Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis.
The de novo pathway of sphingolipid synthesis has been identified recently as a novel means of generating ceramide during apoptosis. Furthermore, it has been suggested that the activation of dihydroceramide synthase is responsible for increased ceramide production through this pathway. In this study, accumulation of ceramide mass in Molt-4 human leukemia cells by the chemotherapy agent etoposide was found to occur primarily due to activation of the de novo pathway. However, when the cells were labeled with a substrate for dihydroceramide synthase in the presence of etoposide, there was no corresponding increase in labeled ceramide. Further investigation using a labeled substrate for serine palmitoyltransferase, the rate-limiting enzyme in the pathway, resulted in an accumulation of label in ceramide upon etoposide treatment. This result suggests that the activation of serine palmitoyltransferase is the event responsible for increased ceramide generation during de novo synthesis initiated by etoposide. Importantly, the ceramide generated from de novo synthesis appears to have a distinct function from that induced by sphingomyelinase action in that it is not involved in caspase-induced poly (ADP-ribose)polymerase proteolysis but does play a role in disrupting membrane integrity in this model system. These results implicate serine palmitoyltransferase as the enzyme controlling de novo ceramide synthesis during apoptosis and begin to define a unique function of ceramide generated from this pathway.


Indoor noise level measurements and subjective comfort: Feasibility of smartphone-based participatory experiments.
We designed and performed a participatory sensing initiative to explore the reliability and effectiveness of a distributed network of citizen-operated smartphones in evaluating the impact of environmental noise in residential areas. We asked participants to evaluate the comfort of their home environment in different situations and at different times, to select the most and least comfortable states and to measure noise levels with their smartphones. We then correlated comfort ratings with noise measurements and additional contextual information provided by participants. We discuss how to strengthen methods and procedures, particularly regarding the calibration of the devices, in order to make similar citizen-science efforts effective at monitoring environmental noise and planning long-term solutions to human well-being.


Intercalation of Copper Phthalocyanine Within Bulk Graphite as a New Strategy Toward the Synthesis of CuO-Based CO Oxidation Catalysts.
Graphite is a widely available natural form of carbon with peculiar chemical and surface properties. It is essentially hydrophobic and consists in very stable stacks of graphene layers held together by highly delocalized π-π interactions. Its use in chemistry and in particular for catalytic applications requires modification of its structure to increase its surface area. This is commonly achieved by harsh oxidation methods which also modifies the chemical composition of graphite and enables subsequent deposition of catalytic phases via common impregnation/reduction methods. Here we show that copper phthalocyanine (CuPc) can be incorporated into unmodified bulk graphite by the straight-forward sonication of a dimethylformamide solution containing CuPc and graphite flakes. Immobilization of the CuPc complex in the graphitic matrix is shown to rely on π-π interactions between the Pc ligand and graphenic surfaces. This strong CuPc-graphene interaction facilitates oxidation of the graphitic matrix upon oxidation of the immobilized complex, as shown by thermogravimetric analysis in air. Nevertheless, a soft oxidation treatment can be designed to produce CuO nanoparticles (NPs) without degrading the dispersing graphitic matrix. These well-dispersed CuO NPs are shown (1) to decrease the degree of stacking of graphite in the solid-state by intercalation in-between graphitic stacks, (2) to be more easily reducible than bulk CuO, and (3) to be catalytically active for the oxidation of carbon monoxide. The higher mass-specific CO oxidation rates observed, as compared with CuO/alumina benchmarks, highlight the beneficial role of the carbon support and the relevance of this new strategy toward the design of copper oxide catalysts from copper phthalocyanine metal complexes.


Antimicrobial susceptibility of gram-negative pathogens isolated from patients with complicated intra-abdominal infections in South African hospitals (SMART Study 2004-2009): impact of the new carbapenem breakpoints.
The Study for Monitoring Antimicrobial Resistance Trends (SMART) follows trends in resistance among aerobic and facultative anaerobic gram-negative bacilli (GNB) isolated from complicated intra-abdominal infections (cIAIs) in patients around the world. During 2004-2009, three centralized clinical microbiology laboratories serving 59 private hospitals in three large South African cities collected 1,218 GNB from complicated intra-abdominal infections (cIAIs) and tested them for susceptibility to 12 antibiotics according to the 2011 Clinical Laboratory Standards Institute (CLSI) guidelines. Enterobacteriaceae comprised 83.7% of the isolates. Escherichia coli was the species isolated most commonly (46.4%), and 7.6% of these were extended-spectrum β-lactamase (ESBL)-positive. The highest ESBL rate was documented for Klebsiella pneumoniae (41.2%). Overall, ertapenem was the antibiotic most active against susceptible species for which it has breakpoints (94.6%) followed by amikacin (91.9%), piperacillin-tazobactam (89.3%), and imipenem-cilastatin (87.1%), whereas rates of resistance to ceftriaxone, cefotaxime, ciprofloxacin, and levofloxacin were documented to be 29.7%, 28.7%, 22.5%, and 21.1%, respectively. Multi-drug resistance (MDR), defined as resistance to three or more antibiotic classes, was significantly more common in K. pneumoniae (27.9%) than in E. coli (4.9%; p<0.0001) or Proteus mirabilis (4.1%; p<0.05). Applying the new CLSI breakpoints for carbapenems, susceptibility to ertapenem was reduced significantly in ESBL-positive E. coli compared with ESBL-negative isolates (91% vs. 98%; p<0.05), but this did not apply to imipenem-cilastatin (95% vs. 99%; p=0.0928). A large disparity between imipenem-cilastatin and ertapenem susceptibility in P. mirabilis and Morganella morganii was documented (24% vs. 96% and 15% vs. 92%, respectively), as most isolates of these two species had imipenem-cilastatin minimum inhibitory concentrations in the 2-4 mcg/mL range, which is no longer regarded as susceptible. This study documented substantial resistance to standard antimicrobial therapy among GNB commonly isolated from cIAIs in South Africa. With the application of the new CLSI carbapenem breakpoints, discrepancies were noted between ertapenem and imipenem-cilastatin with regard to the changes in their individual susceptibilities. Longitudinal surveillance of susceptibility patterns is useful to guide recommendations for empiric antibiotic use in cIAIs.


Regional and ultrastructural distribution of the alpha 8 integrin subunit in developing and adult rat brain suggests a role in synaptic function.
Integrins are heterodimeric cell adhesion molecules comprised of alpha and beta subunits that have been implicated in the regulation of neuronal migration, differentiation, and process outgrowth. They mediate both cell-extracellular matrix and cell-cell interactions. The integrin alpha 8 beta 1 is a receptor for fibronectin, tenascin, and vitronectin that has been localized to axonal tracts and several types of non-neuronal cells in chick embryos and to smooth muscle cells in adult mammalian tissues. In this report, we describe the distribution of the alpha 8 subunit in the developing and adult mammalian brain. By light microscopy, alpha 8 labeling in the rat brain was found predominantly in neurons. It was primarily localized within perikarya and dendrites, but was also observed in certain fiber tracts. alpha 8 immunoreactivity was most concentrated in the olfactory bulb, hippocampal formation, substantia nigra, ventral tegmental area, and superior olivary complex, but was also found at moderate levels in several regions including layer 5 of the cerebral cortex. alpha 8 labeling was detected as early as E16, peaked in most areas during the first 3 postnatal weeks, and persisted in the adult. Electron microscopic analysis of the adult hippocampal formation revealed a striking concentration of alpha 8 immunoreactivity in the spines and postsynaptic densities of dendrites. These results suggest that alpha 8 is involved in the regulation of axonal and dendritic growth of some neurons in the developing central nervous system (CNS) and provide ultrastructural evidence that integrins may participate in the formation, maintenance, or plasticity of synapses.


Design and Comparative Study of O3/P2 Hybrid Structures for Room Temperature Sodium-Ion Batteries.
Rechargeable sodium-ion batteries have drawn increasing attention as candidates for the post lithium-ion batteries in large-scale energy storage systems. Layered oxides are the most promising cathode materials and their pure phases (e.g., P2, O3) have been widely investigated. Here we report a series of cathode materials with O3/P2 hybrid phase for sodium-ion batteries, which possesses advantages of both P2 and O3 structures. The designed material, Na0.78Ni0.2Fe0.38Mn0.42O2, can deliver a capacity of 86 mAh g-1 with great rate capability and cycling performance. 66% capacity is still maintained when the current rate reaches as high as 10C, and the capacity retention is 90% after 1500 cycles. Moreover, in situ XRD was performed to examine the structure change during electrochemical testing in different voltage ranges, and the results demonstrate 4 V as the optimized upper voltage limit, with which smaller polarization, better structural stability, and better cycling performance are achieved. The results obtained here provide new insights in designing cathode materials with optimal structure and improved performance for sodium-ion batteries.


Fringe pattern suppression in intracavity laser spectroscopy.
Absorption spectra obtained by intracavity laser spectroscopy (ILS) often contain fringe patterns that significantly mask absorption features and hamper the quantitative analysis of ILS data. Both the parasitic étalon fringes and the fringes that originate from spatially localized losses can be suppressed by a low-amplitude audio-frequency vibration of a folding mirror in the laser cavity. Using this methodology, we show that ILS spectra recorded with multimode lasers that contain nonideal intracavity surfaces have essentially no fringe contamination. The elimination of fringe contamination improves the detection sensitivity of ILS under normal experimental conditions and thus expands the potential for ILS applications.


[Current results of endoscopic therapy of esophageal varices in children].
The authors present their experience with the endoscopic treatment of oesophageal varices in children. During 1991-1994 they treated 21 children where they performed a total of 156 sclerotizations. The mean age of the patients was 10.08 years. In 17 instances the prehepatic type of portal hypertension was involved, in four the intrahepatic type. In 13 children the varicosities were eradicated. A relapse was recorded in three cases. From the total number of sclerotizations the authors recorded complications 14 times. They emphasize the success of the method used: a minimal number of complications; a reduction of the number of pretentious devascularization operations in haemorrhage from oesophageal varices. Also the number of sclerotizations proper decreased, as many patients suffer no longer from haemorrhage and they do not have varices which require sclerotizations.


Disease resistance through impairment of α-SNAP-NSF interaction and vesicular trafficking by soybean Rhg1.
α-SNAP [soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein] and NSF proteins are conserved across eukaryotes and sustain cellular vesicle trafficking by mediating disassembly and reuse of SNARE protein complexes, which facilitate fusion of vesicles to target membranes. However, certain haplotypes of the Rhg1 (resistance to Heterodera glycines 1) locus of soybean possess multiple repeat copies of an α-SNAP gene (Glyma.18G022500) that encodes atypical amino acids at a highly conserved functional site. These Rhg1 loci mediate resistance to soybean cyst nematode (SCN; H. glycines), the most economically damaging pathogen of soybeans worldwide. Rhg1 is widely used in agriculture, but the mechanisms of Rhg1 disease resistance have remained unclear. In the present study, we found that the resistance-type Rhg1 α-SNAP is defective in interaction with NSF. Elevated in planta expression of resistance-type Rhg1 α-SNAPs depleted the abundance of SNARE-recycling 20S complexes, disrupted vesicle trafficking, induced elevated abundance of NSF, and caused cytotoxicity. Soybean, due to ancient genome duplication events, carries other loci that encode canonical (wild-type) α-SNAPs. Expression of these α-SNAPs counteracted the cytotoxicity of resistance-type Rhg1 α-SNAPs. For successful growth and reproduction, SCN dramatically reprograms a set of plant root cells and must sustain this sedentary feeding site for 2-4 weeks. Immunoblots and electron microscopy immunolocalization revealed that resistance-type α-SNAPs specifically hyperaccumulate relative to wild-type α-SNAPs at the nematode feeding site, promoting the demise of this biotrophic interface. The paradigm of disease resistance through a dysfunctional variant of an essential gene may be applicable to other plant-pathogen interactions.


A Multisite Study on Knowledge, Perceived Motivators, and Perceived Inhibitors to Precepting Nursing Students within the Clinical Environment in Ghana.
Preceptorship constitutes an important component of the educational process of training nursing students. The purpose of this study was to assess the knowledge, perceived motivators, and perceived inhibitors to precepting nursing students at the clinical placement sites in the Cape Coast Metropolis of the Central Region of Ghana. A descriptive cross-sectional study was conducted among 442 nurses and midwives aged 27-56 years with at least three years of work experience. Data were collected with a questionnaire and analyzed using frequency counts, percentages, exploratory factor analysis, and point biserial correlation. The results indicate that the participants had a high knowledge of preceptorship of up to 91.2% (n = 404). A significant proportion of up to 88.2% (n = 390) had an intention to precept nursing students in the near future. The three important perceived motivational factors to precepting nursing students were the learning and professional needs of students, helping students to develop skills, and experience and formal recognition of the role of preceptorship. The main perceived inhibitors to engage in a preceptorship role were lack of preparation for the role, lack of support from faculty and nurse managers, and additional work burden. The results further indicate a significant strong positive correlation between experience and professional recognition of preceptorship and the intention to precept nursing students in the near future (r = 0.99, p=0.037). The nurses and midwives who participated in the study are knowledgeable about preceptorship and have the intention to precept nursing students. Having enough experience on the job and being formally recognized as a preceptor may motivate these professionals to precept nursing students. However, there are critical perceived barriers that need to be addressed, to enable more nurses and midwives with the desire to precept students to engage in the preceptorship role.


Effects of ghrelin on nocturnal melatonin secretion in sheep: An in vitro and in vivo approach.
Recent studies confirmed that pineal melatonin (MEL) secretion is regulated by ghrelin (GHRL) in seasonally reproductive sheep. The first in vivo experiment investigated whether the effect of GHRL on nocturnal secretion of MEL in sheep is mediated by type 2 serotonin receptors. Sheep ( = 16) were intravenously injected with GHRL (2.5 μg/kg of BW) and meta-Chlorophenylpiperazine (mCPP; a mixed agonist of 5-HT2B/5-HT2C receptors; 1 mg/kg BW), either combined or individually, during the short-day (SDS) and long-day (LDS) seasons. Blood samples were collected at 15-min intervals for 4 h. The second in vitro experiment examined the effect of GHRL (10 ng/mL) on MEL secretion by pineal gland (PG) explants incubated for 5 h. The expression levels and/or concentrations of tryptophan 5-hydroxylase 1 (TPH1), aralkylamine N-acetyltransferase (AA-NAT), and the phosphorylated form of AA-NAT (p31T-AA-NAT) were determined at selected time points during the SDS and LDS seasons. The experiments demonstrated that GHRL reduced MEL secretion ( < 0.01) during the SDS season. Administration of mCPP or a combination of GHRL + mCPP stimulated MEL secretion ( < 0.01) regardless of the season. Furthermore, GHRL regulated nightly MEL secretion in a TPH1-independent manner. However, during the SDS season, GHRL reduced p31T-AA-NAT expression and the AA-NAT concentration ( < 0.01) and inhibited MEL secretion ( < 0.001), whereas during the LDS season, GHRL had no effect on MEL secretion or on the expression of the examined enzymes. These findings indicate that GHRL directly and indirectly affects PG activity in sheep and that the photoperiod modulates the effects of GHRL.


Human medial gastrocnemius force-velocity behavior shifts with locomotion speed and gait.
Humans walk and run over a wide range of speeds with remarkable efficiency. For steady locomotion, moving at different speeds requires the muscle-tendon units of the leg to modulate the amount of mechanical power the limb absorbs and outputs in each step. How individual muscles adapt their behavior to modulate limb power output has been examined using computer simulation and animal models, but has not been studied in vivo in humans. In this study, we used a combination of ultrasound imaging and motion analysis to examine how medial gastrocnemius (MG) muscle-tendon unit behavior is adjusted to meet the varying mechanical demands of different locomotor speeds during walking and running in humans. The results highlighted key differences in MG fascicle-shortening velocity with both locomotor speed and gait. Fascicle-shortening velocity at the time of peak muscle force production increased with walking speed, impairing the ability of the muscle to produce high peak forces. Switching to a running gait at 2.0 m·s(-1) caused fascicle shortening at the time of peak force production to shift to much slower velocities. This velocity shift facilitated a large increase in peak muscle force and an increase in MG power output. MG fascicle velocity may be a key factor that limits the speeds humans choose to walk at, and may explain the transition from walking to running. This finding is consistent with previous modeling studies.


Expression of Skp2, a p27(Kip1) ubiquitin ligase, in malignant lymphoma: correlation with p27(Kip1) and proliferation index.
Reduced levels of p27(Kip1) are frequent in human cancers and have been associated with poor prognosis. Skp2, a component of the Skp1-Cul1-F-box protein (SCF) ubiquitin ligase complex, has been implicated in p27(Kip1) degradation. Increased Skp2 levels are seen in some solid tumors and are associated with reduced p27(Kip1). We examined the expression of these proteins using single and double immunolabeling in a large series of lymphomas to determine if alterations in their relative levels are associated with changes in cell proliferation and lymphoma subgroups. We studied the expression of Skp2 in low-grade and aggressive B-cell lymphomas (n = 86) and compared them with p27(Kip1) and the proliferation index (PI). Fifteen hematopoietic cell lines and peripheral blood lymphocytes were studied by Western blot analysis. In reactive tonsils, Skp2 expression was limited to proliferating germinal center and interfollicular cells. Skp2 expression in small lymphocytic lymphomas (SLLs) and follicular lymphomas (FCLs) was low (mean percentage of positive tumor cells, less than 20%) and was inversely correlated (r = -0.67; P <.0001) with p27(Kip1) and positively correlated with the PI (r = 0.82; P <.005). By contrast, whereas most mantle cell lymphomas (MCLs) demonstrated low expression of p27(Kip1) and Skp2, a subset (n = 6) expressed high Skp2 (exceeding 20%) with a high PI (exceeding 50%). Skp2 expression was highest in diffuse large B-cell lymphomas (DLBCLs) (mean, 22%) and correlated with Ki-67 (r = 0.55; P <.005) but not with p27(Kip1). Cytoplasmic Skp2 was seen in a subset of aggressive lymphomas. Our data provide evidence for p27(Kip1) degradative function of Skp2 in low-grade lymphomas. The absence of this relationship in aggressive lymphomas suggests that other factors contribute to deregulation of p27(Kip1) expression in these tumors.


Quantifying stock-price response to demand fluctuations.
We empirically address the question of how stock prices respond to changes in demand. We quantify the relations between price change G over a time interval Deltat and two different measures of demand fluctuations: (a) Phi, defined as the difference between the number of buyer-initiated and seller-initiated trades, and (b) Omega, defined as the difference in number of shares traded in buyer- and seller-initiated trades. We find that the conditional expectation functions of price change for a given Phi or Omega, <G>(Phi) and <G>(Omega) ("market impact function"), display concave functional forms that seem universal for all stocks. For small Omega, we find a power-law behavior <G>(Omega) approximately Omega(1/8) with delta depending on Deltat (delta approximately 3 for Deltat=5 min, delta approximately 3/2 for Deltat=15 min and delta approximately 1 for large Deltat). We find that large price fluctuations occur when demand is very small-a fact that is reminiscent of large fluctuations that occur at critical points in spin systems, where the divergent nature of the response function leads to large fluctuations.


[Impact of a nurse-based heart failure management program on hospitalization rate, functional status, quality of life, and medical costs].
Chronic heart failure is a major health problem for prevalence, morbidity and costs; heart failure management programs may prevent hospital admissions, improve clinical status and reduce medical costs. A care program for chronic heart failure patients was activated by the Cardiology Department, based on a nurse-monitored outpatient clinic, ran in cooperation with cardiologists, who were responsible for optimal pharmacological treatment. Nurses provided patient education, monitoring of clinical status and symptoms and verified adherence to pharmacologic and dietary therapy. To assess the impact of the program on hospitalization rate, functional status and quality of life we compared: 1) hospital admission rate for heart failure in the 6 months before and the 6 months after referral; 2) Minnesota Living with Heart Failure Questionnaire (MLHFQ) score and NYHA functional class at referral time and after 6 months. A cost-based analysis was performed to compare the two periods. Between January 1999 and November 2000, 107 patients were followed up for at least 6 months. Hospitalization declined by 70% (57 admissions in the 6 months before referral, 17 in the 6 months afterwards, p = 0.0001). Functional status improved after 6 months: 41 patients were in NYHA class III-IV at referral time, 26 after 6 months. The mean total score of MLHFQ was reduced from 33.9 to 28.7 (p = 0.005). The average cost of the program was estimated to be [symbol: see text] 218 (Itl 423,000) per patient in 6 months. The savings in overall cost of care was [symbol: see text] 615 (Itl 1,192,000) per patient in 6 months. A management program based on a nurse-monitored outpatient clinic can reduce hospitalization rate, improve functional status and quality of life and decrease medical costs for chronic heart failure patient's care.


SUBCLINICAL IMPAIRMENT OF LEFT VENTRICULAR LONGITUDINAL FUNCTION IN PATIENTS WITH PROLACTINOMAS.
Hyperprolactinemia has been associated with endothelial dysfunction and a wide range of cardiovascular risk factors, thus it can potentially lead to cardiac dysfunction. The present study was designed to interrogate our hypothesis that hyperprolactinemia can contribute to preclinical impaired left ventricular function. Thirty-one prolactinoma patients and 60 healthy volunteers were prospectively recruited. Left ventricular function was evaluated using conventional two dimensions and M-mode echocardiography, as well as Doppler tissue imaging (DTI). The Tei index (0.45 ± 0.06 vs. 0.41 ± 0.03, P = .005) and ratio of transmitral and myocardial early diastolic velocities (E/Em; 6.30 ± 1.45 vs. 5.64 ± 0.69, P = .045) were significantly higher, and septal systolic velocity (Sm; 9.88 ± 1.45 vs. 11.58 ± 1.28 cm/s, P<.001) was significantly lower in prolactinoma patients. Furthermore, significant motional abnormalities were detected in regional segments of prolactinoma patients. Pearson's correlation analysis revealed that prolactin level was inversely associated with Sm (r = -0.373, P = .009) and late diastolic phase (Am; r = -0.293, P = .043). Moreover, inverse correlations between prolactin and partial left ventricular segment wall motion were found, including the basal (r = -0.363, P = .014), middle (r = -0.418, P = .004), and apical segment (r = -0.574, P<.001) of the posterior ventricular septum. Multivariate linear regression analysis revealed that prolactin (β = -0.28, 95% confidence interval -0.011 to 0, P = .035), as a single factor, can significantly predict decreased Sm, independent of traditional vascular risk factors. Our results suggest that subclinical cardiac dysfunction occurs in untreated prolactinoma patients and is characterized by impaired systolic and diastolic function of the left ventricle, as well as regional segment motional abnormality. A = transmitral late diastolic velocity Am = late diastolic phase Apo = apolipoprotein DTI = Doppler tissue imaging E = transmitral early diastolic velocity Em = myocardial early diastolic velocity FMD = flow-mediated dilation HOMA-IR = homeostasis model assessment of insulin resistance hsCRP = high-sensitivity C-reactive protein IMT = intima media thickness LDL-C = low-density lipoprotein cholesterol LV = left ventricular PPCM = postpartum cardiomyopathy Sm = septal systolic velocity.


Acute Cerebral Venous Thrombosis: Three-Dimensional Visualization and Quantification of Hemodynamic Alterations Using 4-Dimensional Flow Magnetic Resonance Imaging.
Cerebral venous thrombosis (CVT) affects venous hemodynamics and can provoke severe stroke and chronic intracranial hypertension. We sought to comprehensively analyze 3-dimensional blood flow and hemodynamic alterations during acute CVT including collateral recruitment and at follow-up. Twenty-two consecutive patients with acute CVT were prospectively included and underwent routine brain magnetic resonance imaging (MRI) and 4-dimensional flow MRI at 3 T for the in vivo assessment of cerebral blood flow. Neurological and MRI follow-up at 6 months was performed in 18 patients. Three-dimensional blood flow visualization and quantification of large dural venous sinuses and deep cerebral veins was successfully performed in all patients. During acute CVT, we observed abnormal flow patterns including stagnant flow, flow acceleration in stenoses, and change of flow directions. In patients with complete recanalization, flow trajectories resembled those known from previously published 4-dimensional flow MRI data in healthy adults. There was a trend toward a relationship between occluded segments and cerebral lesions (not significant). Furthermore, patients with versus without cerebral lesions showed increased mean (0.08±0.09 versus 0.005±0.014 m/s) and peak velocities (0.18±0.21 versus 0.006±0.02 m/s) within partially thrombosed left and right transverse sinuses (P<0.05) at baseline. Four-dimensional flow MRI was successfully applied for the 3-dimensional visualization and quantification of venous hemodynamics in patients with CVT and provided new dynamic information regarding vessel recanalization. This technique seems promising to investigate the contribution of hemodynamic parameters and collaterals in a larger cohort to identify those at risk of stroke.


Phenylpropanoids and neolignans isolated from Myristica fragrans enhance glucose uptake in myotubes.
Nutmeg is the seed of Myristica fragrans or its powder and is used as a spice and a traditional medicine. The antidiabetic effect of nutmeg is not fully understood yet. In this study, we examine the isolation and identification of the active compounds of Myristica fragrans with regards to glucose uptake and elucidate their mechanism in L6 myotubes. Myrisiticin, licarin B, erythro-2-(4-allyl-2,6-dimethoxy-phenoxy)-1-(3,4-dimethoxyphenyl)-propan-1-ol (ADDP) and (7S,8R)-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)-propan-1-ol (ADTP) were isolated and identified as the active compounds. Myristicin or a mixture of ADDP and ADTP promoted the translocation of glucose transporter 4 (GLUT4) through phosphorylation of AMP-activated protein kinase in L6 myotubes 15 min after treatment, while licarin B promoted it 240 min after treatment. Oral administration of the fraction from Myristica fragrans containing these active compounds to ICR mice suppressed post-prandial hyperglycemia. Thus, Myristica fragrans is a promising functional food to prevent post-prandial hyperglycemia and type 2 diabetes mellitus by promoting glucose uptake in muscle.


Dermatophagoides pteronyssinus specific IgM antibody and its complement activation in children with bronchial asthma.
Western blotting analysis and ELISA were used to examine Dp specific IgM abs in the sera and sputa of bronchial asthmatic and non-atopic children. With Western blotting Dp specific IgM abs were detected binding diffusely to high molecular weight (greater than 65 kD) components of Dp extracts and from the intensities of the staining of the sera the asthmatic children were divided into two groups: an intensive staining and a faint staining group. The non-atopic children showed still fainter staining than the latter group. ELISA titers of Dp specific IgM abs in the intensive staining group were significantly higher than in the faint staining group and the non-atopic children (p less than 0.01). Dp specific IgM abs in sputa were also detected more intensively in asthma than in non-atopy by Western blotting. The hemolytic complement activities of the fresh sera were consumed when they were incubated with Dp extracts at 37 degrees C. The degree of consumption was significantly higher in the intensive staining group than in the faint staining group and the non-atopic children (p less than 0.05). High molecular weight fractions of Dp extracts were responsible for this complement inactivation. From these results we suspected that Dp specific IgM abs might react with high molecular weight components of Dp to induce complement activation by the classical pathway and might cause chronic inflammatory changes in the respiratory mucosa. This chronic inflammation might emphasize IgE mediated asthmatic reactions to cause late phase reactions or chronic asthma.


ECT for major depression and mania with advanced dementia.
Two patients with advanced dementia and severe affective disorders were successfully treated with electroconvulsive therapy (ECT) without significant adverse effects. These reports illustrate that ECT can be effective for depression and mania even when complicated by moderate or severe dementia.


Spirometer-guided breath-hold breast VMAT verified with portal images and surface tracking.
Fast rotating closed-bore gantry linacs are ideally suited for breath-hold treatments due to reduced imaging and delivery times. We evaluated the reproducibility and stability of spirometer-guided breath-hold breast treatments, using intra-bore surface monitoring and portal imaging on Halcyon (Varian Medical Systems). Seven left-sided breast cancer patients were treated in breath-hold using the SDX spirometer (Dyn'R) with an integrated boost volumetric arc protocol on Halcyon. A dual depth-camera surface scanning system monitored the left breast. The interfraction, intrafraction and intrabreath-hold motion was determined in the anterior-posterior (AP) and superior-inferior (SI) direction. Portal images (PI), acquired at a tangential gantry angle were manually registered to the planning-CT to determine inter- and intrafraction breath-hold errors for the SI and tangential-anterior-posterior ("AP") axis. Correlations between PI and surface imaging deviations were investigated. To evaluate workflow efficiency, the total time and the number of breath-holds were recorded. Systematic and random variability of breath-hold amplitude was below 0.7 mm for the AP and below 1.2 mm for the SI component as detected by surface monitoring (N = 130). Systematic and random errors retrieved from portal images (N = 140) were below 1.2 mm for the "AP" and 2.1 mm for SI axis. A limited correlation was found between PI and surface monitoring deviations for both the SI and "AP" axes (R2 = 0.27/0.38, p < 0.01). 75% of fractions were completed using four breath-holds and 82% within 10 min. Surface imaging indicated spirometer-guided breath-hold VMAT breast radiotherapy can be accurately and quickly performed on a closed-bore gantry linac. Intra-bore surface scanning proved a valuable technique for monitoring breathing motion in closed-bore systems.


An agonistic anti-Toll-like receptor 4 monoclonal antibody as an effective adjuvant for cancer immunotherapy.
Immune-checkpoint blockade antibodies have been approved for the treatment of cancer. However, poorly immunogenic tumours are less responsive to such therapies. Agonistic anti-Toll-like receptor 4 (TLR4) monoclonal antibodies (mAbs) activate only cell-surface TLR4; in contrast, lipopolysaccharide (LPS) activates both TLR4 and intracellular inflammatory caspases. In this study, we investigated the adjuvant activity of an anti-TLR4 mAb in T-cell-mediated antitumour immunity. The anti-TLR4 mAb induced the activation of antigen-specific T-cells in adoptive transfer studies. The growth of ovalbumin (OVA)-expressing tumours was significantly suppressed by administration of OVA and the anti-TLR4 mAb in combination, but not individually. The antitumour effect of anti-PD-1 mAb was enhanced in mice administered with OVA plus the anti-TLR4 mAb. The OVA-specific IFN-γ-producing CD8 T-cells were induced by administration of OVA and the anti-TLR4 mAb. The suppression of tumour growth was diminished by depletion of CD8, but not CD4, T-cells. The inflammatory response to the anti-TLR4 mAb was of significantly lesser magnitude than that to LPS, as assessed by NF-κB activation and production of TNF-α, IL-6 and IL-1β. Administration of LPS (at a dose that elicited levels of proinflammatory cytokines comparable to those by the anti-TLR4 mAb) plus OVA induced no or less-marked activation of OVA-specific T-cells and failed to suppress tumour growth in mice. In conclusion, the agonistic anti-TLR4 mAb induces potent CD8 T-cell-dependent antitumour immunity and an inflammatory response of lesser magnitude than does LPS. The agonistic anti-TLR4 mAb has potential as an adjuvant for use in vaccines against cancer.


Acute myocardial infarction in a young man with ankylosing spondylitis: A case report.
Ankylosing spondylitis (AS) is a chronic progressive inflammatory disease that mainly affects the spine and sacroiliac joints. To the best of our knowledge, AS with acute myocardial infarction (AMI) has rarely been reported. Here, we report an unusual case of AS with AMI in a young patient. A 37-year-old man was admitted to the Department of Rheumatology and Immunology of our hospital on March 14, 2020, for low back pain. Further evaluation with clinical examinations, laboratory tests, and imaging resulted in a diagnosis of AS. Treatment with a non-steroidal anti-inflammatory drug and a tumor necrosis factor inhibitor partially improved his symptoms. However, his back pain persisted. After 6 wk of treatment, he was admitted to the emergency room of another hospital in this city for sudden-onset severe chest pain consistent with a diagnosis of AMI. Angiography revealed severe narrowing of the coronary arteries. Surgical placement of two coronary stents completely relieved his back pain. AS can cause cardiovascular diseases, including AMI. It is important to consider the cardiovascular risks in the management of AS.


Synthesis, Characterization, and Antimicrobial Activity of Magnesium-Doped Hydroxyapatite Suspensions.
Obtaining nanoscale materials has allowed for the miniaturization of components, which has led to the possibility of achieving more efficient devices with faster functions and much lower costs. While hydroxyapatite [HAp, Ca10(PO4)6(OH)2] is considered the most widely used material for medical applications in orthopedics, dentistry, and general surgery, the magnesium (Mg) is viewed as a promising biodegradable and biocompatible implant material. Furthermore, Mg is regarded as a strong candidate for developing medical implants due to its biocompatibility and antimicrobial properties against gram-positive and gram-negative bacteria. For this study, magnesium-doped hydroxyapatite (Ca10-xMgx (PO4)6 (OH)2, xMg = 0.1), 10MgHAp, suspensions were successfully obtained by an adapted and simple chemical co-precipitation method. The information regarding the stability of the nanosized 10MgHAp particles suspension obtained by ζ-potential analysis were confirmed for the first time by a non-destructive ultrasound-based technique. Structural and morphological studies of synthesized 10MgHAp were conducted by X-ray diffraction (XRD), Fourier-transform infrared (FTIR) spectroscopy in attenuated total reflectance (ATR) mode and scanning electron microscopy (SEM). The XRD analysis of the 10MgHAp samples confirmed that a single crystalline phase associated to HAp with an average grain size about 93.3 nm was obtained. The FTIR-ATR spectra revealed that the 10MgHAp sample presented broader IR bands with less visible peaks when compared to a well-crystallized pure HAp. The SEM results evidenced uniform MgHAp nanoparticles with spherical shape. The antimicrobial activity of the 10MgHAp suspension against gram-positive strains (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212), gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853), as well as a fungal strain (Candida albicans ATCC 90029) were evaluated.


Zupan's descriptors in QSAR applied to the study of a new class of cardiotonic agents.
Recently a new class of molecular descriptors has been proposed and used in QSAR with simulated data and with regression performed by neural networks. In the present paper these descriptors (Zups, from the name of their author, Juri Zupan) have been slightly modified and then applied to a real data set with the aim of studying the structure-activity relationships of a new class of cardiotonics. Forty-one molecules (thirty-seven milrinone analogues, the two lead compounds amrinone and milrinone, and two commercial products) have been studied using classical chemometrical techniques such as PCA (Principal Components Analysis) and PLS (Partial Least Squares regression). Zups describe essentially the local geometry of the molecules. They show promising performances, as compared with other classical geometrical descriptors (as molecular volume, etc.), both in that regards the overall performances, measured by the C.V. Explained variance and in the interpretability of the regression equation. However they have not all the requirements of a good structure representation. Moreover some selectable parameters seem to have a great importance, so that the refinement of the regression model requires time and the evaluation step must be performed in condition of full-validation, because predictive optimisation is used in the selection of parameters, and the final model must be checked on molecules never used to refine the model or, in this case, the parameters of the structure representation.


Influence of pitch, loudness, and timbre on the perception of instrument dynamics.
The effect of variations in pitch, loudness, and timbre on the perception of the dynamics of isolated instrumental tones is investigated. A full factorial design was used in a listening experiment. The subjects were asked to indicate the perceived dynamics of each stimulus on a scale from pianissimo to fortissimo. Statistical analysis showed that for the instruments included (i.e., clarinet, flute, piano, trumpet, and violin) timbre and loudness had equally large effects, while pitch was relevant mostly for the first three. The results confirmed our hypothesis that loudness alone is not a reliable estimate of the dynamics of musical tones.


Comparison of postprandial lipemia between women who are on oral contraceptive methods and those who are not.
Postprandial Lipemia (PPL) is a physiological process that reflects the ability of the body to metabolize lipids. Even though the influence of oral contraceptives (OC) on PPL is not known, it is a known fact that their use increases fasting lipid values. To compare the PPL between women who are on OC and those who are not. A prospective analytical study which assessed eutrophic women, aged between 18 and 28 years old, who were irregularly active and with fasting triglycerides ≤ 150 mg/dL. They were divided into two groups: oral contraceptive group (COG) and non-oral contraceptive group (NCOG). Volunteers were submitted to the PPL test, in which blood samples were collected in time 0 (12-hour fasting) and after the intake of lipids in times 180 and 240 minutes. In order to compare the triglyceride deltas, which reflect PPL, the two-tailed Mann-Whitney test was used for independent samples between fasting collections and 180 minutes (Δ1) and between fasting and 240 minutes (Δ2). Forty women were assessed and equally divided between groups. In the fasting lipid profile, it was observed that HDL did not present significant differences and that triglycerides in COG were twice as high in comparison to NCOG. Medians of Δ1 and Δ2 presented significant differences in both comparisons (p ≤ 0.05). The results point out that women who are irregularly active and use OC present more PPL in relation to those who do not use OC, which suggests that in this population, its chronic use increases the risk of heart conditions.


Use of a tungsten filament lamp as a calibration standard in the vacuum ultraviolet.
A tungsten ribbon filament lamp fitted with a sapphire window and operated at a temperature of 2800 K is shown to be a stable reproducible calibration source over the wavelength range 1500-2700 A. Spectra of the lamp obtained using a 50-cm Ebert spectrometer and an extreme-solar-blind photomultiplier with pulse-counting electronics are reproducible to better than +/-10% over this spectral range. Careful calibration of the spectrometer and photomultiplier has allowed a direct measurement of the absolute spectral radiance of the lamp, hence the apparent emissivity of the hot tungsten filament, from 1500 A to 2700 A.


Biophysical Elucidation of Fibrillation Inhibition by Sugar Osmolytes in α-Lactalbumin: Multispectroscopic and Molecular Docking Approaches.
Protein aggregation is among the most challenging new frontiers in protein chemistry as well as in molecular medicine and has direct implications in protein misfolding. This study investigated the role of sugar molecules (glucose, fructose, sucrose, and the mixture of glucose and fructose) in protecting the structural integrity of α-lactalbumin (α-LA) against aggregation. The research focused here is the inhibitory capabilities of sugars against α-LA fibril formation investigated employing diverse multispectroscopic and microscopic techniques. The aggregation was induced in α-LA thermally with a change in concentration. UV-vis spectroscopy, ThT binding assay, Trp fluorescence, Rayleigh scattering, and turbidity assay depicted synchronized results. Further, transmission electron microscopy (TEM) complemented that a mixture of glucose and fructose was the best inhibitor of α-LA fibril formation. Inhibition of α-LA aggregation by sugar osmolytes is attributed to the formation of hydrogen bonds between these osmolytes, as evidenced by the molecular docking results. This hydrogen bonding is a key player that prevents aggregation in α-LA in the presence of sugar osmolytes. This study provides an insight into the ability of naturally occurring sugar osmolytes to inhibit fibril formation and can serve as a platform to treat protein misfolding and aggregation-oriented disorders.


Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis.
The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5s) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to reduced motor neuron excitability for weeks after resolution of sepsis. To assess whether additional contributions from myopathy, neuropathy and defects in neuromuscular transmission contributed to the reduction in force generation, we measured whole-muscle force production in response to electrical stimulation of the muscle nerve. We found no abnormality in force generation that would suggest the presence of myopathy, neuropathy or defective neuromuscular transmission. These data suggest disruption of repetitive firing of motor neurons is an important contributor to weakness induced by sepsis in rats and raise the possibility that reduced motor neuron excitability contributes to disability that persists after resolution of sepsis.


Itaconic acid inhibits growth of a pathogenic marine Vibrio strain: A metabolomics approach.
The antimicrobial role of itaconic acid (ITA) has been recently discovered in mammalian cells. In our previous studies, we discovered that marine molluscs biosynthesise substantial quantities of ITA when exposed to marine pathogens, but its antimicrobial function to Vibrio bacteria is currently unknown. Thus, in this study, we used an untargeted gas chromatography-mass spectrometry (GC-MS) platform to identify metabolic changes of Vibrio sp. DO1 (V. corallyliticus/neptunius-like isolate) caused by ITA exposure. Vibrio sp. DO1 was cultured in Luria-Bertani broth supplemented with 3 mM sodium acetate and with different concentrations of ITA (0, 3 and 6 mM) for 24 h. The results showed that ITA completely inhibited Vibrio sp. growth at 6 mM and partially inhibited the bacterial growth at 3 mM. A principal component analysis (PCA) revealed a clear separation between metabolite profiles of Vibrio sp. DO1 in the 3 mM ITA treatment and the control, which were different in 25 metabolites. Among the altered metabolites, the accumulation of glyoxylic acid and other metabolites in glyoxylate cycle (cis-aconitic acid, isocitric acid and fumaric acid) together with the increase of isocitrate lyase (ICL) activity in the 3 mM ITA treatment compared to the control suggest that ITA inhibited Vibrio sp. growth via disruption of central carbon metabolism.


Invariant Natural Killer T-Cells and Total CD1d Restricted Cells Differentially Influence Lipid Metabolism and Atherosclerosis in Low Density Receptor Deficient Mice.
Natural killer T (NKT) cells are a distinct subset of lymphocytes that bridge the innate and adaptive immune response and can be divided into type I invariant NKT cells (iNKT) and type II NKT cells. The objective of this study is to examine the effects of NKT cell on lipid metabolism and the initiation and progression of atherosclerosis in LDL receptor deficient (LDLR-/-) mice. Mice were fed an atherogenic diet for 4 or 8 weeks and plasma lipids, lipoproteins, and atherosclerosis were measured. The selective absence of iNKT cells in Jα18-/-LDLR-/- mice led to an increase in plasma cholesterol levels in female mice. Transgenic Vα14tg/LDLR-/- mice with elevated numbers of iNKT cells had increased late atherosclerosis of the innominate artery, though absence of either iNKT cells or all NKT cells and other CD1d expressing cells had varying effects on atherosclerotic lesion burden in the ascending aortic arch and aortic root. These studies not only highlight the potential modulatory role played by NKT cells in atherosclerosis and lipid metabolism, but also raise the possibility that divergent roles may be played by iNKT and CD1d restricted cells such as type II NKT cells or other CD1d expressing cells.


Gene Import or Deletion: A Study of the Different Genes in Escherichia coli Strains K12 and O157:H7.
By comparing two strains of Escherichia coli (K12 and O157:H7) with an outgroup of Salmonella and Klebsiella species and analyzing the sets of genes which are present or absent in either of the three groups, we study the gene history of K12, in particular, since the respective divergences of these bacteria. Furthermore, by using a compositional method based on context bias, we evaluate not only recently imported genes but also deleted genes. In addition, we examine recent gene duplications in the two E. coli strains. It is found that turnover of DNA is high in E. coli and, more importantly, that turnover is highest for genes of low GC content. Although levels of import are high, most of the imported genes seem to be "junk" or have poorly understood functions. Nevertheless, selected genes do persist, and may even define some E. coli strains as pathogenic. Our results support the conclusion that some of the pathogenic islands in O157:H7 are likely to have been imported in recent time.


Crusted (Norwegian) scabies.
Crusted (Norwegian) scabies, a rare variant of ordinary scabies, is a highly contagious infection in which the skin is infested with thousands to millions of mites. The infection is frequently overlooked because of its atypical presentations. Patients with cognitive deficiency or an immunodeficiency disorder (including immunosuppressive therapy) are predisposed to developing crusted scabies. The infection often presents as generalized dermatitis with crusted hyperkeratosis on the palms and soles. Diagnosis is made by examining skin scrapings from the crusted lesions. Lindane is the scabicide most widely used in the treatment of crusted scabies. Eradication frequently requires repeated applications, and care must be taken to avoid lindane toxicity. Permethrin cream is as efficacious as lindane in the treatment of ordinary scabies. Because of its wider margin of safety, permethrin may become the preferred treatment for crusted scabies.


Eyebrows Are Important in the Treatment of Alopecia Areata.
Alopecia areata affects not only scalp hair but also other sites of body hair, including eyebrows. Our objective was to investigate the importance of eyebrows in the treatment goals of patients with alopecia areata. Through an online questionnaire, subjects were asked to assess satisfaction with the visually depicted level of response to treatment, using edited photographs depicting a range of eyebrows and scalp hair growth. The questionnaire was completed by 1,741 adults. Absent or partial growth of eyebrows and scalp hair elicited <25% satisfaction. Images depicting either complete eyebrows or complete scalp hair achieved satisfaction in >50% of participants. More participants were satisfied with complete eyebrows and no scalp hair (69%) than complete eyebrows and partial scalp hair (51%). Only when both eyebrows and scalp hair were completely regrown did extreme satisfaction levels reach 90.4%. Limitations include the online nature of the survey, lack of control group, and self-reported severity of alopecia areata in participants. These results suggest that eyebrows may be as important as scalp hair for patients assessing theoretical responses to treatment for alopecia areata. Future clinical studies should consider growth of eyebrows as an outcome measure on par with scalp hair growth.


Cancer therapy with chemically modified enzymes. I. Antitumor properties of polyethylene glycol-asparaginase conjugates.
The covalent attachment of monomethoxypolyethylene glycol (PEG) to asparaginases from Escherichia coli and Vibrio succinogenes by new coupling methodology produced conjugates that are active, stable, without significant immune response, and with greatly extended plasma half-lives in mice. Therapeutic efficacies were greater for the PEG-asparaginases than for the unmodified asparaginases in mice infected with the L5178Y lymphosarcoma or the 6C3HED tumor. Large single doses of native or modified enzymes were more effective against tumors than the same amount of enzyme given in smaller doses over several days.


PathVisio-Validator: a rule-based validation plugin for graphical pathway notations.
The PathVisio-Validator plugin aims to simplify the task of producing biological pathway diagrams that follow graphical standardized notations, such as Molecular Interaction Maps or the Systems Biology Graphical Notation. This plugin assists in the creation of pathway diagrams by ensuring correct usage of a notation, and thereby reducing ambiguity when diagrams are shared among biologists. Rulesets, needed in the validation process, can be generated for any graphical notation that a developer desires, using either Schematron or Groovy. The plugin also provides support for filtering validation results, validating on a subset of rules, and distinguishing errors and warnings.


Association Between Fasting Hyperglycemia and New-Onset Atrial Fibrillation in Patients With Acute Myocardial Infarction and the Impact on Short- and Long-Term Prognosis.
Background: The relationship between fasting hyperglycemia (FHG) and new-onset atrial fibrillation (AF) in patients with acute myocardial infarction (AMI) is unclear, and whether their co-occurrence is associated with a worse in-hospital and long-term prognosis than FHG or AF alone is unknown. Objective: To explore the correlation between FHG and new-onset AF in patients with AMI, and their impact on in-hospital and long-term all-cause mortality. Methods: We performed a retrospective cohort study comprising 563 AMI patients. The patients were divided into the FHG group and the NFHG group. The incidence of new-onset AF during hospitalization was compared between the two groups and sub-groups under different Killip grades. Logistic regression was used to assess the association between FHG and new-onset AF. In-hospital mortality and long-term all-cause mortality were compared among patients with FHG, AF, and with both FHG and AF according to 10 years of follow-up information. Results: New-onset AF occurred more frequently in the FHG group than in the NFHG group (21.6 vs. 9.2%, p < 0.001). This trend was observed for Killip grade I (16.6 vs. 6.5%, p = 0.002) and Grade II (17.1 vs. 6.9%, p = 0.005), but not for Killip grade III-IV (40 vs. 33.3%, p = 0.761). Logistic regression showed FHG independently correlated with new-onset AF (OR, 2.56; 95% CI, 1.53-4.30; P < 0.001), and 1 mmol/L increased in fasting glucose was associated with a 5% higher rate of new-onset AF, after adjustment for traditional AF risk factors. AMI patients complicated with both fasting hyperglycemia and AF showed the highest in-hospital mortality and long-term all-cause mortality during an average of 11.2 years of follow-up. Multivariate Cox regression showed FHG combined with AF independently correlated with long-term all-cause mortality after adjustment for other traditional risk factors (OR = 3.13, 95% CI 1.64-5.96, p = 0.001), compared with the group with neither FHG nor new-onset AF. Conclusion: FHG was an independent risk factor for new-onset AF in patients with AMI. AMI patients complicated with both FHG and new-onset AF showed worse in-hospital and long-term all-cause mortality than with FHG or AF alone.


Phytochrome structure and signaling mechanisms.
Phytochromes are a widespread family of red/far-red responsive photoreceptors first discovered in plants, where they constitute one of the three main classes of photomorphogenesis regulators. All phytochromes utilize covalently attached bilin chromophores that enable photoconversion between red-absorbing (P(r)) and far-red-absorbing (P(fr)) forms. Phytochromes are thus photoswitchable photosensors; canonical phytochromes have a conserved N-terminal photosensory core and a C-terminal regulatory region, which typically includes a histidine-kinase-related domain. The discovery of new bacterial and cyanobacterial members of the phytochrome family within the last decade has greatly aided biochemical and structural characterization of this family, with the first crystal structure of a bacteriophytochrome photosensory core appearing in 2005. This structure and other recent biochemical studies have provided exciting new insights into the structure of phytochrome, the photoconversion process that is central to light sensing, and the mechanism of signal transfer by this important family of photoreceptors.


Nano-plasmonic antennas in the near infrared regime.
Plasmonic nano-antennas constitute a central research topic in current science and engineering with an enormous variety of potential applications. Here we review the recent progress in the niche of plasmonic nano-antennas operating in the near infrared part of the spectrum which is important for a variety of applications. Tuning of the resonance into the near infrared regime is emphasized in the perspectives of fabrication, measurement, modeling, and analytical treatments, concentrating on the vast recent achievements in these areas.


On the nature of the protein folding code.
This paper investigates quantitatively the characteristics of the local folding code. The overlapping four-residue fragments which make up the amino acid sequences of 114 proteins are divided into classes on the basis of the physical properties of their constituent amino acids. The distribution of structural types associated with each class of sequence fragment is determined and compared with an ensemble of random structural distributions of the same size selected from the actual protein structures. A criterion is proposed, based on the relative entropies of the two types of distribution, and on a hypothesis as to the characteristics of fragments which code for local structure, that makes it possible to identify those four-residue sequence elements which encode specific time-averaged structure. It is determined that, by this criterion, only 60-70% of the four-residue fragments encode specific structures. It is suggested that the remaining sequence fragments intrinsically encode susceptibility to conformational alteration under the influence of long-range interactions and that this susceptibility is required for correct folding of the molecule. This feature introduces an inherent indeterminacy into the local folding code. The implications of this observation for the prediction of protein structure by various methods are briefly discussed.


Fine tuning brings noteworthy success.
Over the past year the estates and facilities team at London's UCLH NHS Foundation Trust and Interserve Consulting have jointly analysed energy consumption at University College Hospital to identify saving opportunities and potential carbon footprint reduction measures. The project, under which measures proposed could see electrical energy demand cut by 25%, is just part of a wider drive to reduce carbon emissions and cut energy bills at one of London's largest hospitals. Jonathan Baillie reports.


Environmental Surveillance of Norovirus Genogroups I and II for Sensitive Detection of Epidemic Variants.
Sewage samples have been investigated to study the norovirus concentrations in sewage or the genotypes of noroviruses circulating in human populations. However, the statistical relationship between the concentration of the virus and the number of infected individuals and the clinical importance of genotypes or strains detected in sewage are unclear. In this study, we carried out both environmental and clinical surveillance of noroviruses for 3 years, 2013 to 2016. We performed cross-correlation analysis of the concentrations of norovirus GI or GII in sewage samples collected weekly and the reported number of gastroenteritis cases. Norovirus genotypes in sewage were also analyzed by pyrosequencing and compared with those identified in stool samples. The cross-correlation analysis found the peak coefficient (R = 0.51) at a lag of zero, indicating that the variation in the GII concentration, expressed as the log10 number of copies per milliliter, was coincident with that in the gastroenteritis cases. A total of 15 norovirus genotypes and up to 8 genotypes per sample were detected in sewage, which included all of the 13 genotypes identified in the stool samples except 2. GII.4 was most frequently detected in both sample types, followed by GII.17. Phylogenetic analysis revealed that a strain belonging to the GII.17 Kawasaki 2014 lineage had been introduced into the study area in the 2012-2013 season. An increase in GI.3 cases was observed in the 2015-2016 season, and sewage monitoring identified the presence of GI.3 in the previous season (2014-2015). Our results demonstrated that monitoring of noroviruses in sewage is useful for sensitive detection of epidemic variants in human populations.IMPORTANCE We obtained statistical evidence of the relationship between the variation in the norovirus GII concentration in sewage and that of gastroenteritis cases during the 3-year study period. Sewage sample analysis by a pyrosequencing approach enabled us to understand the temporal variation in the norovirus genotypes circulating in human populations. We found that a strain closely related to the GII.17 Kawasaki 2014 lineage had been introduced into the study area at least 1 year before its appearance and identification in clinical cases. A similar pattern was observed for GI.3; cases were reported in the 2015-2016 season, and closely related strains were found in sewage in the previous season. Our observation indicates that monitoring of noroviruses in sewage is useful for the rapid detection of an epidemic and is also sensitive enough to study the molecular epidemiology of noroviruses. Applying this approach to other enteric pathogens in sewage will enhance our understanding of their ecology.


Feeding status and serotonin rapidly and reversibly modulate a Caenorhabditis elegans chemosensory circuit.
Serotonin (5-HT) modulates synaptic efficacy in the nervous system of vertebrates and invertebrates. In the nematode Caenorhabditis elegans, many behaviors are regulated by 5-HT levels, which are in turn regulated by the presence or absence of food. Here, we show that both food and 5-HT signaling modulate chemosensory avoidance response of octanol in C. elegans, and that this modulation is both rapid and reversible. Sensitivity to octanol is decreased when animals are off food or when 5-HT levels are decreased; conversely, sensitivity is increased when animals are on food or have increased 5-HT signaling. Laser microsurgery and behavioral experiments reveal that sensory input from different subsets of octanol-sensing neurons is selectively used, depending on stimulus strength, feeding status, and 5-HT levels. 5-HT directly targets at least one pair of sensory neurons, and 5-HT signaling requires the Galpha protein GPA-11. Glutamatergic signaling is required for response to octanol, and the GLR-1 glutamate receptor plays an important role in behavioral response off food but not on food. Our results demonstrate that 5-HT modulation of neuronal activity via G protein signaling underlies behavioral plasticity by rapidly altering the functional circuitry of a chemosensory circuit.


Hydrogen peroxide metabolism in soybean embryonic axes at the onset of germination.
Hydrogen peroxide steady state levels of 5 micromolar were determined in soybean (Glycine max) embryonic axes incubated for 2 hours and in axes pretreated with aminotriazole or cyanide, where these levels were 50 and 1 micromolar, respectively. The activities of catalase (105 picomoles H(2)O(2) per minute per axis), peroxidase (10-44 picomoles H(2)O(2) per minute per axis), glutathione peroxidase (3 picomoles H(2)O(2) per minute per axis) and superoxide dismutase (3.5 units per axis), were also determined. Catalase seems to be the most important H(2)O(2) consuming enzyme at the physiological concentration of H(2)O(2). A short treatment with aminotriazole, while substantially increasing H(2)O(2) level, did not affect the growth of the axes. The production of superoxide anion by the mitochondria isolated from soybean axes was measured from the superoxide dismutase-sensitive rate of adrenochrome formation in the presence of NADH or succinate as substrate and amounted to 1.3 and 0.8 nanomole O(2) (-) per minute per milligram protein, respectively. According to the stoichiometry of O(2) (-) and H(2)O(2) dismutation reactions, it is apparent that about 0.9 to 1.5% of the total oxygen uptake proceeds through the formation of the free intermediates of the partial reduction of oxygen.


[Imaging methods in diagnosis and differential diagnosis of breast cancer].
The diagnosis of breast cancer is primarily based on X-ray mammography. Under optimal conditions, a sensitivity of approximately 90% can be achieved. When strict criteria of indication are observed for the additional use of ultrasound or contrast-enhanced MRI, the sensitivity can be increased to about 98%. In addition, the differential diagnosis between benign and malignant lesions can be improved and the rate of biopsies due to false-positive mammograms can be reduced. However, further investigation with ultrasound or MRI of dense or mastopathic breasts that are clinically asymptomatic is not indicated, since it reduces specificity without significant gain of sensitivity.


Transforming growth factor-beta 1 enhances the generation of allospecific cytotoxic T lymphocytes.
We investigated the effects of transforming growth factor-beta 1 (TGF-beta 1) on the proliferation and generation of murine T lymphocytes in vitro. TGF-beta 1 suppressed T- and B-lymphocyte proliferation, mixed lymphocyte reaction (MLR), and the generation of natural killer (NK) cells and lymphokine-activated killer (LAK) cells. On the other hand, TGF-beta 1 significantly enhanced the generation of allospecific cytotoxic T lymphocytes (CTL) at low concentrations (0.01-1 ng/ml) in a dose-dependent manner and restored it to the control level at higher concentrations (10-40 ng/ml). Allospecific CTL generation by TGF-beta 1 was maximally enhanced when added at the beginning of culture. Less enhancement occurred when the addition was delayed. Anti-TGF-beta 1 antibody completely abolished the enhancing effects of TGF-beta 1. Furthermore, platelet-derived TGF-beta (pTGF-beta) as well as recombinant TGF-beta 1 similarly enhanced the generation of allospecific CTL. These data demonstrate that TGF-beta has not only immunosuppressive effects but also immuno-enhancing effects in vitro.


Invalidity pension after lumbar disc operation.
A total of 753 patients (328 women, 425 men) below 65 years of age and without previous pension living in the South-West of Finland, were operated on for the first time for lumbar disc herniation during the period 1975-1979. The frequency of a new invalidity pension was observed during a follow up period of two years. Of the 753 patients there were 100 new invalidity pensioners (13%) during one year and 133 (18%) during two years after the first operation. According to a statistical model for the impact of age and nature of work on invalidity pension the greatest risk of pensioning for women was associated with age, pensioning being more than five times higher in the age group 45-54 years than below 35 years. Moderate and heavy work by women constituted a minor risk factor, increasing the risk by less than two times compared with light work. In men the risk correlated clearly to both age and nature of work. Moderate and heavy work increased the risk nearly three times compared with light work. The frequency of pensions among 45-64 year old men was even 6-8 times higher, than the risk for men below 35 years. A second operation increased the risk on average two to three times. Cauda equina syndrome was not a risk factor for receiving an invalidity pension. The primary diagnosis for an invalidity pension was something other than lumbar disc herniation in 20%. Patients with unsatisfactory results after lumbar disc operations account for about 10% of all the new invalidity pensions due to some form of back disease in Finland.


Adverse pregnancy outcomes in women with changing patterns of exposure to the emissions of a municipal waste incinerator.
Municipal solid waste incinerators emissions contain pollutants that, despite their low concentration, might adversely affect reproductive health. In the present study, we examined rates of miscarriage and birth defects among women who resided or were employed in the vicinity of a municipal solid waste incinerator plant from 2003 to 2013. In 2009, a progressive shutdown of the old incineration lines and operation of a new line caused considerably higher atmospheric release of polycyclic aromatic hydrocarbons, particularly of dioxins, due to these irregular operating conditions, technological renovation, and increased capacity. We used dioxin emission levels, based on a dispersion model, to define exposure status of the residing population to air pollutants emitted by the waste incinerator. In women who resided in areas characterized by higher emission exposures compared with a referent area, the relative risk (RR) of miscarriage was 1.04 (95% confidence interval (CI) 0.80-1.32) based on 62 cases overall, with little evidence of a dose-response relation. RRs were similarly null for both 2003-2008 and 2010-2013 periods (RR 1.12 (95% CI 0.80-1.53) and 0.98 (95% CI 0.63-1.48), respectively). Concerning birth defects in the offspring of women residing in the exposed area, no evidence of increased risk emerged, since the prevalence ratio at birth was 0.64 (95% CI 0.29-1.26), with comparable results in the 2003-2008 and 2010-2013 period. Corresponding analyses carried out in municipal residents who worked in the exposed area confirmed these findings. We also did not detect abnormally high rates of miscarriage and birth defects in the exposed cohorts in the single year 2009. Overall, these results do not suggest an effect of exposure to the emissions of the municipal solid waste incinerator we investigated on two indicators of reproductive health. However, the limited statistical stability of the estimates and the absence of individual-based information on some potential confounders suggest caution in the interpretation of study findings.


The Management of Myelomeningocele Study: Short-Term Neonatal Outcomes.
The Management of Myelomeningocele Study was a multicenter randomized trial to compare prenatal and standard postnatal repair of myelomeningocele (MMC). Neonatal outcome data for 158 of the 183 randomized women were published in The New England Journal of Medicine in 2011. Neonatal outcomes for the complete trial cohort (N = 183) are presented outlining the similarities with the original report and describing the impact of gestational age as a mediator. Gestational age, neonatal characteristics at delivery, and outcomes including common complications of prematurity were assessed. Analysis of the complete cohort confirmed the initial findings that prenatal surgery was associated with an increased risk for earlier gestational age at birth. Delivery occurred before 30 weeks of gestation in 11% of neonates that had fetal MMC repair. Adverse pulmonary sequelae were rare in the prenatal surgery group despite an increased rate of oligohydramnios. There was no significant difference in other complications of prematurity including patent ductus arteriosus, sepsis, necrotizing enterocolitis, periventricular leukomalacia, and intraventricular hemorrhage. The benefits of prenatal surgery outweigh the complications of prematurity.


Zebrafish as an Emerging Model for Dyslipidemia and Associated Diseases.
Dyslipidemia related diseases such as hyperlipidemia and atherosclerosis are the leading cause of death in humans. While cellular and molecular basis on the pathophysiology of dyslipidemia has been extensively investigated over decades, we still lack comprehensive understanding on the etiology of dyslipidemia due to the complexity and the innate multimodality of the diseases. While mouse has been the model organism of choice to investigate the pathophysiology of human dyslipidemia, zebrafish, a small freshwater fish which has traditionally used to study vertebrate development, has recently emerged as an alternative model organism. In this review, we will provide comprehensive perspective on zebrafish as a model organism for human dyslipidemia; we will discuss the attributes of zebrafish as a model, and compare the lipid metabolism in zebrafish and humans. In addition, we will summarize current landscape of zebrafish-based dyslipidemia research.


Microiontophoretically applied PACAP blocks excitatory effects of kainic acid in vivo.
Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to be neuroprotective in animal models of different brain pathologies, including focal and global cerebral ischemia. The application of glutaminergic excitotoxin kainic acid (KA), similar to ischemic events, may lead to neurodegeneration. In the present article, we investigated the effects of microiontophoretic application of PACAP on the excitatory effects of KA. During recording-maintained spontaneous activity of single neurons, we microiontophoretized KA, which was followed by the application of PACAP-38. We found that PACAP could block the excitatory effects of KA in several brain areas (cortex: 89%, hippocampus: 36%, and thalamus: 50%). Moreover, we detected a lower level excitatory effect of PACAP alone (41%). The present results may explain the neuroprotective effects of PACAP observed in experimental models of glutamate (GLU)-receptor-mediated degenerative processes.


Seasonal and geographical distribution of Culicoides imicola Kieffer (Diptera: Ceratopogonidae) in southwestern Spain.
Culicoides imicola Kieffer adults were collected in light traps weekly between August 1990 and October 1991. The species was collected at all 62 sites located in 5 provinces of the Autonomous Region of Andalucía (Spain). Culicoides imicola represented 31.7% of the total collection of Culicoides. The highest numbers of C. imicola were collected from September through November 1990 and September and October 1991. The lowest numbers were collected from December 1990 through April 1991. The presence or absence of C. imicola was related to the mean monthly minimum and maximum air temperature. Greatest numbers of C. imicola were collected at daily minimum and maximum temperatures of 18 degrees C and 38 degrees C, respectively. The relevance of this information to previous outbreaks of African horse sickness is discussed.


[Significance of lymph node metastases in differentiated thyroid carcinoma].
464 patients with differentiated thyroid carcinoma were scored and treated using a risk-oriented management scheme employing early surgical re-intervention including compartment-oriented lymph-node dissection in cases of lymph-node metastases or local recurrences without routine external radiotherapy. A multivariate analysis showed that there was no effect of lymph-node metastases on survival. The difference in survival between patients with (24%) and without (76%) lymph-node metastases (univariate analysis) were due to the coincidence of higher tumor stage (T4) and higher incidence of peripheral metastases (M1). Thus, provided surgery is efficient, N1 is not a risk factor influencing survival.


[Effect of Helicobacter pylori eradication on the expression level of SATB1 and c-Myc genes in gastric mucosa of patients with family history of gastric cancer].
Helicobacter pylori (H. pylori) is a class 1 gastric carcinogen with the proved influence on gastric cancer development. The products of SATB1 and c-Myc genes play important role in cancer development and their levels are elevated in gastric cancer tissues. The aim of the study was to analyze an effect of H. pylori eradication on the expression of the SATB1 and c-Myc genes in the gastric mucosa of dyspeptic patients with family history of gastric cancer. Twenty patients enrolled to the studies were divided into two groups: nine patients (group I) without the family history of gastric cancer, and eleven patients with the family history of gastric cancer (group II). Endoscopic biopsies of gastric mucosa were taken from the antrum and corpus of H. pylori-infected subjects before and after bacteria eradication. The corresponding levels of expression were determined by analysis of the respective mRNA levels with the use of the real-time RT-PCR method. The level of each mRNA was normalized to the levels of mRNA of two reference genes, RPL29 and GAPDH. Independently of stomach topography, the antrum versus corpus, in the group I patients the levels of mRNA of SATB1 and c-Myc after eradication were higher in the following cases: SATB1/ GAPDH p = 0.017914 (antrum); SATB1/RPL29 p = 0.046400 (corpus); SATB1/GAPDH p = 0.027709 (corpus). For group II patients no statistically significant increase of the level of the c-Myc and SATB1 genes was observed. Patients with the family history of gastric cancer and H. pylori infection, with reversible histopathological changes of the gastric mucosa, have significantly higher levels of SATB1 and c-Myc genes expression as compared to the patients without family history of gastric cancer, regardless of the topography of the stomach. After successful eradication, the SATB1 mRNA level in samples of patients with the family history of gastric cancer did not increase, in contrast to the control group of patients. Presumably, the observed effect is associated with hypermethylation of the promoter of that gene. However, the level of c-Myc gene expression was not significantly different before and after removal of the bacteria, for both groups of patients.


Clinicovirologic analysis of hepatitis C infection in transfusion-dependent beta-thalassemia major children.
Regular blood transfusion puts beta-thalassemia major patients at a higher risk of developing hepatic iron overload and hepatitis C virus (HCV) infection. The association between several transfusion-related factors and an increased risk of developing HCV viremia has been reported. The effect of HCV infection on liver damage in transfusion-dependent thalassemia patients has been poorly described. A sample of 100 Egyptian transfusion-dependent beta-thalassemia major children were studied. Individual patients underwent full history taking, clinical examination and a panel of laboratory tests including HCV ribonucleic acid polymerase chain reaction (HCV-PCR) in blood samples. Liver biopsy was performed for 24 patients. HCV-PCR was positive in 64% of patients. A statistically significant correlation was found between HCV-PCR positivity (HCV viremia) and shorter inter-transfusion interval. There was a significant positive correlation between mean serum ferritin level and mean levels of alanine aminotransferase and aspartase aminotransferase. Histopathologic features of both chronic hepatitis and siderosis were present in 91.7% of biopsy specimens, and fibrosis was present in 41.67%. A higher risk of HCV viremia is noted with a shorter inter-transfusion interval. The reduced role of HCV infection in chronic liver injury in this group of patients may be surpassed by the associated effects of iron overload because of the chronic transfusion. However, the latter finding should be verified in larger studies.


Knowledge, Attitudes and Practices of Non-Consultant Hospital Doctors In The Immediate Post-Fall Period
Aim The aim of this study is to determine the knowledge, attitudes and practices of Non-Consultant Hospital Doctors (NCHDs) in the immediate post-fall period. Methods A survey study design was employed using an online questionnaire of all NCHDs in SVUH comprising 15 questions that blend dichotomous, multiple choice, scaled and open-ended questions to determine knowledge, attitudes and practices of NCHDs across three constructs; injury management, falls prevention and fracture prevention. Descriptive statistics was used to analyse data. Results There was a 40% response rate (n=105). The respondents reported dissatisfaction with their standard of falls assessment training (mean 4/10). Between 60-70% of NCHDs do not routinely determine hip trauma, joint tenderness, syncope, use of anti-coagulants, visual symptoms, amnesia or vomiting. Half of respondents (n=57) rarely or never rationalised medications. The main reasons for this are lack of knowledge of alternatives (63%), time constraints (65%), benefits outweighing the risks (80%) and reluctance to interfere with care of another medical team (86%). Only 9% always consider a bone health review. Discussion A targeted education programme in the areas of hip assessment, neurological assessment, syncope management, medication rationalisation and bone protection is warranted.


Primary amino-functionalized N-heterocyclic carbene ligands as support for Au(I)···Au(I) interactions: structural, electrochemical, spectroscopic and computational studies of the dinuclear [Au2(NH2(CH2)2imMe)2][NO3]2.
The N-heterocyclic carbene (NHC) precursor, 1-(2-aminoethyl)-3-methylimidazolium nitrate, [NH(2)(CH(2))(2)imMe)]NO(3) ([3][NO(3)]) reacted with Ag(2)CO(3) in dimethyl sulfoxide readily yielding a Ag(I)-(NHC-NH(2)) complex presenting limited stability in solution. The in situ carbene transfer reaction of the latter with [Au(tht)Cl] afforded the first example of a dinuclear gold(I) complex [Au(2)(NH(2)(CH(2))(2)imMe)(2)][NO(3)](2) ([5][NO(3)](2)) bearing a primary amino-functionalized NHC ligand. The complex has been characterized by NMR, mass spectrometry, X-ray crystallography and cyclic voltammetry; the electrochemical behaviour and photophysical properties of [5][NO(3)](2) have been also investigated and the experimental data have been compared with density functional theory (DFT) and Time Dependent (TDDFT) calculations. Single-crystal structural studies showed that the Au(I)-carbene compound contains dinuclear (AuL)(2) cations in which pairs of gold(I) centres are linked by a pair of bridging ligands, with a Au···Au aurophilic contact of 3.2332(17) Å that is maintained in solution as documented by the DFT calculations. Complex [5][NO(3)](2) is photoluminescent in solution at room temperature and the high energy emission peak at 410 nm is remarkably shifted with respect to the absorption band centered at 260 nm.


Pharmacist engagement in a community pharmacy hypertension management program in collaboration with an academic medical center.
To explore the perceptions of pharmacists and administrators who had an integral role in designing and operationalizing an integrated community pharmacist hypertension management program with collaboration between an academic medical center and a regional chain community pharmacy. Community pharmacists (n = 3), ambulatory care pharmacists (n = 2), medical directors (n = 2), and health-system (n = 1) and pharmacy (n = 1) administrators reported positive experiences engaging with the hypertension management program. Strengths of the program included comprehensive training by the ambulatory care pharmacists, community pharmacist access to the electronic health record (EHR), and primary care providers who were receptive to referring patients and accepting recommendations from the community pharmacists. All participants felt that the program had a positive outlook and saw opportunity for expansion, such as extended hours of operation, new locations, and additional pharmacists. Pharmacists are well positioned to extend hypertension management programs from primary care clinics into local pharmacies if they have appropriate training, access to the EHR, and ongoing support from collaborating primary care offices. Additional research using implementation science methods is needed to further test the scalability and replicability of the program among different patient populations, community pharmacies, and health systems.


Podocyte differentiation in the absence of endothelial cells as revealed in the zebrafish avascular mutant, cloche.
The physiological functions of the zebrafish pronephros are blood plasma filtration and osmoregulation. The pronephric glomerulus is vascularized through a capillary network sprouting from the dorsal aorta. Vascularization of the glomerulus, visualized by flk-1 expression and alkaline phosphatase reactivity, involves the intimate association between podocytes and endothelial cells and the formation of an intervening glomerular basement membrane (GBM). Cell-cell interactions between podocytes and endothelial cells are thought to play an important role in glomerular angiogenesis. In order to determine whether endothelial cell-derived signals were required for podocyte differentiation, we employed in situ hybridization and electron microscopy to investigate glomerulogenesis in the zebrafish mutant cloche (clo), where endothelial cell development is blocked at an early stage. In clo mutants, glomerular epithelial cells expressing the podocyte specific marker wt1 display well-formed foot processes and are able to form a GBM, suggesting podocytes are able to morphologically differentiate in the absence of endothelia or endothelial-derived signals. The presence of irregular aggregates in the clo GBM as well as the apparent effacement of podocyte foot processes implies a role for endothelial cells in the maintenance of the mature glomerular filtration barrier.


Salami: By the slice or swallowed whole?
Salami slicing, the practice of extracting multiple papers from the one data set, is generally considered unsound practice in publication. To date critique of this view in the literature is limited. The aim of this paper is to present alternative views to challenge the concept of salami slicing as inherently negative. More specifically the paper will discuss the potential consequences of producing thin and underdeveloped findings with insufficient scope for detailed discussion and articulation of the contribution to knowledge. Practical tips for dealing with multiple papers from one data set will provided.


Distribution and sequence of pyknotic cells in rat fetuses exposed to busulfan.
Busulfan, an antineoplastic bifunctional-alkylating agent, is known to induce developmental anomalies. In the present study, we examined the distribution and sequence of pyknotic cells in rat fetal tissues exposed to busulfan. Pregnant rats on gestation day 13 were administered intraperitoneally 30 mg/kg of busulfan, and fetal tissues were examined at 6, 12, 24, 36, 48, 72 and 96 hours after treatment (HAT). Pyknosis of component cells was observed markedly in the brain, moderately in the eyes and spinal cord and mildly in the craniofacial tissue, mandible, limb buds, tail bud, ganglions, alimentary tract, lungs, kidneys, pancreas and liver. In the brain, mitotic inhibition was also detected. Most of the pyknotic cells were considered to be apoptotic cells judging from the results of TUNEL staining and electron microscopic examination. Commonly in the above-mentioned tissues, pyknotic cells began to increase at 24 HAT, peaked at 36 or 48 HAT and disappeared at 96 HAT, which is when the histological picture returned to normal in most tissues except for the brain, spinal cord and eyes. The present study clarified the outline of busulfan-induced apoptosis in rat fetuses.


Effect of Purple Eggplant Flour on Physicochemical, Lipid Oxidation, and Sensory Properties of Low-Fat Beef Patties.
This study examines the implications of PEF as an alternative fat replacer on nutritional composition, display storage stability, product quality, and its practical application for beef patties. Four different beef patties were formulated with 0, 2.5, 5.0, and 7.5% PEF. Addition of the PEF in beef patties resulted in a significant increase in moisture, ash, and total dietary fiber while decreasing protein and fat contents. The cooking yield, moisture, and fat retention of the PEF beef patties were significantly higher than the control patty. The tenderness and juiciness scores of the PEF beef patties were significantly increased compared to the control. The lightness and redness values of raw patties were superior to the control during storage time. The amounts of thiobarbituric acid-reactive substances (TBARS) were lower in PEF beef patties than the control patties during 7 days of storage at 4°C. These results suggested that PEF could be used as a natural antioxidant fat replacer in beef patties without losing sensory and visual quality. In addition, the utilization of PEF may improve nutritional values including dietary fiber and display storage stability in beef patties.


Modified lateral positioned flap with platelet-rich fibrin graft for treatment of denuded root surfaces: A clinical study.
Root coverage (RC) procedures such as lateral positioned flap (LPF) have been used since long time but with limited success and specific indications. This prospective clinical study was designed to evaluate clinically the effect of modified LPF (mLPF) with platelet-rich fibrin (PRF) graft for the treatment of denuded root surfaces. Fifteen isolated Miller's Class I and II gingival recession of single-rooted teeth were selected for the study. Scaling and root planing was done, and oral hygiene instructions were given to the patients. Plaque index, gingival index, and recession parameters (probing depth, gingival recession height, clinical attachment level [CAL], and width of keratinized tissue [WKT]) were assessed at baseline. Following this, mLPF with PRF was done at the recession sites, and parameters were assessed at 3 and 6 months. To analyze the posttreatment effect, paired t-test was performed at relevant degrees of freedom and 95% confidence level. The mean percentage of RC attained was 72.2% at 3 months and 73.5% at 6 months. The WKT shows a mean gain of 2.93 mm at 3 months and 3 mm at 6 months. mLPF with PRF produced statistically significant reduction in recession depth and gain in both CAL and WKT by the end of 6 months.


Toward selection of internalizing antibodies from phage libraries.
Antibodies which bind cell surface receptors in a manner whereby they are endocytosed are useful molecules for the delivery of drugs, toxins, or DNA into the cytosol of mammalian cells for therapeutic applications. Traditionally, internalizing antibodies have been identified by screening hybridomas. For this work, we studied a human scFv (C6.5) which binds ErbB2 to determine the feasibility of directly selecting internalizing antibodies from phage libraries and to identify the most efficient display format. Using wild-type C6.5 scFv displayed monovalently on a phagemid, we demonstrate that anti-ErbB2 phage antibodies can undergo receptor-mediated endocytosis. Using affinity mutants and dimeric diabodies of C6.5 displayed as either single copies on a phagemid or multiple copies on phage, we define the role of affinity, valency, and display format on phage endocytosis and identify the factors that lead to the greatest enrichment for internalization. Phage displaying bivalent diabodies or multiple copies of scFv were more efficiently endocytosed than phage displaying monomeric scFv and recovery of infectious phage was increased by preincubation of cells with chloroquine. Measurement of phage recovery from within the cytosol as a function of applied phage titer indicates that it is possible to select for endocytosable antibodies, even at the low concentrations that would exist for a single phage antibody member in a library of 10(9).


Pathophysiological role of endothelin in renal transplantation.
To assess the pathophysiological role of endothelin (ET) in the early post-transplantation period, we followed plasma ET concentrations for 2 months from 1 week prior to surgery in four renal transplant patients. Plasma ET concentrations were elevated before transplantation in all patients. In two patients who developed marked pretibial edema, plasma ET concentrations increased before the onset of edema and before the increase in plasma atrial natriuretic peptide (ANP) concentrations, and remained high while the edema persisted. In the other two patients without edema, plasma ET and ANP concentrations fell toward normal immediately after transplantation. Plasma ET concentration increased transiently again in one of these patients when acute rejection occurred. After recovery from this rejection episode, the plasma ET concentration again fell to the normal range. There were significant correlations between plasma ET concentrations and changes in body weight and urine volume. These results suggest that the plasma ET concentration may reflect the function of transplanted kidneys and that ET may modulate body fluid volume regulation after transplantation. In addition, ET may participate in the pathogenesis of acute rejection.


Genome rearrangements with duplications.
Finding sequences of evolutionary operations that transform one genome into another is a classical problem in comparative genomics. While most of the genome rearrangement algorithms assume that there is exactly one copy of each gene in both genomes, this does not reflect the biological reality very well - most of the studied genomes contain duplicated gene content, which has to be removed before applying those algorithms. However, dealing with unequal gene content is a very challenging task, and only few algorithms allow operations like duplications and deletions, especially if the duplicated or deleted segments are of arbitrary size. We recently proposed a heuristic algorithm for sorting unichromosomal genomes by reversals, block interchanges, tandem duplications, and deletions. In this paper, we extend this approach to multichromosomal genomes. We are now able to sort a multichromosomal ancestral genome into a genome of a descendant by a large set of different operations, including tandem duplications and deletions of segments of arbitrary size. Experimental results show that our algorithm finds sorting sequences that have a weight close to the true evolutionary distance.


The incidence of symptoms consistent with cerebellopontine angle lesions in a general ENT out-patient clinic.
To quantify the potential burden for screening for cerebellopontine angle lesions, all adult new patients attending the ENT outpatient department of a district general hospital were documented to see if their presenting symptom(s) could be consistent with the presence of a cerebellopontine angle lesion. Of the patients, 19.7 per cent were found to be potential candidates for screening. A 15 decibel asymmetry at one frequency was found in 11.8 per cent of patients. The burden of screening with a variety of audiological and symptomatic protocols was quantified. Effective age limits to reduce the burden for screening were found to be either 65 or 75 years of age. With such a large potential pool of patients for further investigation, the results of this study could be used to suggest protocols which are likely to produce a load of cases, which matches local resources for screening.


Deep Learning Based Prediction of Atrial Fibrillation Disease Progression with Endocardial Electrograms in a Canine Model.
We sought to determine whether electrical patterns in endocardial wavefronts contained elements specific to atrial fibrillation (AF) disease progression. A canine paced model (n=7, female mongrel, 29±2 kg) of persistent AF was endocardially mapped with a 64-electrode basket catheter during periods of AF at 1 month, 3 month, and 6 months post-implant of stimulator. A 50-layer residual network was then trained to map half-second electrogram samples to their source timepoint. The trained network achieved final validation and testing accuracies of 51.6 and 48.5% respectively. Per class F1 scores were 24%, 59%, and 53% for 1 month, 3 month, and 6 month inputs from the testing dataset. Differentiation of AF based on its time progression was shown to be feasible with a deep learning method. This is promising for differentiating treatment based on disease progression though low accuracy with earlier timepoints may be an obstacle to identifying nascent AF.