Trypan blue uptake as a new method to investigate hepatotoxicity in periportal and pericentral regions of the liver lobule: studies with allyl alcohol in the perfused liver.
A new method based on trypan blue uptake was developed to study zonal hepatotoxicity in specific regions of the liver lobule in perfused livers. Allyl alcohol (350 microM), a hepatotoxin that causes necrosis of periportal regions, was infused into livers from phenobarbital-treated rats for 60 min. The subsequent infusion of trypan blue (0.2 mM) stained nuclei in periportal but not midzonal or pericentral regions of the liver lobule. With this new method of dye uptake, comparison of the temporal relationship between metabolic changes and the onset of cellular damage was possible. During the first 10 min of allyl alcohol infusion, allyl alcohol was taken up at rates of 64 mumol/g/h concomitant with an increase in oxygen uptake of 18 mumol/g/h. Allyl alcohol infusion also increased bile flow from 69 to 167 microliters/min and release of oxidized glutathione from 127 to 217 nmol/g/h, respectively. However, during the next 20-min phase of exposure to allyl alcohol, oxygen uptake was inhibited by 60% and allyl alcohol uptake declined by 80%. Bile flow and release of oxidized glutathione also declined continuously between 10 and 30 min and by 30 min stopped completely. Concomitant with the inhibition of oxygen uptake, rates of glycogenolysis and glycolysis increased by 130 and 85%, respectively. Within minutes after maximal inhibition of oxygen uptake, between 30 and 40 min after initiation of allyl alcohol infusion, trypan blue was taken up by hepatocytes in periportal zones of the liver lobule. Subsequently, lactate dehydrogenase began to appear in the effluent perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)


Large dynamic range optical cavity based sensor using a low cost three-laser system.
An optical cavity based biosensor using a differential detection method has been proposed to provide a novel approach to point-of-care diagnostics. A two-laser based optical cavity based sensor system is designed and experimentally demonstrated. While the calculated differential value of the two-laser system shows larger responsivity compared to individual wavelengths, the dynamic range of the system is rather small. Because of that, it turned out its fabrication tolerance is also small based on the simulation. We employed a three-laser system and redesigned the optical cavity to increase the dynamic range and improve the fabrication tolerance. In this presentation, we report the measurement results of the three-laser system for the first time. This system increases the dynamic range threefold by a chaining action. Because of this large dynamic range, this three-laser system is anticipated to have a larger fabrication tolerance.


Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II.
A major source of vascular smooth muscle cell (VSMC) superoxide is NAD(P)H oxidase. However, the molecular characteristics and regulation of this enzyme are unclear. We investigated whether VSMCs from human resistance arteries (HVSMCs) possess a functionally active, angiotensin II (Ang II)-regulated NAD(P)H oxidase that contains neutrophil oxidase subunits, including p22phox, gp91phox, p40phox, p47phox, and p67phox. mRNA expression of gp91phox homologues, nox1 and nox4, was also assessed in HVSMCs, human aortic smooth muscle cells, and rat VSMCs. HVSMCs were obtained from resistance arteries from gluteal biopsies of healthy subjects. gp91phox and nox4, but not nox1, were detected in HVSMCs. Nox1 and nox4, but not gp91phox, were expressed in human aortic smooth muscle cells and rat VSMCs. All NAD(P)H oxidase subunits were present in HVSMCs as detected by reverse transcriptase-polymerase chain reaction and immunoblotting. Ang II increased NAD(P)H oxidase subunit abundance. These effects were inhibited by cycloheximide. Acute Ang II stimulation (10 to 15 minutes) increased p47phox serine phosphorylation and induced p47phox and p67phox translocation. This was associated with NAD(P)H oxidase activation. In cells transfected with gp91phox antisense oligonucleotides, Ang II-mediated actions were abrogated. NADPH-induced superoxide generation was reduced by gp91ds-tat and apocynin, inhibitors of p47phox-gp91phox interactions. Our results suggest that HVSMCs possess a functionally active gp91phox-containing neutrophil-like NAD(P)H oxidase. Ang II regulates the enzyme by inducing phosphorylation of p47phox, translocation of cytosolic subunits, and de novo protein synthesis. These novel findings provide insight into the molecular regulation of NAD(P)H oxidase by Ang II in HVSMCs. Furthermore, we identify differences in gp91phox homologue expression in VSMCs from rats and human small and large arteries.


Assessment of sarcopenia as a predictor of poor overall survival for advanced non-small-cell lung cancer patients receiving salvage anti-PD-1 immunotherapy.
Sarcopenia, which is defined as the loss of skeletal muscle mass, has been identified as a poor prognostic factor for cancer patients. This study sought to elucidate the effects of sarcopenia on the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving salvage anti-programmed death-1 (PD-1) immunotherapy. In total, 105 NSCLC patients receiving second-line anti-PD-1 immunotherapy at the Sun Yat-sen University Cancer Center between January 2015 and December 2017 were enrolled in this study, and detailed patient data were collected. Available lumbar computed tomography images of the patients were analyzed to determine the total skeletal muscle cross-section area. The efficacy of the predictive and prognostic role of sarcopenia in progression-free survival (PFS) and overall survival (OS) was analyzed using the Kaplan-Meier method, and the risk factors were analyzed using Cox analyses. We found that patients with sarcopenia receiving salvage anti-PD-1 immunotherapy had significantly worse PFS (2.67 vs. 7.96 months; P<0.001) and OS (9.08 vs. 21.84 months; P<0.001) than their non-sarcopenic counterparts. We also found that sarcopenia was associated with the neutrophil-to-lymphocyte ratio (NLR) (P=0.041), and that the NLR acts as a predictor of OS. Sarcopenia was associated with a poor prognosis in advanced NSCLC patients receiving salvage anti-PD-1 immunotherapy. Further research needs to be conducted to identify more biomarkers and the patients most likely to benefit from immunotherapy.


Anterior C1-C2 screw fixation and bony fusion through an anterior retropharyngeal approach.
We present a case that demonstrates an occasion where an alternative method of C1-C2 fusion may be used when a posterior approach limited to the atlantoaxial level is not desirable. A 22-year-old man presented with a symptomatic nonunited Brooks posterior atlantoaxial fusion following a chronically displaced type II odontoid fracture with a two-part fracture of the posterior arch of C1. An anterior retropharyngeal approach was used to perform an anterior C1-C2 fusion with screw fixation. The surgical technique, as well as the merits and indications of this infrequently used procedure, are discussed.


A Comparative Study on a Novel Fibula Malleolus Cap to Increase the Accuracy of Oncologic Jaw Reconstruction.
Although computer-assisted surgery using fibula flap has been widely applied for oncologic jaw reconstruction in recent years, the inaccurate positioning of the fibula harvest guide brings sliding and rotational errors, which leads to compromised accuracy in simultaneous implant placement and dental rehabilitation. This study aimed to develop a novel three-dimensional (3D)-printed patient-specific fibula malleolus cap to increase oncologic reconstruction accuracy. In this prospective comparative study with a recent historical control cohort, patients in need of oncologic jaw reconstruction with fibula free flaps were recruited. In the study group, the fibula was harvested with the guide of the malleolus cap, whereas in the control group, without the malleolus cap. Deviations of location and angulation of distal fibula osteotomies, jaw reconstruction segments, and simultaneous dental implants were compared. Twenty patients were recruited, with 10 in each arm. The application of the malleolus cap significantly reduced the deviations in locations and angles of distal fibula osteotomies, from 9.5 to 4.1 mm and 25.3° to 8.7°. For the simultaneous dental implants placed in the fibula flaps, there was a significant increase in the accuracy of implant platform locations (the average deviation from 3.2 to 1.3 mm), apex locations (from 3.8 to 1.5 mm), and angles (from 11.3° to 4.6°). No significant difference was detected in the accuracy of fibula reconstruction segments. We developed a novel fibula malleolus cap to overcome the sliding and rotational errors during fibula flap harvesting for oncologic jaw reconstruction, with increased accuracy in simultaneous dental implants. This is a step forward to achieve a satisfactory functional outcome of jaw reconstruction with dental rehabilitation.


Granulocyte colony-stimulating factor corrects the neutropenia associated with glycogen storage disease type Ib.
A young woman with glycogen storage disease, type Ib, and chronic neutropenia had severe recurrent infections. In a life-threatening situation, treatment with granulocyte colony-stimulating factor (G-CSF) resulted in the prompt correction of neutropenia. Subsequently, daily G-CSF therapy has allowed the maintenance of a normal neutrophil count and marked clinical improvement over a period of 18 months. The spectrum of neutropenic conditions which are responsive to G-CSF should include this inherited metabolic disorder.


Modeling elasticity in crystal growth.
A new model of crystal growth is presented that describes the phenomena on atomic length and diffusive time scales. The former incorporates elastic and plastic deformation in a natural manner, and the latter enables access to time scales much larger than conventional atomic methods. The model is shown to be consistent with the predictions of Read and Shockley for grain boundary energy, and Matthews and Blakeslee for misfit dislocations in epitaxial growth.


Heat inactivation of starch synthase in wheat endosperm tissue.
The effect of temperature on accumulation of starch was studied in grain slices of wheat (Triticum aestivum cv SUN9E), taken 15 days after anthesis. As compared with pretreatment of such slices at 25 degrees C, pretreatment at 30 or 35 degrees C reduced the subsequent conversion of sucrose to starch. In contrast to rice (Oryza sativa cv Calrose), pretreatment of wheat soluble starch synthase in vitro at 30 degrees C or higher temperatures reduced its activity. In zymograms using nondenaturing polyacrylamide gel electrophoresis followed by activity staining, the slowest migrating band represented the most temperature sensitive isozyme. Although preincubation of a soluble enzyme sample in vitro at 25 degrees C did not result in loss of starch synthase activity, it did result in a gradual shift of zymogram banding pattern toward faster migrating species. Pretreatment of isolated starch granules at 40 degrees C increased their bound starch synthase activity. Both soluble and bound enzymes in the grains of whole wheat plants lost activity when the plants were held above 30 degrees C for 30 minutes or longer. Both activities lost from the grains after a 1 hour treatment at 37 degrees C were restored in 1 to 2 days by a return to 21 degrees C. In slices, inactivation of the soluble starch synthase was increased by incubation with 2,4-dinitrophenol. It is tentatively suggested that in vivo heat inactivation of soluble starch synthase may be a direct effect of heat on the enzyme protein and that of bound enzyme an indirect effect involving metabolic factors.


Nearly arbitrary on-chip optical filters for ultrafast pulse shaping.
We demonstrate a reverse design method for realizing a broad range of optical filters based on integrated optical waveguides and experimentally verify example designs on a CMOS-compatible silicon-on-insulator (SOI) platform. The reflectance-based filters allow for control of both phase and amplitude of the optical response. Among this device's many potential applications we highlight and numerically demonstrate its use for ultrafast on-chip pulse shaping.


Large scale remote sensing for environmental monitoring of infrastructure.
Recent developments in wireless sensor technology afford the opportunity to rapidly and easily deploy large-scale, low-cost, and low-power sensor networks across relatively sizeable environmental regions. Furthermore, the advancement of increasingly smaller and less expensive wireless hardware is further complemented by the rapid development of open-source software components. These software protocols allow for interfacing with the hardware to program and configure the onboard processing and communication settings. In general, a wireless sensor network topology consists of an array of microprocessor boards, referred to as motes, which can engage in two-way communication among each other as well as with a base station that relays the mote data to a host computer. The information can then be either logged and displayed on the local host or directed to an http server for network monitoring remote from the site. A number of wireless sensor products are available that offer off-the-shelf network hardware as well as sensor solutions for environmental monitoring that are compatible with the TinyOS open-source software platform. This paper presents an introduction to wireless sensing and to the use of external antennas for increasing the antenna radiation intensity and shaping signal directivity for monitoring applications requiring larger mote-to-mote communication distances.


Relationship between cumulus cell apoptosis, progesterone production and porcine oocyte developmental competence: temporal effects of follicular fluid during IVM.
The objective of the present study was to determine the temporal effects of sow follicular fluid (FF) in vitro on cumulus cell viability and function, as well as oocyte nuclear and cytoplasmic maturation. Cumulus-oocyte complexes (COCs) recovered from the ovaries of prepubertal pigs were matured in medium with (+FF) or without (-FF) follicular fluid for the first 22 h of IVM. At 22 h of IVM, each group of COCs was then transferred to medium with or without FF and matured for another 22 h, forming four treatment groups (-FF/-FF, -FF/+FF, +FF/-FF and +FF/+FF). The concentration of progesterone in spent IVM medium and the incidence of cumulus cell apoptosis in individual COCs were determined at 22 and 44 h of IVM. Cumulus expansion was also recorded at 44 h of IVM. Finally, the ability of oocytes to complete meiosis to the MII stage and form blastocysts after IVF and embryo culture was assessed. Maturation with FF for part or the whole of IVM increased cumulus expansion and progesterone production and decreased the incidence of cumulus cell apoptosis compared with the -FF/-FF group (P < 0.05). The changes were greatest for the +FF/+FF group and intermediate for the -FF/+FF and +FF/-FF groups. Regression analysis revealed a negative association between cumulus cell progesterone production and the incidence of cumulus cell apoptosis (P < 0.001). Meiotic maturation was enhanced when FF was present during the first half of IVM. Oocytes matured in the presence of FF during the first and/or second half of IVM displayed an increased ability to form blastocysts compared with the -FF/-FF group (P < 0.05). The extent of the increase was similar for all FF-supplemented groups. The results show that FF exerts several beneficial effects at different times during IVM and suggest that a major role of FF is to provide protection from oxidative stress. We propose that the incidence of cumulus cell apoptosis in COCs must be kept below a certain threshold to ensure adequate functionality, including steroidogenic activity, is maintained for the acquisition of oocyte developmental competence.


[Panzytopenia from combination therapy with azathioprin and allopurinol].
Azathioprine has been used in rheumatology for more than twenty years. Indications are collagen diseases with multiorgan involvement, where co-medications are frequently necessary. We describe a patient suffering from pancytopenia following a combination therapy of azathioprine and allopurinol because of lupus erythematodes and diabetic nephropathy with hyperuricemia.


Quantitative structure-property relationships of potentially bioactive fluoro phospho-silicate glasses.
In this work, the glass transition temperature and chemical durability of bioactive phospho-silicate glasses were experimentally determined and correlated to the structural descriptor Fnet derived from classical molecular dynamics simulations. The replacement of CaF2 for Na2O in the parent glass 45S5 enhances both chemical durability and density, while the replacement of CaF2 for CaO lowers chemical durability. The proposed descriptor, Fnet, provides satisfactorily correlations with glass transition temperature and chemical durability over a wide range of compositions.


Curcumin and Quercetin-Loaded Nanoemulsions: Physicochemical Compatibility Study and Validation of a Simultaneous Quantification Method.
Biphasic oil/water nanoemulsions have been proposed as delivery systems for the intranasal administration of curcumin (CUR) and quercetin (QU), due to their high drug entrapment efficiency, the possibility of simultaneous drug administration and protection of the encapsulated compounds from degradation. To better understand the physicochemical and biological performance of the selected formulation simultaneously co-encapsulating CUR and QU, a stability test of the compound mixture was firstly carried out using X-ray powder diffraction and thermal analyses, such as differential scanning calorimetry (DSC) and thermogravimetric analyses (TGA). The determination and quantification of the encapsulated active compounds were then carried out being an essential parameter for the development of innovative nanomedicines. Thus, a new HPLC-UV/Vis method for the simultaneous determination of CUR and QU in the nanoemulsions was developed and validated. The X-ray diffraction analyses demonstrated that no interaction between the mixture of active ingredients, if any, is strong enough to take place in the solid state. Moreover, the thermal analysis demonstrated that the CUR and QU are stable in the nanoemulsion production temperature range. The proposed analytical method for the simultaneous quantification of the two actives was selective and linear for both compounds in the range of 0.5-12.5 µg/mL (R2 > 0.9997), precise (RSD below 3%), robust and accurate (recovery 100 ± 5 %). The method was validated in accordance with ICH Q2 R1 "Validation of Analytical Procedures" and CDER-FDA "Validation of chromatographic methods" guideline. Furthermore, the low limit of detection (LOD 0.005 µg/mL for CUR and 0.14 µg/mL for QU) and the low limit of quantification (LOQ 0.017 µg/mL for CUR and 0.48 µg/mL for QU) of the method were suitable for the application to drug release and permeation studies planned for the development of the nanoemulsions. The method was then applied for the determination of nanoemulsions CUR and QU encapsulation efficiencies (> 99%), as well as for the stability studies of the two compounds in simulated biological fluids over time. The proposed method represents, to our knowledge, the only method for the simultaneous quantification of CUR and QU in nanoemulsions.


The social support experiences of major junior ice hockey players in a physically removed region of Canada.
The present report from a larger project overviews the sources and types of social support resourced by 10 major junior athletes while they performed out of one physically removed Canadian region. Retrospective interviews and content analysis were conducted during three stages (3, 3, and 4 respondents). The data were segmented into meaning units, coded into a hierarchy of themes, and verified by each respondent and an expert panel (former athlete, coach, parent of former athlete). The respondents sought out three types of social support from four different sources (providers) that were adapted to their remote location, including teachers and general community support. Implications are considered in terms of applied research and practice with aspiring adolescent athletes located in removed locations. Key pointsThe study extends knowledge about the sources and types of social support resourced by elite major junior ice hockey players located in one physically removed Canadian region.From the respondents' views, three types of social support were sought from four different sources.Implications are considered in terms of sport psychology research and applied practice.


Identifying spots in microarray images.
Microarray technology has provided a way to quantitate the simultaneous expression of a large number of genes. This approach is dependent on reproducible, accurate identification and quantitation of spot intensities. In this paper, clustering-based image segmentation is described to extract the target intensity of the microarray spots. While the technique is generic, its effectiveness on extracting spot intensities on arrays obtained from a two-color (Cy3/Cy5) experiment is discussed. The approximate boundaries of the spots are determined initially by manual alignment of rectangular grids. The pixel intensities of the image (I) inside a grid, is mapped onto a one-dimensional vector (v). The k-means clustering technique is applied to generate a binary partition of v. The median value of the pixel intensities inside each of the clusters for a given spot determines its foreground and the local background intensity. The difference in the median value of the foreground and the background intensity is the desired target intensity of the spot. The results are compared against those obtained using a region growing approach.


Biological activity of blackcurrant Extracts (Ribes nigrum L.) in relation to erythrocyte membranes.
Compounds contained in fruits and leaves of blackcurrant (Ribes nigrum L.) are known as agents acting preventively and therapeutically on the organism. The HPLC analysis showed they are rich in polyphenol anthocyanins in fruits and flavonoids in leaves, that have antioxidant activity and are beneficial for health. The aim of the research was to determine the effect of blackcurrant fruit and leaf extracts on the physical properties of the erythrocyte membranes and assess their antioxidant properties. The effect of the extracts on osmotic resistance, shape of erythrocytes and hemolytic and antioxidant activity of the extracts were examined with spectrophotometric methods. The FTIR investigation showed that extracts modify the erythrocyte membrane and protect it against free radicals induced by UV radiation. The results show that the extracts do not induce hemolysis and even protect erythrocytes against the harmful action of UVC radiation, while slightly strengthening the membrane and inducing echinocytes. The compounds contained in the extracts do not penetrate into the hydrophobic region, but bind to the membrane surface inducing small changes in the packing arrangement of the polar head groups of membrane lipids. The extracts have a high antioxidant activity. Their presence on the surface of the erythrocyte membrane entails protection against free radicals.


Innate cellular immunity and xenotransplantation.
This review assesses the recent progress in xenograft rejection by innate immune responses, with a focus on innate cellular xenoreactivity. Current literature was reviewed for new insights into the role of innate cellular immunity in xenograft rejection. Increasing evidence confirms that vigorous innate immune cell activation is accounted for by a combination of xenoantigen recognition by activating receptors, and incompatibility in inhibitory receptor-ligand interactions. Although both innate humoral and cellular xenoimmune responses are predominantly elicited by preformed and induced xenoreactive antibodies in nonhuman primates following porcine xenotransplantation, innate immune cells can also be activated by xenografts in the absence of antibodies. The latter antibody-independent response will likely persist in recipients even when adaptive xenoimmune responses are suppressed. In addition to xenograft rejection by recipient innate immune cells, phagocytic cells within liver xenografts are also deleterious to recipients by causing thrombocytopenia. Strategies of overcoming innate immune responses are required for successful clinical xenotransplantation. In addition to developing better immunosuppressive and tolerance induction protocols, endeavors towards further genetic modifications of porcine source animals are ultimately important for successful clinical xenotransplantation.


[The effect of nifedipine in hypertensive cardiopathy. An echocardiographic and electrocardiographic study].
To assess whether antihypertensive therapy by nifedipine can reverse left ventricular (LV) hypertrophy, 15 hypertensive patients, mean age 47 years, were serially studied during 12 months of treatment with nifedipine in slow release (40-60 mg/day), by recordings of blood pressure (BP), ECG and echocardiogram. Blood pressure decreased from 161 +/- 6/104 +/- 3 mmHg to 131 +/- 3/89 +/- 1 mmHg, p < 0.001, and this fall first became statistically significant at 1 month. From the hemodynamic view point, BP decreased for a reduction in total peripheral resistance. The Sokolow-Lyon voltage decreased significantly after 6 months (from 33.5 +/- 2.7 to 28.1 +/- 2.1 mm, p < 0.01) without further changes in the subsequent months. Left ventricular mass, by echocardiography, decreased after 6 months (from 189 +/- 15 to 176 +/- 13 g/m2, p < 0.05) and further after 12 months (169 +/- 13 g/m2, p < 0.001). The reduction in LV mass was secondary to the decrease in wall thickness, particularly in posterior wall thickness. No significant changes were observed in LV fractional shortening throughout the study. Thus, nifedipine was an effective antihypertensive agent and reverted LV hypertrophy secondary to arterial hypertension without impairment of LV systolic function.


[Identification of the origin of 7q+ marker chromosome in a mental retard patient].
The present chromosome-specific and chromosome-band-specific probe pools constructed by the technique of human chromosome microdissection and PCR were taken as painting probes. Using the forward chromosome painting and chromosome screening method, we had identified a chromosome additional fragment of a 7 q+ marker chromosome in a patient originated from 3 q 26-->3 qter, and ascertained the patient's karyotype was 46, XX, -7, + der (7) t (7;3) (7 pter-->7 q 32::3 q 26-->3 qter). Applying this strategy, we can identify the origin of marker chromosomes fastly and effectively.


Evidence that a "memory' for glucose metabolism desensitizes A-cell responsiveness in the perfused pancreas of the rat.
The effects of prior exposure to glucose or an inhibitor of glycolysis (iodoacetate) on A-cell sensitivity to glucose in the perfused pancreas of the rat was investigated. Inhibition of glucagon secretion by a high glucose concentration (22 mM) was attenuated and delayed when tested 20 min after a previous infusion with the same glucose concentration. Previously elevated glucose also delayed for 2 min a glucagon response to glucose omission whereas the total response was not significantly affected. During a 20 min perfusion with 1 mM iodoacetate, glucagon secretion increased and rates of secretion were further augmented after withdrawal of iodoacetate. When introduced 10 min after cessation of the iodoacetate pulse, 22 mM glucose failed to affect insulin or somatostatin release but, conversely, induced a profound decrease in glucagon secretion which was more marked than during control conditions. A-cell sensitivity to glucose is diminished and enhanced by prior fuel abundance and deprivation, respectively. Such effects could be due to persisting changes in A-cell energy availability rather than to pertubations in insulin or somatostatin secretion.


[Isolated stenosis of the anterior interventricular artery. Comparison of the effects of medical and surgical treatment (in a randomised series)].
Forty-five patients presenting with unstable angina having 70 p. 100 stenosis of the left anterior descending artery judged acceptable for coronary bypass surgery were randomly allocated, using a table of random numbers, for medical (21 patients) or surgical treatment (24 patients). There were no significant differences between the two groups with regards to age (53 +/- 10 years for the medical group; 55 +/- 9 years for the surgical group), the length of follow-up (55 +/- 26 vs 61 +/- 28 months), left ventricular end diastolic volumes (87 +/- 27 vs 84 +/- 18 ml/m2) or ejection fraction (62 +/- 8 vs 59 +/- 11 p. 100). There were no deaths in the medical group; two patients developed uncomplicated myocardial infarction 19 days and 7 months after coronary angiography, respectively. 5 patients had recurrent angina and were referred for surgery. This operation of second intention did not pose any special problems. 6 of the 14 patients with stenosis of the LAD before the origin of the first septal artery had complications (infarction in 1 case, recurrent angina in 5 cases). In the surgical group, 1 patient died in the immediate postoperative period, of resistant cardiac arrhythmia; 2 patients developed uncomplicated peroperative myocardial infarction; 21 patients had no complications at all. The surgical patients were heparinised in the immediate postoperative period and anticoagulant therapy was continued with oral vitamin K antagonists for 6 months to 1 year, followed in some cases, by platelet antiaggregant therapy. 20 patients in this group underwent maximal exercise stress testing which was negative in 19 cases.(ABSTRACT TRUNCATED AT 250 WORDS)


Expression of the VLDL receptor in endothelial cells.
In this article we describe the cellular distribution of the very low density lipoprotein receptor (VLDLR), a transmembrane protein that is expressed at high concentrations in skeletal muscle, heart, adipose tissue, and brain but in only trace amounts in the liver. Indirect immunofluorescence localization studies were performed in murine and bovine tissues using a rabbit polyclonal anti-human VLDLR antibody. Immunoreactive VLDLR protein was detected in the endothelium of capillaries and small arterioles but not in veins or venules of bovine skeletal muscle, heart, ovary, and brain. In the liver, there was intense staining of the capillaries and arterioles that supply the capsule and hepatic vessels but no staining of the sinusoidal surfaces. We failed to detect any signal from nonendothelial cells in the liver or peripheral organs. The VLDLR was also expressed at high levels on the endothelial surface of bovine coronary arteries; in contrast, little or no staining was seen in aortic endothelium. Antibody staining of cultured bovine coronary artery endothelial cells demonstrated punctate cell-surface staining, as well as staining of large and small cytoplasmic vesicles. This tissue and cell pattern of expression suggests that the VLDLR plays a role in the transport of VLDL or another plasma constituent from the vascular compartment to adjacent tissues.


Up-regulation of two distinct p53-DNA binding functions by covalent poly(ADP-ribosyl)ation: transactivating and single strand break sensing.
We used a [(32)P] p53 sequence-specific oligodeoxynucleotide and Electrophoretic-Mobility-Shift-Assays to monitor p53 DNA sequence-specific binding with p53-R267W, a nonbinding point mutant; and p53-Δ30, a deletion-mutant which lacks the carboxy-terminus that recognizes DNA-strand-breaks. Recombinant p53 and poly(ADP-ribose)polymerase-1 (PARP-1) were incubated with labeled βNAD(+) with/without DNA. The poly(ADP-ribosyl)ation of each protein increased with incubation-time and βNAD(+) and p53 concentration(s). Since p53-Δ30 was efficiently labeled, poly(ADP-ribosyl)ation target site(s) of wt-p53 must reside outside its carboxy-terminal-domain. The poly(ADP-ribosyl)ation of p53-Δ30 did not diminish its DNA binding; Instead, it enhanced DNA-sequence-specific-binding. Therefore, we conclude that DNA-sequence-specific-binding and DNA-nick-sensing of mutant-p53 are differentially regulated by poly(ADP-ribosyl)ation.


Serum markers of biological ageing provide long-term prediction of life expectancy-a longitudinal analysis in middle-aged and older German adults.
lifestyle behaviours and chronic co-morbidities are leading risk factors for premature mortality and collectively predict wide variability in individual life expectancy (LE). We investigated whether a pre-selected panel of five serum markers of biological ageing could improve predicting the long-term mortality risk and LE in middle-aged and older women and men. we conducted a case-cohort study (n = 5,789 among which there were 2,571 deaths) within the European Prospective Investigation into Cancer-Heidelberg cohort, a population cohort of middle-aged and older individuals, followed over a median duration of 18 years. Gompertz models were used to compute multi-adjusted associations of growth differentiation factor-15, N-terminal pro-brain natriuretic peptide, glycated haemoglobin A1c, C-reactive protein and cystatin-C with mortality risk. Areas under estimated Gompertz survival curves were used to estimate the LE of individuals using a model with lifestyle-related risk factors only (smoking history, body mass index, waist circumference, alcohol, physical inactivity, diabetes and hypertension), or with lifestyle factors plus the ageing-related markers. a model including only lifestyle-related factors predicted a LE difference of 16.8 [95% confidence interval: 15.9; 19.1] years in men and 9.87 [9.20; 13.1] years in women aged ≥60 years by comparing individuals in the highest versus the lowest quintiles of estimated mortality risk. Including the ageing-related biomarkers in the model increased these differences up to 22.7 [22.3; 26.9] years in men and 14.00 [12.9; 18.2] years in women. serum markers of ageing are potentially strong predictors for long-term mortality risk in a general population sample of older and middle-aged individuals and may help to identify individuals at higher risk of premature death, who could benefit from interventions to prevent further ageing-related health declines.


The C677T methylenetetrahydrofolate reductase polymorphism influences the homocysteine-lowering effect of hormone replacement therapy.
Elevated homocysteine is an independent risk factor for cardiovascular disease and has been associated with a common C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. Estrogen use has been shown to reduce homocysteine concentrations, suggesting that this might contribute to the cardiovascular benefit of hormone replacement therapy. We examined 90 postmenopausal women to determine if MTHFR genotype affected the response of homocysteine to hormone replacement therapy. Women with the TT genotype did not show decreased homocysteine in response to hormone replacement therapy as demonstrated for women with the CC genotype and may receive decreased cardiovascular benefits from hormone replacement therapy.


The kidney and hypertension: novel insights from transgenic models.
Despite decades of study, the pathogenesis of essential hypertension remains obscure, but the kidney appears to play a central role. Technology for manipulation of the mouse genome has been immensely valuable in dissecting pathways involved in blood pressure control. This review summarizes recent studies employing this technology to understand signaling pathways and specific cell lineages within the kidney that are involved in the regulation of sodium excretion impacting blood pressure homeostasis. We review a series of recent studies of regulatory pathways affecting sodium excretion by the kidney including the renin-angiotensin system, the mineralocorticoid receptor, the endothelin system, nitric oxide, and the with-no-lysine (K)/sterile 20-like kinase pathway. We have specifically highlighted studies utilizing transgenic mouse models, which provide a powerful mechanism for defining the role of proteins and pathways on sodium balance and blood pressure in the intact organism. These studies underscore the importance of the kidney in regulation of blood pressure and the pathogenesis of hypertension. Transgenic mouse models provide a powerful approach to identifying key cell lineages and molecular pathways causing hypertension. These pathways represent potential targets for novel antihypertensive therapies.


18FDG-PET imaging in canine lymphoma and cutaneous mast cell tumor.
Positron Emission Tomography (PET) using the glucose analog 2-deoxy-2-[18F]fluoro-D-glucose (18FDG) is a common imaging modality for diagnosis and management of many human malignancies. We evaluated 18FDG-PET in dogs with either multicentric lymphoma (LSA) or cutaneous mast cell tumor (MCT). A prototype large field-of-view PET scanner was used to collect whole-body images in nine dogs with LSA or MCT. Both tumors were characterized by avidity for 18FDG. In dogs with LSA, 18FDG-PET correctly identified involvement of superficial and internal lymph nodes, liver, and spleen. Repeated PET scans after induction chemotherapy demonstrated resolution of abnormal 18FDG uptake within these sites. In dogs with MCT, 18FDG-PET correctly identified MCT metastasis to regional lymph nodes in all dogs in which this was suspected or confirmed with cytology or biopsy before the PET scan. In two dogs, additional sites of mast cell disease were identified with 18FDG-PET that were undetected on physical examination and/or regional lymph node cytology. 18FDG-PET holds promise as a whole-body staging method for canine LSA and MCT.


Effect of morning exercise on counterregulatory responses to subsequent, afternoon exercise.
The aim of this study was to determine whether a bout of morning exercise (EXE(1)) can alter neuroendocrine and metabolic responses to subsequent afternoon exercise (EXE(2)) and whether these changes follow a gender-specific pattern. Sixteen healthy volunteers (8 men and 8 women, age 27 +/- 1 yr, body mass index 23 +/- 1 kg/m(2), maximal O(2) uptake 31 +/- 2 ml x kg(-1) x min(-1)) were studied after an overnight fast. EXE(1) and EXE(2) each consisted of 90 min of cycling on a stationary bike at 48 +/- 2% of maximal O(2) uptake separated by 3 h. To avoid the confounding effects of hypoglycemia and glycogen depletion, carbohydrate (1.5 g/kg body wt po) was given after EXE(1), and plasma glucose was maintained at euglycemia during both episodes of exercise by a modification of the glucose-clamp technique. Basal insulin levels (7 +/- 1 microU/ml) and exercise-induced insulin decreases (-3 microU/ml) were similar during EXE(1) and EXE(2). Plasma glucose was 5.2 +/- 0.1 and 5.2 +/- 0.1 mmol/l during EXE(1) and EXE(2), respectively. The glucose infusion rate needed to maintain euglycemia during the last 30 min of exercise was increased during EXE(2) compared with EXE(1) (32 +/- 4 vs. 7 +/- 2 micromol x kg(-1) x min(-1)). Although this increased need for exogenous glucose was similar in men and women, gender differences in counterregulatory responses were significant. Compared with EXE(1), epinephrine, norepinephrine, growth hormone, pancreatic polypeptide, and cortisol responses were blunted during EXE(2) in men, but neuroendocrine responses were preserved or increased in women. In summary, morning exercise significantly impaired the body's ability to maintain euglycemia during later exercise of similar intensity and duration. We conclude that antecedent exercise can significantly modify, in a gender-specific fashion, metabolic and neuroendocrine responses to subsequent exercise.


Purification and characterization of a phospholipase A2-IIA from common stingray (Dasyatis pastinaca) intestine.
A phospholipase A2 belonging to IIA group secretory PLA2 was isolated and purified to homogeneity from the intestine of common stingray (Dasyatis pastinaca) using acidic treatment (pH 1.5) and ammonium sulphate precipitation methods combined with single-column ion-exchange chromatography. The purified enzyme was found to be a glycosylated monomeric protein with a molecular mass of about 14 kDa. The stingray sPLA2-IIA had optimum activity at 45 degrees C, unlike known mammalian PLA2-IIAs, which show optimum activity at 37 degrees C. The purified enzyme exhibited a specific activity of 290 U/mg at optimal conditions (pH 9.5 and 45 degrees C) in the presence of 6 mM NaDC and 8 mM CaCl2 with egg yolk as substrate. The NH2-terminal sequence of the enzyme and some protein fragments obtained from its tryptic digestion were also determined. All sequences obtained were similar to those of sPLA2-IIA. The enzyme also showed good stability in the presence of organic solvents, acidic and alkaline pH media and high temperature conditions. Thus, the purified enzyme exhibited a number of unique and promising properties, making it a potential possible candidate for future applications in the treatment of phospholipid-rich industrial effluents and synthesis of useful preparations for the food production and processing industry.


Calceolariaflavida (Calceolariaceae) a new endemic species to central Chile.
A new species of Calceolariasect.Cheiloncos endemic to central Chile is described. A comparison with the morphologically similar species Calceolariaasperula and Calceolariapetioalaris is made, and a key as well as detailed images to differentiate them is provided. The species is only known from the Natural Sanctuary Cerro El Roble, which is part of the coastal mountain range of central Chile and can be considered as Critically Endangered (CR) under the IUCN categories and criteria.


Highly interwoven communities of a gene regulatory network unveil topologically important genes for maize seed development.
The complex interactions between transcription factors (TFs) and their target genes in a spatially and temporally specific manner are crucial to all cellular processes. Reconstruction of gene regulatory networks (GRNs) from gene expression profiles can help to decipher TF-gene regulations in a variety of contexts; however, the inevitable prediction errors of GRNs hinder optimal data mining of RNA-Seq transcriptome profiles. Here we perform an integrative study of Zea mays (maize) seed development in order to identify key genes in a complex developmental process. First, we reverse engineered a GRN from 78 maize seed transcriptome profiles. Then, we studied collective gene interaction patterns and uncovered highly interwoven network communities as the building blocks of the GRN. One community, composed of mostly unknown genes interacting with opaque2, brittle endosperm1 and shrunken2, contributes to seed phenotypes. Another community, composed mostly of genes expressed in the basal endosperm transfer layer, is responsible for nutrient transport. We further integrated our inferred GRN with gene expression patterns in different seed compartments and at various developmental stages and pathways. The integration facilitated a biological interpretation of the GRN. Our yeast one-hybrid assays verified six out of eight TF-promoter bindings in the reconstructed GRN. This study identified topologically important genes in interwoven network communities that may be crucial to maize seed development.


Intensive Care Unit Admission and Survival among Older Patients with Chronic Obstructive Pulmonary Disease, Heart Failure, or Myocardial Infarction.
Admission to an intensive care unit (ICU) may be beneficial to patients with pneumonia with uncertain ICU needs; however, evidence regarding the association between ICU admission and mortality for other common conditions is largely unknown. To estimate the relationship between ICU admission and outcomes for hospitalized patients with exacerbation of chronic obstructive pulmonary disease (COPD), exacerbation of heart failure (HF), or acute myocardial infarction (AMI). We performed a retrospective cohort study of all acute care hospitalizations from 2010 to 2012 for U.S. fee-for-service Medicare beneficiaries aged 65 years and older admitted with COPD exacerbation, HF exacerbation, or AMI. We used multivariable adjustment and instrumental variable analysis to assess each condition separately. The instrumental variable analysis used differential distance to a high ICU use hospital (defined separately for each condition) as an instrument for ICU admission to examine marginal patients whose likelihood of ICU admission depended on the hospital to which they were admitted. The primary outcome was 30-day mortality. Secondary outcomes included hospital costs. Among 1,555,798 Medicare beneficiaries with COPD exacerbation, HF exacerbation, or AMI, 486,272 (31%) were admitted to an ICU. The instrumental variable analysis found that ICU admission was not associated with significant differences in 30-day mortality for any condition. ICU admission was associated with significantly greater hospital costs for HF ($11,793 vs. $9,185, P < 0.001; absolute increase, $2,608 [95% confidence interval, $1,377-$3,840]) and AMI ($19,513 vs. $14,590, P < 0.001; absolute increase, $4,922 [95% confidence interval, $2,665-$7,180]), but not for COPD. ICU admission did not confer a survival benefit for patients with uncertain ICU needs hospitalized with COPD exacerbation, HF exacerbation, or AMI. These findings suggest that the ICU may be overused for some patients with these conditions. Identifying patients most likely to benefit from ICU admission may improve health care efficiency while reducing costs.


Simple pressure gauge for uranium hexafluoride.
A sensitive detector and pressure gauge for uranium hexafluoride in high-vacuum systems is described. Negative surface ionization of UF(6) occurs on ribbon filaments operated at temperatures too low for electron emission to be significant. The ion current measured on a cylindrical collector surrounding the filament assembly varies regularly with UF(6) pressure below 10(-3) Torr. Different filament materials are considered, including rhenium, thoriated tungsten, and platinum. Rhenium is found to be the most satisfactory material for operation of diode emitters as a pressure gauge. Gauge constants (in A Torr(-1)) are derived from comparing negative surface ionization currents with the response of a capacitance manometer and are shown to be independent of temperature within a reasonable operating range. The effects of exposing the rhenium filament to various gases is considered, and it is shown that brief exposure to acetylene substantially improves the operating characteristics of the gauge.


Preparation and evaluation of double-walled microparticles prepared with a modified water-in-oil-in-oil-in-water (w1/o/o/w3) method.
In this study, a modified water-in-oil-in-oil-in-water (w1/o/o/w3) method was developed to prepare double-walled microparticles containing ovalbumin (OVA). The microparticles were characterized with respect to their morphology, particle size, encapsulation efficiency, production yield, thermal properties and in vitro drug release. Microscopy observations clearly showed that microparticles have spherical shape and smooth surface. These microparticles were characterized to have double-walled structure, with a cavity in the centre. By using w1/o/o/w3 method, a significant decrease in mean particle size and a significant increase in encapsulation efficiency were obtained. The mean particle size and the encapsulation efficiency of double-walled microparticles were also affected by the changing amount of OVA and mass ratio of polymers. Microparticles prepared with two polymers exhibited a significantly lower initial burst release followed by sustained release compared to microparticles made from poly(d,l-lactide-co-glycolide) 50/50 only. It can be concluded that these microparticles can be a potential delivery system for therapeutic proteins.


Turnover of Phospholipids in Normal and Phosphorus-deficient Spirodela.
When (32)P(1) was supplied as a 15-minute pulse to normal Spirodela oligorrhiza plants, the first phospholipid to become fully labeled was phosphatidic acid. Phosphatidyl glycerol reached maximum labeling before the other major phospholipids. In phosphorus-deficient plants, however, phosphatidyl glycerol became labeled much more slowly than either phosphatidyl choline or phosphatidyl ethanolamine, and also the proportion of phosphatidyl glycerol present was smaller. Thus, phosphatidyl glycerol synthesis is sensitive to phosphorus deficiency. Since most of the phosphatidyl glycerol present in Spirodela was localized in the chloroplast, this effect appeared to be specifically one on chloroplast composition. The phosphorus-deficient chloroplast had a 60% lower phospholipid content and a normal phospholipid pattern, but the phospholipid which was present was apparently cycling much less rapidly. Zeatin, which ameliorates the visual symptoms of phosphorus deficiency, also reduces the effect of phosphorus deficiency on phospholipid synthesis.


Wearable Internet of Things - from human activity tracking to clinical integration.
Wearable devices for human activity tracking have been emerging rapidly. Most of them are capable of sending health statistics to smartphones, smartwatches or smart bands. However, they only provide the data for individual analysis and their data is not integrated into clinical practice. Leveraging on the Internet of Things (IoT), edge and cloud computing technologies, we propose an architecture which is capable of providing cloud based clinical services using human activity data. Such services could supplement the shortage of staff in primary healthcare centers thereby reducing the burden on healthcare service providers. The enormous amount of data created from such services could also be utilized for planning future therapies by studying recovery cycles of existing patients. We provide a prototype based on our architecture and discuss its salient features. We also provide use cases of our system in personalized and home based healthcare services. We propose an International Telecommunication Union based standardization (ITU-T) for our design and discuss future directions in wearable IoT.


Topical antimicrobials in the control of wound bioburden.
Bacterial colonization and infection are important factors in compromised wound healing, particularly in chronic wounds. Although "best practice" for controlling these factors currently is not defined, systemic antibiotics are generally accepted as the preferred choice for treating infection, provided ischemia does not reduce their bioavailability. However, widespread use of systemic and topical antibiotics is associated with the emergence of resistant bacterial strains such as methicillin-resistant Staphylococcus aureus. Colonization of wounds presents a double problem--potentially delayed healing and a potential source for cross-contamination. The judicious use of dressings, notably those containing certain antiseptic agents, can be a valuable option to control infection and promote healing. A review of the literature underscores the importance of considering the antiseptic route as part of a concerted approach to wound management and infection control.


Production of guard cell protoplasts from onion and tobacco.
Guard cell protoplasts (GCP) from young cotyledons of onion and tobacco were isolated in culture microchambers where optimal isolating and culture conditions could be determined in situ. The digestion course was quantified by following under polarized light the loss of.retardation of the birefringent cellulose of the guard cells. The assay showed that driselase has a 5-fold higher cellulytic activity than cellulysin. Driselase is, however, harmful to the GCP. Calcofluor staining was less adequate for establishing digestion courses because it increases sharply after exposing guard cells to cellulysin.Osmotic conditions were crucial for GCP survival. Onion guard cells fragment in the presence of strong plasmolyticum (>0.45 m) indicating cytoplasmic connections between neighboring guard cells and/or cytoplasmic attachments to the wall. Tobacco guard cells plasmolyzed with 0.7 m mannitol revealed several areas of strong attachment to the wall which resulted in severe damage to the cells. Healthy tobacco GCP are obtained by an initial digestion with 4% (w/v) cellulysin in 0.23 m mannitol for 2 to 3 hours followed by an increase in the osmoticum to 0.7 m to stabilize the forming protoplasts.Onion GCP were obtained by digesting paradermal slices with 4% (w/v) cellulysin in 0.23 m mannitol. Protoplasts can be osmotically released by replacing the enzyme solution with 0.23 m mannitol at early stages of digestion. They are also available after prolonged digestion (6-12 hours). Paradermal slices also yield mesophyll and epidermal cell protoplasts but they can be selectively washed away if a pure preparation of GCP is desired. Onion GCP have been kept alive in a simple culture solution for up to 10 days.


[Advances in molecular targeted therapy of thyroid carcinoma].
Thyroid carcinoma is the most common endocrine maligancy, and the worldwide incidence has been rising in recent years. Differentiated thyroid carcinoma is the most common thyroid malignancy, which include thyroid papillary carcinoma and follicular thyroid carcinoma, accounting for about 90 percent of thyroid carcinoma incidence. Currently, surgical treatment, iodine radiotherapy and TSH suppressive therapy are the commonly accepted effective treatments for differentiated thyroid carcinoma, and most patients can be cured. But there are still some patients not sensitive to the general treatments, who have lost the treatment of opportunity. Molecular targeted therapy is an agonistic or suppressive treatment for molecular biology targets of malignant tumor, and currently is a frontier research in the field of malignancy treatment. By retrieving and analyzing the related literature of molecular targeted therapy of thyroid carcinoma through PUBMED in the past 5 years, the article introduced the current status of molecular targeted therapy of thyroid carcinoma.


Plexiform schwannoma: an unusual clitoral mass.
Acquired clitoral enlargement is a rare condition resulting from a variety of etiologies, including tumors and excess androgens. Few cases of nonmalignant schwannoma, a benign tumor of the peripheral nerve sheath, have been reported in the literature as causes of clitoral enlargement in patients without known neurofibromatosis. These painless, slow-growing tumors rarely recur once excised. We present the initial investigation of a patient with a large clitoral schwannoma and subsequent treatment with partial vulvectomy. The workup, including advanced pelvic imaging for diagnosis and surgical planning, as well as removal of the clitoral tumor with preservation of functional tissue and restoration of normal vulvar anatomy despite a large excision, is demonstrated.


Highly potent and selective alphaVbeta3-receptor antagonists: solid-phase synthesis and SAR of 1-substituted 4-amino-1H-pyrimidin-2-ones.
Solid-phase synthesis and SAR of alpha(V)beta(3)-receptor antagonists based on a N(1)-substituted 4-amino-1H-pyrimidin-2-one scaffold are described. The most potent compounds exhibited IC(50) values towards alpha(V)beta(3) in the nano- to subnanomolar range and high selectivity versus related integrins like alpha(IIb)beta(3). For selected examples efficacy in functional cellular assays was demonstrated.


A selective drug delivery system based on phospholipid-type nanobubbles for lung cancer therapy.
Aim: To develop a micelle-type nanobubble decorated with fluorescein-5-isothiocyanate-conjugated transferrin, with encapsulation of paclitaxel (PTX@FT-NB) for lung cancer treatment. Materials & methods: PTX@FT-NBs were characterized to determine their physicochemical properties, structural stability and cytotoxicity. Lung cancer cell and mouse xenograft tumor models were used to evaluate the therapeutic effectiveness of PTX@FT-NB. Results: The PTX@FT-NBs not only showed selective targeting to lung cancer cells but also inhibited tumor growth significantly via paclitaxel release. Furthermore, paclitaxel-induced microtubule stabilization demonstrated the release of the drug from PTX@FT-NB in the targeted tumor cell both in vitro and in vivo. Conclusion: PTX@FT-NB has the potential as an anticancer nanocarrier against lung cancer cells because of its specific targeting and better drug delivery capacity.


A dose-dense short-term therapy for human immunodeficiency virus/acquired immunodeficiency syndrome patients with high-risk Burkitt lymphoma or high-grade B-cell lymphoma: safety and efficacy results of the "CARMEN" phase II trial.
A few prospective trials in HIV-positive patients with Burkitt lymphoma (BL) or high-grade B-cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose-dense, short-term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36-day polychemotherapy induction followed by high-dose cytarabine-based consolidation and response-tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)- conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV-positive adults (median age 42, range 26-58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double-hit lymphoma (n = 1) were enrolled. All patients had high-risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non-haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41-54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77-100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow-up of 55 (41-89) months, 14 patients are relapse-free and 15 are alive, with a five-year progression-free survival and an overall survival of 70% (95% CI = 60-80%) and 75% (95% CI = 66-84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability.


The experience of working with people that hoard: a Q-sort exploration.
The impact and burden of working with people that hoard is largely unexplored. To explore professionals' varied experiences of engagement and intervention with this client group. Five semi-structured interviews were initially conducted with professionals with detailed experience of working with people that hoard. A thematic analysis then identified key statements for a 49-item Q-set. The Q-sort was subsequently administered to public sector professionals with wide experience of working with people who hoard (N= 36; fire-fighters, environmental health, housing and mental health). Organizational support and job-related wellbeing measures (anxiety/contentment and depression/enthusiasm) were also administered. Factor analysis identified three distinct clusters (a) therapeutic and client focused (N = 15), (b) shocked and frustrated (N = 2) and (c) pragmatic and task focused (N = 5). Therapeutic and client focused professionals were significantly more content and enthusiastic regarding their work with clients with hoarding difficulties. Professionals experience and approach their work with people that hoard in discrete and dissimilar ways. Service delivery and training implications are considered.


Atomic force microscopy at ambient and liquid conditions with stiff sensors and small amplitudes.
We report on atomic force microscopy (AFM) in ambient and liquid environments with the qPlus sensor, a force sensor based on a quartz tuning fork with an all-electrical deflection measurement scheme. Small amplitudes, stiff sensors with bulk diamond tips and high Q values in air and liquid allow to obtain high resolution images. The noise sources in air and liquid are analyzed and compared for standard silicon cantilevers and qPlus sensors. First, epitaxial graphene was imaged in air, showing atomic steps with 3 Å height and ridges. As a second sample system, measurements on calcite (CaCO(3)) in liquids were performed in water and polyethylenglycol (PEG). We demonstrate high resolution images of steps in PEG on calcite and nanolithography processes, in particular with frequency-modulation AFM the controlled dissolution of calcite monolayers.


Comparative Insecticide Application Techniques (Micro-Sprinkler) Against Drosophila suzukii Matsumura (Diptera: Drosophilidae) in Highbush Blueberry.
Drosophila suzukii (Matsumura), spotted-wing drosophila, is a major pest in small fruit crops including highbush blueberry. Controlling D. suzukii is challenging and chemical control is the main method to manage D. suzukii populations. Growers have expressed interest in using micro-sprinklers as an alternative method to apply insecticides. The current study aimed to evaluate if insecticide applications using micro-sprinklers can be used as an alternative method to protect the fruit from D. suzukii egg-laying. Modeling was used as an additional tool to parameterize the relative insecticide efficacy on oviposition. Field measurements of different treatments were conducted over periods of eleven days on commercial-standard highbush blueberry. Cyantraniliprole and spinetoram were applied using both a micro-sprinkler and a backpack sprayer. Treatments of Chromobacterium subtsugae and zeta-cypermethrin were only applied using a backpack sprayer. Both cyantraniliprole and spinetoram treatments resulted in moderate suppression of D. suzukii egg-laying. No statistical significance was found between micro-sprinkler and backpack sprayer applications for these two insecticides. Zeta-cypermethrin treatments using a backpack sprayer resulted in the most significant suppression of D. suzukii egg-laying over eleven days, while C. subtsugae was less effective at preventing D. suzukii egg-laying. Modeling simulations estimate the impact of the control methods on D. suzukii populations dynamics and simulation outputs indicated that backpack sprayers reduced D. suzukii populations at more pronounced levels compared to micro-sprinkler applications. The present study indicates that there is an underlying value of micro-sprinkler systems as an alternative and rapid spray application technique to help suppress D. suzukii pest populations during high-pressure periods in highbush blueberry production.


The Role of NLRP3 Inflammasome in Alzheimer's Disease and Potential Therapeutic Targets.
Alzheimer's disease (AD) is a common age-related neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. The typical pathological characteristics of AD are extracellular senile plaques composed of amyloid ß (Aβ) protein, intracellular neurofibrillary tangles formed by the hyperphosphorylation of the microtubule-associated protein tau, and neuron loss. In the past hundred years, although human beings have invested a lot of manpower, material and financial resources, there is no widely recognized drug for the effective prevention and clinical cure of AD in the world so far. Therefore, evaluating and exploring new drug targets for AD treatment is an important topic. At present, researchers have not stopped exploring the pathogenesis of AD, and the views on the pathogenic factors of AD are constantly changing. Multiple evidence have confirmed that chronic neuroinflammation plays a crucial role in the pathogenesis of AD. In the field of neuroinflammation, the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a key molecular link in the AD neuroinflammatory pathway. Under the stimulation of Aβ oligomers and tau aggregates, it can lead to the assembly and activation of NLRP3 inflammasome in microglia and astrocytes in the brain, thereby causing caspase-1 activation and the secretion of IL-1β and IL-18, which ultimately triggers the pathophysiological changes and cognitive decline of AD. In this review, we summarize current literatures on the activation of NLRP3 inflammasome and activation-related regulation mechanisms, and discuss its possible roles in the pathogenesis of AD. Moreover, focusing on the NLRP3 inflammasome and combining with the upstream and downstream signaling pathway-related molecules of NLRP3 inflammasome as targets, we review the pharmacologically related targets and various methods to alleviate neuroinflammation by regulating the activation of NLRP3 inflammasome, which provides new ideas for the treatment of AD.


Synthesis of high-value 1,6-enynes by tandem fragmentation/olefination.
A tandem process provides high-value 1,6-enynes that are otherwise difficult to prepare. Two base-mediated reactions-fragmentation and olefination-are executed in a coordinated manner that is overall more efficient than either reaction on its own. The 1,6-enynes can be strategically employed in conjunction with carbocyclization to deliver important targets, as noted for reported syntheses of hirsutene and illudol.


[Arterial hypertension secondary to curable causes in adults].
EXTENSIVE AND COSTLY INVESTIGATIONS: Are not warranted in the vast majority of hypertensive patients. Characteristics identifying the patients at risk for secondary hypertension can be used to define the small percentage of patients with hypertension who require more extensive diagnostic testing and management of their condition. Exposure to certain medicines, foods or drugs may cause reversible rises in blood pressure. Renovascular and adrenal diseases cause curable forms of hypertension. IN MANY CASES, THE PATIENT'S HISTORY: Examination and simple tests can detect such exposures and disorders. Checking for secondary hypertension is therefore an early step required for the management of all patients with hypertension, provided it is based on clinical signs and inexpensive tests. This primary screening cannot exclude the possibility of renovascular or adrenal disease in a small number of asymptomatic patients. The risk of missing a diagnosis is acceptable provided that blood pressure is normalized by non-specific antihypertensive treatment. However, more extensive etiologic investigation is required in patients who subsequently develop resistant hypertension. This secondary screening requires imaging and biochemical tests that are not required for primary screening. CORRECTION OF THE CAUSES: Of secondary forms of hypertension may restore blood pressure to normal. The patient's age affects the reversibility of renovascular and adrenal hypertension after etiologic treatment: the younger the patient, the higher the probability of blood pressure normalization.


Role of biofilm in Staphylococcus aureus and Staphylococcus epidermidis ventricular assist device driveline infections.
Infections, especially those involving drivelines, are among the most serious complications that follow ventricular assist device implantation. Staphylococci are the most common causes of these infections. Once driveline infections are established, they can remain localized or progress as an ascending infection to cause metastatic seeding of other tissue sites. Although elaboration of biofilm appears to be critical in prosthetic device infections, its role as a facilitator of staphylococcal infection and migration along the driveline and other prosthetic devices is unclear. A murine model of driveline infection was used to investigate staphylococcal migration along the driveline. A biofilm-producing strain of Staphylococcus epidermidis and a Staphylococcus aureus strain and its intercellular adhesion gene cluster (ica)-negative (biofilm-deficient) isogenic mutant were used in these studies. Bacterial density on the driveline and the underlying tissue was measured over time. Scanning electron microscopy was used to examine the morphology of S epidermidis biofilm formation as the infection progressed. The biofilm-deficient S aureus mutant was less effective at infecting and migrating along the driveline than the wild-type strain over time. However, the ica mutation had no effect on the ability of the strain to infect underlying tissue. S aureus exhibited more rapid migration than S epidermidis. Scanning electron microscopy revealed the deposition of host matrix on the Dacron material after implantation. This was followed by elaboration of a bacterial biofilm that correlated with more rapid migration along the driveline. Biofilm formation is a critical virulence determinant that facilitates the progression of drivelines infections.


Spatiotemporal Signatures of Lexical-Semantic Prediction.
Although there is broad agreement that top-down expectations can facilitate lexical-semantic processing, the mechanisms driving these effects are still unclear. In particular, while previous electroencephalography (EEG) research has demonstrated a reduction in the N400 response to words in a supportive context, it is often challenging to dissociate facilitation due to bottom-up spreading activation from facilitation due to top-down expectations. The goal of the current study was to specifically determine the cortical areas associated with facilitation due to top-down prediction, using magnetoencephalography (MEG) recordings supplemented by EEG and functional magnetic resonance imaging (fMRI) in a semantic priming paradigm. In order to modulate expectation processes while holding context constant, we manipulated the proportion of related pairs across 2 blocks (10 and 50% related). Event-related potential results demonstrated a larger N400 reduction when a related word was predicted, and MEG source localization of activity in this time-window (350-450 ms) localized the differential responses to left anterior temporal cortex. fMRI data from the same participants support the MEG localization, showing contextual facilitation in left anterior superior temporal gyrus for the high expectation block only. Together, these results provide strong evidence that facilitatory effects of lexical-semantic prediction on the electrophysiological response 350-450 ms postonset reflect modulation of activity in left anterior temporal cortex.


αA-Crystallin associates with α6 integrin receptor complexes and regulates cellular signaling.
α-Crystallins are small heat-shock proteins important to lens transparency that provide the lens with its refractive properties. In their role as molecular chaperones, these crystallins also prevent protein aggregation, affect cytoskeletal remodeling, enhance resistance to cell stress, and provide lens cells with protection against apoptosis. While many of the functions assigned to αA-crystallin are attributable to its presence in the cytoplasm of lens cells, αA-crystallin also has been detected at the lens plasma membrane. However, how αA-crystallin becomes linked to the plasma membrane or what its functions are at this site has remained unknown. In this study, we examined the mechanisms by which αA-crystallin becomes associated with the lens membrane, focusing specifically on its interaction with membrane receptors, and the differentiation-specificity of these interactions. We also determined how the long-term absence of αA-crystallin alters receptor-linked signaling pathways. αA-crystallin association with membrane receptors was determined by co-immunoprecipitation analysis; its membrane localization was examined by confocal imaging; and the effect of αA-crystallin loss-of-function on the activation state of signaling molecules in pathways linked to membrane receptors was determined by immunoblot analysis. The results show that, in lens epithelial cells, plasma membrane αA-crystallin was primarily localized to apicolateral borders, reflecting the association of αA-crystallin with E-cadherin complexes. These studies also provide the first evidence that αA-crystallin maintained its association with the plasma membrane in lens cortical fiber cells, where it was localized to lateral interfaces, and further show that this association was mediated, in part, by αA-crystallin interaction with α6 integrin receptor complexes. We report that the absence of αA-crystallin led to constitutive activation of the stress kinases p38 and JNK, classical inducers of apoptotic cell death, and the loss of the phospho-Bad pro-survival signal, effects that were greatest in differentiating lens fiber cells. Concurrent with this, activation of FAK and ERK kinases was increased, demonstrating that these receptor-linked pathways also were dysregulated in the absence of αA-crystallin. These data link αA-crystallin plasma membrane association to its differentiation-state-specific interaction with E-cadherin and α6 integrin receptor complexes. The changes in cell signaling in αA-crystallin-null lenses suggest that dysregulation of receptor-linked cell-signaling pathways that accompany the failure of αA-crystallin to associate with membrane receptors may be responsible for the induction of apoptosis. The observed changes in lens cell signaling likely reflect long-term functional adaptations to the absence of the αA-crystallin chaperone/small heat-shock protein.


Identification of the absorbed components and metabolites in rat plasma after oral administration of Rhizoma Chuanxiong decoction by HPLC-ESI-MS/MS.
An HPLC-ESI-MS/MS method was established to identify the absorbed components and metabolites in rat plasma after oral administration of Rhizoma Chuanxiong decoction (RCD), a well-known traditional Chinese medicine. By comparing the extracted ion chromatograms (EICs) obtained from dosed rat plasma, blank rat plasma and RCD, a total of 25 compounds were detected in dosed rat plasma. Among them, 13 compounds were absorbed into rat plasma in prototype and identified as ferulic acid, senkyunolide J, senkyunolide I, senkyunolide D or 4,7-dihydroxy-3-butylphthalide, senkyunolide F, senkyunolide M, senkyunolide Q, senkyunolide A, E-butylidenephthalide, E-ligustilide, neocnidilide, Z-ligustilide, levistolide A, according to the retention times, UV, MS, MS/MS spectra. In addition, 12 conjugated metabolites including 6 senkyunolide I-related metabolites, 4 senkyunolide J-related metabolites and 2 butylidenephthalide-related metabolites were also detected and identified by comparing their MS, MS/MS spectra with that of corresponding original components. Conjugated with glutathione, cysteine, glucuronic acid and sulphuric acid were the main metabolic reactions of phthalides. Finally the in vivo metabolic pathways of chemical constituents of Chuanxiong in rat plasma were proposed in this study.


First report of Anthracnose on 'Purple Dream' Solanum melongena in Malaysia Caused by Colletotrichum siamense.
'Purple Dream' eggplant (Solanum melongena) is widely grown for its edible fruits in Malaysia. In July 2021, anthracnose symptoms were observed on fruit with a disease severity of approximately 80% and an incidence of 10% in a field (14.6 m2) (5°56'50.9"N, 116°04'31.9"E) located in the Penampang district of Sabah province. The symptoms initially appeared as irregular light brown spots. As the disease progressed, the spots enlarged and merged into extensive lesion patches that appeared in concentric circles. The symptomatic fruit tissues (5 x 5 mm) were surface sterilized based on Khoo et al. (2022), and plated onto potato dextrose agar (PDA), and incubated at 25°C in the dark. Colonies with gray-white fluffy mycelia developed after 7 days, and the reverse of the colonies was dark brown. A representative isolate named Penampang was characterized morphologically and molecularly. The conidia were one-celled, cylindrical, blunt at the ends, hyaline, smooth, and measured 13.3 to 16.1 x 3.9 to 6.0 µm (n= 20). Appressoria ranged in size from 7.6 to 9.3 m x 5.5 to 6.6 µm (n= 20) and were spherical to irregular in shape and dark brown in colour. Genomic DNA was extracted from fresh mycelia of isolate Penampang based on Khoo et al. (2021) and Khoo et al. (2022). ITS1/ITS4, CL1C/CL2C, ACT-512F/ACT-783R, CHS-79F/CHS-354R, and GDF1/GDR1 primer pairs were used to amplify the isolate's internal transcribed spacer region (ITS), and partial calmodulin (CAL), actin (ACT), chitin synthase (CHS-1), and glyceraldehyde-3-phosphate dehydrogenase genes (GAPDH) (Weir et al. 2012). PCR products were sequenced by Apical Scientific Sdn. Bhd. (Selangor, Malaysia). Sequences were deposited in GenBank under the accession numbers OL957466 (ITS), OL953035 (CAL), OL953032 (ACT), OL953038 (CHS-1), and OL953041 (GAPDH). They were 99% to 100% identical to the Colletotrichum ti ITS (NR_120143) (515 bp out of 519 bp), and C. siamense CAL (JX009714) (729 bp out of 731 bp), ACT (JX009518) (282 bp out of 282 bp), CHS-1 (JX009865) (299 bp out of 299 bp), and GAPDH (JX009924) (276 bp out of 277 bp) sequences. ITS sequences do not reliably resolve relationships within the C. gloeosporioides complex (Weir et al. 2012). The phylogenetic maximum likelihood analysis using the combined ITS, CAL, ACT, CHS-1, and GAPDH sequences indicated that the isolate was part of the C. siamense clade (100% bootstrap value) that also contained the type isolate ICMP 18578 of this species. Morphological and molecular characterization matched the description of C. siamense (Huang et al. 2021; Ismail et al. 2021). Koch's postulates were performed similarly as described by Chai et al. (2017) but using spray-inoculation (108 spores/ml) of three healthy 'Purple Dream' eggplant fruit with isolate Penampang. Water was sprayed on three additional fruits that served as controls. All the fruits were incubated at 25°C and less than 90% relative humidity. Symptoms similar to those observed in the field developed 5 days after inoculation. No symptoms occurred on controls. The experiment was repeated two more times. The reisolated fungi were identical to the pathogen morphologically and molecularly. To our knowledge, this is the first report of C. siamense causing anthracnose on fruit of 'Purple Dream' S. melongena in Malaysia as well as worldwide. Our findings expand the host range of C. siamense and indicate that the pathogen could potentially limit 'Purple Dream' eggplant production in Malaysia.


Current Knowledge on Mechanisms Preventing Photosynthesis Redox Imbalance in Plants.
Photosynthesis includes a set of redox reactions that are the source of reducing power and energy for the assimilation of inorganic carbon, nitrogen and sulphur, thus generating organic compounds, and oxygen, which supports life on Earth. As sessile organisms, plants have to face continuous changes in environmental conditions and need to adjust the photosynthetic electron transport to prevent the accumulation of damaging oxygen by-products. The balance between photosynthetic cyclic and linear electron flows allows for the maintenance of a proper NADPH/ATP ratio that is adapted to the plant's needs. In addition, different mechanisms to dissipate excess energy operate in plants to protect and optimise photosynthesis under adverse conditions. Recent reports show an important role of redox-based dithiol-disulphide interchanges, mediated both by classical and atypical chloroplast thioredoxins (TRXs), in the control of these photoprotective mechanisms. Moreover, membrane-anchored TRX-like proteins, such as HCF164, which transfer electrons from stromal TRXs to the thylakoid lumen, play a key role in the regulation of lumenal targets depending on the stromal redox poise. Interestingly, not all photoprotective players were reported to be under the control of TRXs. In this review, we discuss recent findings regarding the mechanisms that allow an appropriate electron flux to avoid the detrimental consequences of photosynthesis redox imbalances.


Effects of different expiratory maneuvers on inspiratory muscle force output.
We assessed the effects of two different expiratory maneuvers (fast [F] or slow [S]) on the ability of normal subjects (n = 12, age 35 +/- 6 yr) to generate maximal inspiratory pressures and maximal inspiratory flows near residual volume (RV). With the F maneuver, the subject exhaled rapidly to RV and immediately performed a maximal inspiratory effort, whereas with the S maneuver the subject exhaled slowly to RV, paused for 4 to 6 s at RV, and then inspired forcefully. Maximal static inspiratory pressure against an occluded airway (PImax), and maximal dynamic inspiratory pressure (PIdyn) and maximal inspiratory flow (V Imax) with no added resistance, as well as the electromyographic activity of the parasternal muscles, were measured during each maneuver. Both maneuvers were initiated from TLC and were performed randomly. In comparison with the S maneuver, the F maneuver yielded values of higher (mean +/- SE) PImax (148 +/- 5 cm H2O versus 135 +/- 7 cm H2O, p < 0.05), PIdyn (33 +/- 2 cm H2O versus 28 +/- 2 cm H2O, p < 0.05), and V Imax (12.3 +/- 0.4 L/s versus 11.4 +/- 0.6 L/s, p < 0.05). In addition, the rate of rise of PImax, the rate of rise of PIdyn, and the integrated peak electromyographic activity of the parasternal muscles were significantly greater with the F than with the S maneuver, suggesting greater inspiratory muscle (IM) activation. The enhanced IM activation may be related to a specific inspiratory-expiratory muscle interaction similar to the agonist-antagonist interactions described for a pair of skeletal muscles.


Deconfinement transition in three-dimensional compact U(1) gauge theories coupled to matter fields.
It is shown that permanent confinement in three-dimensional compact U(1) gauge theory can be destroyed by matter fields in a deconfinement transition. This follows from a nontrivial infrared fixed point caused by matter, and an anomalous scaling dimension of the gauge field. This leads to a logarithmic interaction between the defects of the gauge fields, which form a gas of magnetic monopoles. For logarithmic interactions, the original electric charges are unconfined. The confined phase, which is permanent in the absence of matter fields, is reached at a critical electric charge, where the interaction between magnetic charges is screened by a pair-unbinding in a Kosterlitz-Thouless-like phase transition.


Scotopic foveal afterimages.
If, after being in the dark for many minutes, one views an extended surface under dim (scotopic) illumination, one fails to see any hint of the dark spot at the center of gaze that might be expected from the absence of rods in the fovea. Here we report that, if the surface is suddenly completely darkened, one sees for a few seconds a relatively bright spot, about 2 deg in size, at the point of fixation. If the surface is now restored to its original brightness, a dark spot of similar size appears where one fixates, that again lasts for several seconds. All this can be observed with no elaborate apparatus.


Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists.
We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A1AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarilly evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure-activity and structure-selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R4 and R6 of the pyrimidine core but most importantly the prominent role to the unprecedented A1AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure-activity relationship trends on both A1 and A2AARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.


Effect of solvent and temperature on the size distribution of casein micelles measured by dynamic light scattering.
The objectives of this study were to investigate the effect of the solvent on the accuracy of casein micelle particle size determination by dynamic light scattering (DLS) at different temperatures and to establish a clear protocol for these measurements. Dynamic light scattering analyses were performed at 6, 20, and 50 degrees C using a 90Plus Nanoparticle Size Analyzer (Brookhaven Instruments, Holtsville, NY). Raw and pasteurized skim milk were used as sources of casein micelles. Simulated milk ultrafiltrate, ultrafiltered water, and permeate obtained by ultrafiltration of skim milk using a 10-kDa cutoff membrane were used as solvents. The pH, ionic concentration, refractive index, and viscosity of all solvents were determined. The solvents were evaluated by DLS to ensure that they did not have a significant influence on the results of the particle size measurements. Experimental protocols were developed for accurate measurement of particle sizes in all solvents and experimental conditions. All measurements had good reproducibility, with coefficients of variation below 5%. Both the solvent and the temperature had a significant effect on the measured effective diameter of the casein micelles. When ultrafiltered permeate was used as a solvent, the particle size and polydispersity of casein micelles decreased as temperature increased. The effective diameter of casein micelles from raw skim milk diluted with ultrafiltered permeate was 176.4 +/- 5.3 nm at 6 degrees C, 177.4 +/- 1.9 nm at 20 degrees C, and 137.3 +/- 2.7 nm at 50 degrees C. This trend was justified by the increased strength of hydrophobic bonds with increasing temperature. Overall, the results of this study suggest that the most suitable solvent for the DLS analyses of casein micelles was casein-depleted ultrafiltered permeate. Dilution with water led to micelle dissociation, which significantly affected the DLS measurements, especially at 6 and 20 degrees C. Simulated milk ultrafiltrate seemed to give accurate results only at 20 degrees C. Results obtained in simulated milk ultrafiltrate at 6 degrees C could not be explained based on the known effects of temperature on the casein micelle, whereas at 50 degrees C, precipitation of amorphous calcium phosphate affected the DLS measurement.


Frozen section of lung specimens.
Frozen section of lung tissue is performed to guide the surgeon in subsequent therapy. Practical experience in frozen section of the lung was reviewed in the medical literature and from the records of several academic hospitals. Most frozen sections of the lung are performed for evaluation of a solitary nodule, a mass, or the surgical margins of a resection. Frozen section may also be used to assess the adequacy of a lung wedge biopsy taken for later diagnosis of a condition. The pathologic evaluation of intraoperative pulmonary lesions is indicated for the differential diagnosis of pulmonary nodules and masses, both neoplastic and nonneoplastic, surgical resection margins, and mediastinal lymph nodes. The most worrisome pitfalls involve differentiating benign reactive atypia from malignancy on frozen section.


N-Glycosylation of Gel1 or Gel2 is vital for cell wall β-glucan synthesis in Aspergillus fumigatus.
Fungal cell wall is a dynamic structure that communicates with and protects the cell from outside stress. In Aspergillus fumigatus, the cell wall β-glucans are mainly elongated by β-1,3-glucanosyltransferases Gels, which consist of seven family members (Gel1-7) utilizing β-1,3-glucan chains as substrates. Previously, we have shown that the mutant deficient of N-glycan processing displays a reduction in the cell wall β-glucans, suggesting that N-glycosylation is required for the proper function of β-1,3-glucanosyltransferase. To verify this hypothesis, in this study, the gene encoding β-1,3-glucanosyltransferase Gel1 or Gel2 was deleted in the Δcwh41 mutant to construct a double-mutant Δgel1Δcwh41 or Δgel2Δcwh41. The growth phenotypes of both double mutants were similar to the single-mutant Δcwh41, suggesting that Gel1 and Gel2 are proteins that are mainly affected by deficient N-glycan processing in Δcwh41. Furthermore, the mutant Δgel1(Gel1-NM) or Δgel2(Gel2-NM), in which all potential N-glycosylation sites on Gel1 or Gel2 were removed by site-directed mutagenesis, showed phenotypes similar to the single-mutant Δgel1 or Δgel2. Biochemical analysis revealed that N-glycosylation was essential for the function of Gel1 or Gel2 and thus required for β-glucan synthesis in A. fumigatus.


In the shadow of "death with dignity": medicine and cultural quandaries of the vegetative state.
In this paper I address one site of technological development and cultural production, the permanent or persistent comatose condition and the institutions and practices that enable this life form to exist. As with other medical sites of ambiguity and change under recent scrutiny by anthropologists, the locations in which comatose bodies thrive are those in which the routinization of technology use in the clinic and a legitimating social and economic context come together to permit and create a further remapping of the notions of "life" and "person." I explore the new forms of knowledge, practice, and the body that are created at this site and how they are negotiated, and I discuss how the shifting understanding of "culture" and "nature" both have an impact on and are informed by American quandaries about approaching death. I argue that beings who are neither fully alive, biologically dead, nor "naturally" self-regulating, yet who are sustained by modern medical practice, destabilize the existing social order in ways that are different from other hybrid forms.


Molecular Mechanisms of Bone Metastasis: Which Targets Came from the Bench to the Bedside?
Bone metastases ultimately result from a complex interaction between cancer cells and bone microenvironment. However, prior to the colonization of the bone, cancer cells must succeed through a series of steps that will allow them to detach from the primary tumor, enter into circulation, recognize and adhere to specific endothelium, and overcome dormancy. We now know that as important as the metastatic cascade, tumor cells prime the secondary organ microenvironment prior to their arrival, reflecting the existence of specific metastasis-initiating cells in the primary tumor and circulating osteotropic factors. The deep comprehension of the molecular mechanisms of bone metastases may allow the future development of specific anti-tumoral therapies, but so far the approved and effective therapies for bone metastatic disease are mostly based in bone-targeted agents, like bisphosphonates, denosumab and, for prostate cancer, radium-223. Bisphosphonates and denosumab have proven to be effective in blocking bone resorption and decreasing morbidity; furthermore, in the adjuvant setting, these agents can decrease bone relapse after breast cancer surgery in postmenopausal women. In this review, we will present and discuss some examples of applied knowledge from the bench to the bed side in the field of bone metastasis.


Resonance Fluorescence of an InGaAs Quantum Dot in a Planar Cavity Using Orthogonal Excitation and Detection.
The ability to perform simultaneous resonant excitation and fluorescence detection is important for quantum optical measurements of quantum dots (QDs). Resonant excitation without fluorescence detection - for example, a differential transmission measurement - can determine some properties of the emitting system, but does not allow applications or measurements based on the emitted photons. For example, the measurement of photon correlations, observation of the Mollow triplet, and realization of single photon sources all require collection of the fluorescence. Incoherent excitation with fluorescence detection - for example, above band-gap excitation - can be used to create single photon sources, but the disturbance of the environment due to the excitation reduces the indistinguishability of the photons. Single photon sources based on QDs will have to be resonantly excited to have high photon indistinguishability, and simultaneous collection of the photons will be necessary to make use of them. We demonstrate a method to resonantly excite a single QD embedded in a planar cavity by coupling the excitation beam into this cavity from the cleaved face of the sample while collecting the fluorescence along the sample's surface normal direction. By carefully matching the excitation beam to the waveguide mode of the cavity, the excitation light can couple into the cavity and interact with the QD. The scattered photons can couple to the Fabry-Perot mode of the cavity and escape in the surface normal direction. This method allows complete freedom in the detection polarization, but the excitation polarization is restricted by the propagation direction of the excitation beam. The fluorescence from the wetting layer provides a guide to align the collection path with respect to the excitation beam. The orthogonality of the excitation and detection modes enables resonant excitation of a single QD with negligible laser scattering background.


Spectroscopic Ellipsometry and Quartz Crystal Microbalance with Dissipation for the Assessment of Polymer Layers and for the Application in Biosensing.
Polymers represent materials that are applied in almost all areas of modern life, therefore, the characterization of polymer layers using different methods is of great importance. In this review, the main attention is dedicated to the non-invasive and label-free optical and acoustic methods, namely spectroscopic ellipsometry (SE) and quartz crystal microbalance with dissipation (QCM-D). The specific advantages of these techniques applied for in situ monitoring of polymer layer formation and characterization, biomolecule immobilization, and registration of specific interactions were summarized and discussed. In addition, the exceptional benefits and future perspectives of combined spectroscopic ellipsometry and QCM-D (SE/QCM-D) in one measurement are overviewed. Recent advances in the discussed area allow us to conclude that especially significant breakthroughs are foreseen in the complementary application of both QCM-D and SE techniques for the investigation of polymer structure and assessment of the interaction between biomolecules such as antigens and antibodies, receptors and ligands, and complementary DNA strands.


Sleep deprivation, sleep apnea and cardiovascular diseases.
Sleep dramatically influences cardiovascular regulation. Changes in sleep duration or quality as seen in sleep disorders may prevent blood pressure to fall during sleep as expected in human physiology. This supports the increased prevalence of hypertension and drug-resistant hypertension in those with sleep loss. Other cardiovascular outcomes i.e. coronary lesions seem to be associated with sleep duration. Systemic inflammation, oxidative stress and endothelial dysfunction seem to be associated with both sleep loss and sleep disorders. The most critical example is Obstructive Sleep Apnea (OSA). Sympathetic activation, oxidative stress and systemic inflammation are the main intermediary mechanisms associated with sleep apnea and intermittent hypoxia. There are now convincing data regarding the associations between hypertension, arrhythmias, stroke, coronary heart disease, increased cardiovascular mortality and OSA. There are also data in OSA and in animal models supporting the link between sleep apnea and atherosclerosis and dysmetabolism. Whether treating sleep apnea enables the reversal of chronic cardiovascular and metabolic consequences of OSA, remains to be studied in adequately designed studies, particularly in comparison with usual treatment strategies.


Nifedipine solid dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend for controlled drug delivery. Effect of drug loading on release kinetics.
In order to elucidate the controlled-release mechanism of a poorly water-soluble drug from microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend prepared by a phase-separation method, nifedipine-loaded microparticles with different levels of drug loading were evaluated by micromeritic properties, drug physical state, matrix internal structure, drug dissolution, and release modeling. Drug release study indicated that nifedipine release from the microparticles followed the Fickian diffusion mechanism, which supported the study hypothesis that as a result of formation of a nifedipine molecular dispersion, nifedipine dissolution inside the matrix was no longer the rate-limiting step for drug release, and the drug diffusion in matrix became the slowest step instead. Moreover, study results indicated that even though drug loading did not significantly affect the microparticle size distribution and morphology, nifedipine release rate from those microparticles was more or less influenced by the level of drug loading, depending on matrix formulation. At lower levels of drug loading, nifedipine release was well described by the Baker and Lonsdale's matrix diffusion model for microspheres containing dissolved drug and nifedipine had a plasticizing effect on the polymers that caused an increase in drug effective diffusion coefficient with increasing drug loading. However, at higher levels of drug loading, probably due to formation of solid nifedipine domains in microparticles, a change in the release kinetics was observed.