar puncture. Seizure frequency before and during the diet was determined. Highly significant changes were found for HVA (p=0.0002) and 5-HIAA (p=0.004), which were both decreased during the KD compared to before diet. The levels of HMPG were unchanged. However, no differences were found between response groups. Valproate medication affected the levels of HMPG during diet with decreased levels in children on valproate and increased in those not on valproate (p=0.04). Our study indicates that the KD significantly alters the levels of metabolites of dopamine and serotonin but with a stable ratio HVA/5-HIAA in the CSF of children with refractory epilepsy, which finding may be of importance for the mechanism of action.


Teaching bedside sonography using peer mentoring: a prospective randomized trial.
Bedside sonography is a growing field of medicine, but there is little evidence about how to teach it to medical students. A peer-mentoring system may help preclinical medical students learn bedside sonography. In 2008 and 2009, participating first-year medical students completed an image recognition test at 0, 2, and 4 months and were randomized to an early or a late intervention group. In hands-on sessions, senior medical students taught the early intervention group how to perform a Trinity hypotensive ultrasound protocol between months 0 and 2 and then taught the late intervention group the Trinity protocol between months 2 and 4. Participants completed a practical examination at month 4. We measured the improvement in knowledge after the intervention and retention of knowledge and skills in the early intervention group at month 4. First-year medical students completed precourse and postcourse surveys about comfort and skills with sonography. Eighty-six first-year medical students enrolled; 79 completed the precourse survey; 54 completed all knowledge tests; 52 completed the practical examination; and 49 completed the postcourse survey. Of the 125 nonparticipants, 109 completed the precourse survey, and 25 completed the postcourse survey. Participants' knowledge scores increased by 30% after the intervention. The early intervention group retained 92% of the knowledge gained. Thirty-six percent of participants were able to complete the Trinity protocol in 15 minutes during the practical examination, with no significant difference between the early and late intervention groups. Participants responded positively about the experience and indicated that hands-on sessions were helpful. Peer mentoring is a useful method for teaching sonography to preclinical medical students.


Kinematic alignment results in clinically similar outcomes to mechanical alignment: Systematic review and meta-analysis.
It is unclear whether a difference in functional outcome exists between kinematically aligned (KA) and mechanically aligned (MA) knee replacements. The aim of this study is to perform a comprehensive systematic review and meta-analysis of the available level I-IV evidence. A meta-analysis of randomised controlled trials and observational studies comparing patient reported outcome measures (PROMs), range of motion (ROM), gait analysis and complications in TKA with KA and MA was performed. Quality assessment was performed for each study using the Joanna Briggs Institute (JBI) critical appraisal tools. Twelve randomised controlled trials and fourteen observational studies published between 2014 and 2022 were included in the final analysis. Meta-analysis revealed KA to have significantly better Oxford Knee Score (OKS) (p = 0.02), Forgotten Joint Score (FJS) (p = 0.006), Knee Society Score (KSS) Objective Knee (p = 0.03) and KSS Functional Activity (p = 0.008) scores. However, these improvements did not exceed the minimum clinically important difference (MCID) values reported in the literature. Subgroup analysis showed robotic assisted KA-TKA to have a clinically superior FJS (p = 0.0002) and trend towards KSS Objective Knee score (p = 0.10), compared to PSI. Gait and plantar pressure distribution of KA cohorts more closely represented healthy cohorts, and KA showed a weak association of a decreased knee adduction moment (KAM) compared to MA. Differences in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), range of motion and complications were not significant between groups. Although KA results in several improved functional outcomes, these do not reach clinical significance. Further standardised large-scale randomised studies are required to improve the quality of evidence. As it stands, it is difficult to recommend one philosophy over the other.


Sequential drug delivery for liver diseases.
The liver performs critical physiological functions such as metabolism/detoxification and blood homeostasis/biliary excretion. A high degree of blood access means that a drug's resident time in any cell is relatively short. This short drug exposure to cells requires local sequential delivery of multiple drugs for optimal efficacy, potency, and safety. The high metabolism and excretion of drugs also impose both technical challenges and opportunities to sequential drug delivery. This review provides an overview of the sequential events in liver regeneration and the related liver diseases. Using selected examples of liver cancer, hepatitis B viral infection, fatty liver diseases, and drug-induced liver injury, we highlight efforts made for the sequential delivery of small and macromolecular drugs through different biomaterials, cells, and microdevice-based delivery platforms that allow fast delivery kinetics and rapid drug switching. As this is a nascent area of development, we extrapolate and compare the results with other sequential drug delivery studies to suggest possible application in liver diseases, wherever appropriate.


Preoperative cerebrospinal fluid biomarkers may be associated with postoperative delirium in patients undergoing knee/hip arthroplasty: the PNDABLE study.
In the global aging population, the incidence of postoperative delirium (POD) is increasing. Therefore, finding its effective predictive tools becomes crucial. We aimed to identify potential Cerebrospinal fluid (CSF)biomarkers for POD. A total of 825 patients undergoing knee/hip arthroplasty under combined spinal-epidural anesthesia were selected. The patients were aged 40 to 90 years with American Society of Anesthesiologists physical status I~II. The Mini-Mental State Examination was completed 1 day before the operation. CSF was extracted after successful spinal-epidural combined puncture, and α-synuclein (α-syn), amyloid beta40 (Aβ40), amyloid beta42 (Aβ42), t-Tau, phosphorylated Tau (p-Tau), progranulin (PGRN) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF were measured by enzyme-linked immunosorbent assays (ELISA). The patient's operation time, anesthesia time, intraoperative blood loss and fluid input were also recorded. After the operation, the occurrence rate and severity of POD were determined by the Confusion Assessment Method and the Memorial Delirium Assessment Scale (MDAS), respectively. Patients were categorized into POD group and non-POD group. Logistic regression analysis was performed on the indicators with statistically significant differences, and the area under the ROC curve (AUC) was used to estimate the predictive accuracy of the biomarkers for POD. A total of 92 patients developed POD and the incidence of POD was 11.15%. The results of the multivariable logistic regression showed that CSF t-Tau (P = 0.004, OR = 1.006, 95%CI 1.002~1.009) and α-syn (P = 0.004, OR = 1.001, 95%CI 1.000~1.001) were positively associated with the occurrence rate of POD, while Aβ42 (P < 0.001, OR = 0.989, 95%CI 0.986~0.993), CSF PGRN (P = 0.002, OR = 0.999, 95%CI 0.999~1.000), Aβ42/ t-Tau (P < 0.001, OR = 0.181, 95%CI 0.102~0.319) and Aβ42/p-Tau (P < 0.001, OR = 0.617, 95%CI 0.526~0.725) were inversely proportional to the occurrence of POD. ROC curve analysis indicated that Aβ42/t-Tau (AUC = 0.823), CSF Aβ42 (AUC = 0.813), Aβ42/p-Tau (AUC = 0.810), α-syn (AUC = 0.644) and PGRN (AUC = 0.638) could predict the occurrence rate of POD. The combination of all these biomarkers showed a greater AUC(0.896) than using any of them alone. CSF Aβ42, PGRN, α-syn, Aβ42/t-Tau and Aβ42/p-Tau might be associated with the occurrence rate of POD in patients undergoing knee/hip arthroplasty. Clinical Registration No. ChiCTR2000033439.


Evaluation of VEGF mediated pro-angiogenic and hemostatic effects and chemical marker investigation for Typhae Pollen and its processed product.
Typhae Pollen (TP) is a well-known Traditional Chinese Medicine (TCM) to remove blood stasis. Carbonized Typhae Pollen (CTP), a processed product of TP after being stir-fried, has been widely applied to clinical practice with its capability of hemostasis. However, the underlying mechanism of TP and CTP are still not fully elucidated and discrimination against TP and CTP remains a challenge. The aim of this study is to investigate whether TP could remove blood stasis by promoting angiogenesis and the process of carbonizing it could enhance hemostatic effect. Meanwhile, some chemical markers for quality control of CTP had better to be found. The changes of constituents between TP and CTP were analyzed by UPLC-QTOF-MS/MS. We investigated pro-angiogenic and hemostatic effects of TP and CTP in two zebrafish models: VRI-induced ISV insufficiency model and Ator-induced cerebral hemorrhage model. Subsequently, quantitative real-time PCR (qRT-PCR) was applied to investigate the mechanism of pharmacological effects. Finally, chemometric method was applied to find chemical markers. A total of 19 compounds were identified in qualitative analysis. The loss rate of each compound was calculated and compared. Two compounds (huaicarbon A/B) could only be detected in CTP and the content of flavonoid glycosides in CTP was significantly decreased compared with TP. The average content of the three identified flavonoid aglycones (quercetin, isorhamnetin and kaempferol) was increased about 30 percent in CTP. TP promoted pro-angiogenesis by up-regulating the expression of VEGFA, flt1 and kdr. After heating process, the pro-angiogenic activity was reduced and hemostatic activity was enhanced in CTP. Then qRT-PCR analysis found that CTP could significantly up-regulate the expression of VEGFA and vWF. In the discovery of markers, 6 chemical markers for discrimination of TP and CTP were obtained by chemometric method. Our research indicated that the pro-angiogenic activity of TP was involved in VEGF signaling pathway. After processing, hemostatic activity of CTP has been enhanced by up-regulating the expression of VEGFA and vWF. A chemical marker database was established to provide a scientific evidence for quality control, mechanism and the clinical application of TP and CTP.


Spatio-temporal characterization of intercostal activity during breathing in the cat.
It is envisaged that the motor control of the intercostal musculature--an assembly of mobile structures--can be characterized in terms of a conceptual spatially continuous control function, that underlies the discretely distributed muscular activity and reflects an inferred global dynamic control of the thoracic cage during breathing. The global control function is estimated by the spatio-temporal pattern obtained by averaging in time and space and interpolation of multichannel simultaneous intercostal EMG recording in the anaesthetized cat. Different examples of the experimental preparation in the presence of stimuli of different kinds are analysed. The resultant signal patterns are found to be self-consistent and capable of exhibiting systematically differing features in systematically differing experimental conditions, thus supporting the validity of the analysis and the choice of the estimator. It is concluded that a more detailed analysis of the requirements of this approach is then warranted. Such requirements are discussed, and, specifically, results that bear on the adequacy of spatial sampling rate are presented. It is suggested that such methods offer a promising approach in the study of motor control strategies of the respiratory apparatus.


Controlled photoluminescence from self-assembled semiconductor-metal quantum dot hybrid array films.
Thin films of hybrid arrays of cadmium selenide quantum dots and polymer grafted gold nanoparticles have been prepared using a BCP template. Controlling the dispersion and location of the respective nanoparticles allows us to tune the exciton-plasmon interaction in such hybrid arrays and hence control their optical properties. The observed photoluminescence of the hybrid array films is interpreted in terms of the dispersion and location of the gold nanoparticles and quantum dots in the block copolymer matrix.


Cherry tomato and persimmon kaki conservation with a natural and biodegradable film.
The chemical composition of Essential Oils Satureja montana and Mentha longifolia was determined, and their activity against important phytopathogenic and post-harvest fungi was studied, to evaluate their potential as natural food preservatives. The major compounds were carvacrol (24.0%), γ-terpinene (15.9%) and p-cymene (14.2%) in S. montana, and piperitenone oxide (52.7%) and piperitone oxide (23.5%) in M. longifolia. EOs were tested in vitro on Alternaria alternata, Botryotinia fuckeliana, Curvularia hawaiiensis, Fusarium equiseti, F. oxysporum lycopersici, Rhizoctonia solani and Verticillium dahliae. S. montana demonstrated excellent results. At 300 μg mL-1 the growth of all fungi was inhibited with 100% mycelial growth inhibition (MGI), except for B. fuckeliana (92%). M. longifolia was less effective, and its best result was against Verticillium dahliae (100% MGI) at 400 and 300 μg mL-1. S. montana EO was selected for in vivo antifungal tests in Cherry tomatoes and kaki "Persimmon" against A. alternata. The S. montana EO biofilm reduced post-harvest fungi development. In tomato, it inhibited up to 90% after 20 days. Necrosis did not occur for 2 months in the persimmon fruits. S. montana EO is an effective non-toxic preservative that can be considered to develop a botanical and enviro-friendly low-risk biofungicide.


Patient information and patient preparation in orthognathic surgery. The role of an information brochure a medical audit study.
In a retrospective study on 166 patients who had undergone orthognathic surgery, the influence of an information brochure on patient information, satisfaction and dissatisfaction was investigated. Although the use of an information manual was appreciated by the patients and can be recommended, its influence on patient preparation for surgery was poorer than was expected. Verbal information by effective communication between the surgeon and the patient remains the key to patient preparation.


Growth and survival of peritrich ciliates in an urban stream.
A computerized system was devised to trace the attachment, growth and disappearance of peritrich ciliates in an urban river. By tracing the development of each Carchesium polypinum colony in the river, it was possible to estimate the actual growth rate of this species without considering the effect of immigration. The survival and colonization rates of the colonies and individuals of solitary species could also be estimated. C. polypinum showed high growth rates (r=1.370 day-1, doubling time 12.14 h). The number of daily colonizers also increased at a high rate, and the combination of growth and colonization caused very high population increase rates at the area level. Because of its low survivorship, the rate of Vorticella microstoma increase was much lower than previously reported. The survival of solitary species and small colonies was lower than with large colonies, and fewer new colonizers survived with the development of the attached microbial community.


Mesenteric venous infarction presenting as an upper GI bleeding and diagnosed by upper GI endoscopy.
A case of primary mesenteric vein thrombosis with extensive small bowel infarct beginning at the ligament of Treitz presented as upper gastrointestinal bleeding. Although endoscopy of the upper GI tract disclosed erosive gastritis this finding was considered insufficient to explain the hematemesis; therefore the endoscope was advanced further until a necrotic and aperistaltic-looking mucosa was found in the area of the ligament of Treitz. This paper describes the endoscopic picture of necrotic duodenal mucosa, and stresses the importance of a deeper examination into the duodenum when a clear-cut cause for the bleeding is not found in the stomach or duodenal bulb.


Expanding potential of radiofrequency nurse call systems to measure nursing time in patient rooms.
The objective of this study was to determine the utility and feasibility of using data from a nurse call system equipped with radiofrequency identification data (RFID) to measure nursing time spent in patient rooms. Increasing the amount of time nurses spend with hospitalized patients has become a focus after several studies demonstrating that nurses spend most of their time in nondirect care activities rather than delivering patient care. Measurement of nursing time spent in direct care often involves labor-intensive time and motion studies, making frequent or continuous monitoring impractical. Mixed methods were used for this descriptive study. We used 30 days of data from an RFID nurse call system collected on 1 unit in a community hospital to examine nurses time spent in patient rooms. Descriptive statistics were applied to calculate this percentage by role and shift. Data technologists were surveyed to assess how practical the access of data would be in a hospital setting for use in monitoring nursing time spent in patient rooms. The system captured 7393 staff hours. Of that time, 7% did not reflect actual patient care time, so these were eliminated from further analysis. The remaining 6880 hours represented 91% of expected worked time. RNs and nursing assistants spent 33% to 36% of their time in patient rooms, presumably providing direct care. Radiofrequency identification data technology was found to provide feasible and accurate means for capturing and evaluating nursing time spent in patient rooms. Depending on the outcomes per unit, leaders should work with staff to maximize patient care time.


Beta-1,3-galactosyl-N-acetylhexosamine phosphorylase from Bifidobacterium bifidum DSM 20082: characterization, partial purification and relation to mucin degradation.
A new enzyme has been characterized in a cell-free extract of Bifidobacterium bifidum that catalysed the reversible phosphorolytic cleavage of beta-1,3-galacto-oligosaccharides. In the presence of Pi, the phosphorolysis reaction was favoured and was accompanied by a Walden reaction. Cleavage of the beta-glycosidic linkage gave an alpha-galactoside derivative (alpha-D-galactose 1-phosphate). The enzyme possesses a high specificity for beta-D-galactosido-(1, 3)-N-acetylglucosamine and beta-D-galactosido-(1, 3)-N-acetylgalactosamine. This purified intracellular enzyme had an estimated molecular mass of 140 kDa. The galactophosphorolytic activity on disaccharides was optimal at pH 6-6.5 and the reverse reaction was optimal at pH 5.5-6. The temperature optimum for phosphorolysis and the reverse reaction was approx. 50-55 degrees C. This enzyme is of particular interest in degrading some beta-D-Gal(1, 3) linkages and should be classified as EC 2.4.1.-.


Corrigendum to "Synthesis and characterization of a (+)-catechin and L-(+)-ascorbic acid cocrystal as a new functional ingredient for tea drinks" [Heliyon 5 (8) (August 2019) e02291].
[This corrects the article DOI: 10.1016/j.heliyon.2019.e02291.].


Feasibility of combined risk stratification with coronary CT angiography and stress myocardial SPECT in patients with chronic coronary artery disease.
To examine the additional prognostic value of coronary CT angiography (CTA) over myocardial perfusion imaging (MPI) in patients with suspected or known coronary artery disease. A series of 157 patients (mean age 69 ± 9 years; 76% male; median follow-up 49 months; range 12-82 months) underwent stress MPI with SPECT and coronary CTA within a 6-month interval. Summed stress score (SSS) and summed difference score (SDS) of stress MPI, number of vessels with stenosis, and presence of left main trunk stenosis and high-risk plaques on coronary CTA were examined. Primary endpoints were cardiac death, acute myocardial infarction, or unstable angina requiring revascularization. Secondary endpoints were revascularization > 60 days after the latter imaging test. All patients were followed up for at least 1 year (mean 45 ± 19 months; range 12-82 months). Nine (6%) patients reached primary endpoints. Cardiac death occurred in 1 (0.6%) patient, myocardial infarction in 5 (3%), and unstable angina requiring hospitalization in 3 (2%). Elective revascularization within 60 days was performed in 31 (20%) patients. Sixteen (10%) patients required revascularization after > 60 days. Primary endpoint event-free survival rates were significantly lower in patients with myocardial ischemia (SDS ≥ 2) and high-risk plaques (HRP), and secondary endpoint event-free survival rates in patients with SSS ≥ 4 and 3VD. In multivariate analysis, Cox proportional hazards regression analysis revealed HRP (HR = 8.02; P = 0.006) and myocardial ischemia (HR = 11.487; P = 0.025) were significant predictors of primary endpoints, and 3VD of secondary endpoints (HR = 4.981; P = 0.008). Combined ischemia and HRP resulted in the significant increase of the model Chi square in prediction of primary end points from ischemia or HRP alone (17.4 vs. 9.41; P = 0.005, 17.4 vs. 9.39; P = 0.005, respectively). Coronary CT angiography may provide additional prognostic information over MPI.


Characteristics of patient and staff victims of assaults in community residences by previously nonviolent psychiatric inpatients.
There currently exists a large body of empirical research examining patient assaults in inpatient psychiatric facilities. These studies have focused primarily on staff and have found younger, male mental health workers with lower levels of formal education and experience as well as nurses involved in restraint procedures to be most at risk. However, despite the increased utilization of community-based services, little attention has been directed toward patient assaults on patients and staff in community settings, particularly residential services. This study began to respond to this need by examining patient assaults toward other patients and staff in community residences during the first twelve months post-discharge for a group of newly discharged patients who were not violent as inpatients. This study found female patients and staff to be at greater risk for assault than male patients. Lack of experience by staff was also a risk factor. The clinical, administrative, and research implications of these findings are discussed.


Changes in gene expression due to chronic exposure to environmental pollutants.
Populations of the teleost fish Fundulus heteroclitus inhabit and have adapted to highly polluted Superfund sites that are contaminated with persistent toxic chemicals. Populations inhabiting different Superfund sites provide independent contrasts for studying mechanisms of toxicity and resistance due to exposure to environmental pollutants. To identify both shared and unique responses to chronic pollutant exposure, liver, metabolic gene expression in F. heteroclitus populations from each of three Superfund sites (New Bedford Harbor, MA; Newark Bay, NJ; and Elizabeth River, VA) were compared to two flanking reference site populations (nine populations in total). In comparisons to their two clean reference sites, the three Superfund sites had 8-32% of genes with altered expression patterns. Between any two Superfund populations, up to nine genes (4%) show a conserved response, yet among all three populations, there was no gene which had a conserved, altered pattern of expression. Across all three Superfund sites in comparison to all six-reference populations, the most significant gene was fatty acid synthase. Fatty acid synthase is involved in the storage of excess energy as fat, and its lesser expression in the polluted populations suggests that the polluted populations may have limited energy stores. In contrast to previous studies of metabolic gene expression in F. heteroclitus, body weight was a significant covariate for many of the genes which could reflect accumulation and different body burdens of pollutants. Overall, the altered gene expression in these populations likely represents both induced and adaptive changes in gene expression.


Genotype-Clinical Correlations in Polycystic Kidney Disease with No Apparent Family History.
Genetic characteristics of polycystic kidney disease (PKD) patients without apparent family history were reported to be different from those with a positive family history. However, the clinical course of PKD patients with no apparent family history is not well documented in the literature. We evaluated the relationship between genotype and the clinical course of 62 PKD patients with no apparent family history. The annual decline of renal function was faster in the patients with PKD1/PKD2 mutation (PKD1 truncating [-3.08; 95% CI -5.30 to -0.87, p = 0.007], PKD1 nontruncating [-2.10; -3.82 to -0.38, p = 0.02], and PKD2 [-2.31; -4.40 to -0.23, p = 0.03]) than in the other patients without PKD1/PKD2 mutation. Similar results were obtained after adjustment for gender, age, estimated glomerular filtration rate (eGFR), height-adjusted total kidney volume (TKV), and mean arterial pressure (MAP). There was no significant difference in the annual decline of renal function among the different PKD1/PKD2 groups, but Kaplan-Meier analysis showed that progression to eGFR < 15 mL/min/1.73 m2 was significantly faster in PKD1 truncating group (p = 0.05). The annual rate of TKV increase was larger in the patients with PKD1/PKD2 mutation (PKD1 truncating [4.63; 95% CI 0.62-8.64, p = 0.03], PKD1 nontruncating [3.79; 0.55-7.03, p = 0.02], and PKD2 [2.11; -1.90 to 6.12, p = 0.29]) than in the other patients without PKD1/PKD2 mutation. Similar results were obtained after adjustment for gender, age, eGFR, and MAP. Detection of PKD1/PKD2 mutation, especially PKD1 truncating, is useful for predicting the renal outcome and rate of TKV increase in PKD patients with no apparent family history.


Deep radiomic model based on the sphere-shell partition for predicting treatment response to chemotherapy in lung cancer.
The prognosis of chemotherapy is important in clinical decision-making for non-small cell lung cancer (NSCLC) patients. To develop a model for predicting treatment response to chemotherapy in NSCLC patients from pre-chemotherapy CT images. This retrospective multicenter study enrolled 485 patients with NSCLC who received chemotherapy alone as a first-line treatment. Two integrated models were developed using radiomic and deep-learning-based features. First, we partitioned pre-chemotherapy CT images into spheres and shells with different radii around the tumor (0-3, 3-6, 6-9, 9-12, 12-15 mm) containing intratumoral and peritumoral regions. Second, we extracted radiomic and deep-learning-based features from each partition. Third, using radiomic features, five sphere-shell models, one feature fusion model, and one image fusion model were developed. Finally, the model with the best performance was validated in two cohorts. Among the five partitions, the model of 9-12 mm achieved the highest area under the curve (AUC) of 0.87 (95% confidence interval: 0.77-0.94). The AUC was 0.94 (0.85-0.98) for the feature fusion model and 0.91 (0.82-0.97) for the image fusion model. For the model integrating radiomic and deep-learning-based features, the AUC was 0.96 (0.88-0.99) for the feature fusion method and 0.94 (0.85-0.98) for the image fusion method. The best-performing model had an AUC of 0.91 (0.81-0.97) and 0.89 (0.79-0.93) in two validation sets, respectively. This integrated model can predict the response to chemotherapy in NSCLC patients and assist physicians in clinical decision-making.


A pancreatic-like ribonuclease is synthesized in rat brain.
The distribution and cell localization of a pancreatic-like ribonuclease (RNAase) in the rat brain has been studied by RNA blot analysis and in situ hybridization using as a probe the cDNA coding for the rat pancreas RNAase, and by immunocytochemistry using an antiserum raised against the rat pancreas RNAase. RNA blot analysis and in situ hybridization experiments have shown that the RNAase mRNA is present in all the cerebral areas investigated and that neurons appeared to be actively expressing RNAase mRNA while glial cells were devoid of hybridization signals. In agreement with these results the immunocytochemical analysis has shown that neurons are specifically immunostained. These experiments demonstrate that a pancreatic-like ribonuclease is synthesized in the neurons of the rat brain.


Papillary meningioma arising from the confluens sinuum with multidirectional extension through venous sinuses.
Successful removal of a meningioma arising from the confluens sinuum is described. This tumor extended multidirectionally through the venous sinuses (superior sagittal sinus, bilateral transverse sinuses, straight sinus, and occipital sinus) and protruded like a club in nodular pattern from the left inner surface of the confluens sinuum into the left occipital lobe. The tumor was completely removed via a bilateral large parieto-occipito-suboccipital craniotomy. Angiographically, unusual venous drainage from the vein of Galen into the superior sagittal sinus was demonstrated. Histologically, this tumor was a papillary meningioma characterized by two types of papillary structure in many areas.


Development and validation of Transfusion Risk Understanding Scoring Tool (TRUST) to stratify cardiac surgery patients according to their blood transfusion needs.
Allogeneic blood transfusion is associated with transfusion reactions, infection transmission, and postoperative morbidity and mortality. The objective of this study was to develop and validate an accurate and simple clinical index to stratify cardiac surgery patients according to their blood transfusion needs. Data on consecutive adult patients who underwent cardiac surgery at Toronto General Hospital (n = 11,113) and Sunnybrook and Women's College Health Sciences Center (n = 5316) between May 1999 and June 2004 were collected for the development, validation, and external validation of the index. Primary outcome was the exposure to blood transfusion in the operative and first postoperative days. Multivariable logistic regression modeling techniques were used to determine the relationship between each independent variable and the exposure to allogeneic blood transfusion. Score assignment for each predictor variable was based on its regression coefficient. The predicted probabilities at each total score were compared to the observed proportions of patients exposed to blood transfusion. The clinical tool consists of eight preoperative variables: preoperative hemoglobin, weight, female sex, age, nonelective procedure, preoperative creatinine, previous cardiac surgical procedure, and nonisolated procedure. Based on the standards of measurement in clinical research, a valid clinical tool was developed for predicting the need for blood transfusion in patients undergoing cardiac surgery. The clinical tool was internally and externally validated, and the results suggest that it should perform well at other institutions.


The evaluation of a quantitative enzyme-linked immunosorbent assay (ELISA) for anti-Aspergillus fumigatus IgG.
A standard enzyme-linked immunosorbent assay method for anti-Aspergillus fumigatus IgG in human serum was modified to produce a quantitative assay. The resulting assay was reproducible and capable of separating individual precipitin line groups and provided a means of monitoring the variation in antibody levels over long periods in patients with pulmonary aspergillosis.


Nature and outcomes of sanctioned medical misconduct in six international jurisdictions: a case series.
Objective The aim of this study was to determine the types of medical misconduct, the practitioner, specialities and jurisdictions at risk, patient outcomes and the sanctions imposed. Methods This study was a retrospective case series of 822 adverse medical tribunal determinations in Australia, New Zealand, Canada (Ontario, Alberta), Pennsylvania (USA), Singapore and Hong Kong in 2013-17. Results Inappropriate medical care and illegal or unethical prescribing were the most common types of misconduct. Misconduct varied with practitioner sex, international medical graduate status, speciality and jurisdiction (P<0.05). Cases of inappropriate medical care were more common in Singapore (46.7% of all Singapore cases; 95% confidence interval (CI) 31.9-62.0) and among surgeons (47.6% of all surgeon cases; 95% CI 36.5-58.8). Illegal or unethical prescribing was more common in Australia (31.1%; 95% CI 24.8-38.2) and among general or family practitioners (26.9%; 95% CI 20.0-35.0). Misconduct not related to patients was more common in Pennsylvania (30.3%; 95% CI 25.2-36.0) and among local graduates (20.5%; 95% CI 17.1-24.5). Sexual misconduct was more common in Australia (29.6%; 95% CI 23.4-36.6) and among males (19.6%, 95% CI 16.7-22.8). Healthcare dishonesty was more common in Hong Kong (21.8%; 95% CI 14.0-32.2) and among surgeons (13.4%; 95% CI 7.2-23.2). The most common patient outcomes were patient risk (40.6%; 95% CI 36.1-45.4) and death and actual physical harm combined (31.2%; 95% CI 26.9-35.7). Sanctions were most commonly suspension or deregistration. Deregistration was most common in cases of sexual misconduct. Conclusion Medical misconduct varies widely. Risk factors for particular misconduct types are apparent among jurisdictions and practitioner characteristics. The nature of patient harm varied by type of misconduct, with illegal unethical prescribing commonly leading to drug dependency and sexual misconduct leading to psychiatric injury. What is known about the topic? Medical misconduct is a continuing problem. Tribunals and medical boards sanction misconduct to protect patient safety and public trust. What does this paper add? Tribunals and boards differ in misconduct reporting and permitting public access to determinations. Types of misconduct vary between international jurisdictions, practitioner sex, international graduate status and speciality. Risk and physical injury (including death) are the most common patient outcomes. The nature of patient harm varied by type of misconduct, with illegal unethical prescribing commonly leading to drug dependency and sexual misconduct leading to psychiatric injury. What are the implications for practitioners? Medical colleges should tailor trainee programs to address the common types of misconduct within their specialities. Standardisation of misconduct reporting, and report access, across jurisdictions would facilitate ongoing surveillance and intervention evaluation.


Serum pyruvate kinase in carriers of Duochenne muscular dystrophy.
Independent studies by two different groups (Madras and Edinburgh) have failed to confirm the suggestion that measurement of the serum level of pyruvate kinase (EC 184.108.40.206, PK) may be superior to measurement of the serum level of creatine kinase (EC 126.96.36.199, CK) for detecting female carriers of X-linked Duchenne muscular dystrophy (DMD). At present the serum level of creatine kinase remains the best test for this purpose.


Juvenile myasthenia: diagnosis and treatment.
Myasthenia in children can be juvenile (autoimmune) or congenital. Juvenile myasthenia (JM) is an autoimmune disorder characterised by fluctuating weakness and fatigue in the ocular, facial, bulbar or limb muscles. Diagnosis is confirmed by electromyography (EMG), single fibre EMG and the patient's clinical response to anticholinesterase medication. Serology is less helpful in children because acetylcholine receptor antibodies, usually positive in adults, are frequently absent in patients with prepubertal onset of the disease. Treatment methods in JM include anticholinesterase drugs, thymectomy and immunomodulatory agents. Plasmapheresis and intravenous immunoglobulin are used in myasthenic crisis. The prognosis of patients with JM is usually good, clinical remission being achieved in the majority of patients with the current treatment methods.


Divergent effects of ACE-inhibition and calcium channel blockade on NO-activity in systemic and renal circulation in essential hypertension.
Nitric oxide is a vasodilating and blood pressure lowering substance. To investigate whether calcium antagonists or angiotensin-converting enzyme (ACE) inhibitors increase vascular nitric oxide activity, we assessed systemic and renal vascular sensitivity to nitric oxide synthase inhibition in hypertensives on and off medication. Ten essential hypertensive patients, aged 22-51 years, were studied 3 times: > or = 4 weeks off medication, after 3 weeks treatment with enalapril 20 mg twice a day and after 3 weeks nifedipine 60 mg/day. Each time, 24-h blood pressure registration was performed, followed by a clearance study to obtain a 3-h dose-response curve for intravenously infused NG-monomethyl-L-arginine (L-NMMA, respectively 0.75, 1.5 and 3.0 mg/kg/h). L-NMMA dose-dependently increased mean arterial pressure with 5 +/- 2 mmHg and systemic vascular resistance with 24 +/- 5% at maximum dose, whereas cardiac output decreased (all P < 0.001). Enalapril and nifedipine treatment decreased blood pressure, while the L-NMMA-induced increase in systemic vascular resistance was potentiated (enalapril: 45 +/- 7% and nifedipine: 46 +/- 8%; both P < 0.01). L-NMMA also dose-dependently decreased renal blood flow by 58 +/- 8% at maximum dose (P < 0.001), but neither drug potentiated these effects. These results indicate that, in essential hypertensives, antihypertensive therapy with enalapril or nifedipine increases nitric oxide dependency of systemic vascular tone, which may play a role in the blood pressure lowering effect of these drugs. However, this phenomenon cannot be observed in the renal circulation, suggesting a different regulation of endothelium-dependent vasomotion in the hypertensive kidney.


Probable herpes simplex pneumonia after aortic valve replacement.
Herpesvirus pneumonia developed in a 68-year-old man after aortic valve replacement and two-vessel aortocoronary bypass. The complication was fatal, and the diagnosis was made only after death. The source of the herpesvirus could not be determined.