Comparative study of neutral proteoglycanase activity by growth plate zone.
The degradation of proteoglycans has been considered an essential step in the process of endochondral ossification. Neutral proteases, described in the growth plate, have been implicated in this process. If these neutral proteases are important in the endochondral process, their level of activity should be highest at the point where calcification is occurring. This study measures neutral protease activity with a quantitative viscometric assay throughout all zones of the bovine growth plate. The results demonstrate that the enzyme is present throughout all zones of the growth plate. However, enzyme levels in the lower hypertrophic and calcifying zones are significantly higher than anywhere else. The enzymes came from the cartilage cells and not from the invading vasculature. This implied proof of the role of neutral proteases in the endochondral process implies that by inhibiting this class of enzymes, one should be able to block endochondral ossification.


The time to initiate trophic feeding and its predictors among preterm neonate admitted to neonatal intensive care unit, Multicenter study, Northwest Ethiopia.
Trophic feeding is a small volume, hypo-caloric feeding, gut priming or minimal enteral feeding acclimate the immature gut of enteral fasting preterm neonates. Delayed starting of trophic feeding had resulted in short and long-term physical and neurological sequels. The current study aimed to estimate the time to initiate trophic feeding and its predictors among preterm neonates admitted in the neonatal intensive care unit of Debre Markos, Felege Hiwot, and Tibebe Ghion comprehensive specialized hospitals. An institutional-based prospective follow-up study was conducted among 210 neonates. The data were collected with interview and chart review, entered into Epi data 3.1 and exported to Stata 14.1 for analysis. Multivariable Cox regression models were fitted to identify predictors of time to initiate trophic feeding. A total of 210 neonates were followed for 10136 person-hours of risk time and 191 (90.95%) of neonates were started trophic feeding. The overall incidence of starting trophic feeding was 2 per 100 (95% CI: 2, 2.2) person-hours observations. The median survival time was 42 hours (95% CI: 36, 48). APGAR- score at first minute <7 (AHR: 0.6, 95% CI: 0.44, 0.82), gestational age of <34 weeks (AHR: 0.69, 95% CI: 0.5, 0.94), presence of respiratory distress syndrome (AHR: 0.5, 95% CI: 0.36, 0.68), presence of hemodynamic instability (AHR: 0.37, 95% CI: 0.24, 0.57), presence of perinatal asphyxia (AHR: 0.63, 95% CI: 0.44, 0.89), cesarean section delivery (AHR: 0.63, 95% CI: 0.44, 89) and being delivered within the study hospitals (AHR: 0.54, 95% CI: 0.39, 0.74) were found to be statistically significant predictors of time to initiate trophic feeding. There was a significant delay to initiate trophic feeding in the studied hospitals. Gestational age of below 34 weeks, APGAR-score of less than seven, out-born delivery, cesarean delivery, presence of respiratory distress syndrome; perinatal asphyxia, and hemodynamic instability were predictors of delay in starting of trophic feeding. Standardized feeding guideline has to be implemented to overcome delays in enteral feeding initiation.


The past, present, and future of patient-reported outcomes in oncology.
Patient-reported outcomes capture a unique and important perspective of oncology therapy. Surveys to properly capture patient-reported outcome measures have been under development for more than 2 decades. More recent efforts to understand the clinical significance of patient-reported outcomes, called performance measures, are underway. Patient-reported outcomes can be used in a variety of ways, including therapy decisions for an individual patient, payment for treatment, research into disease progression, or new drug development. Technology has already enabled electronic systems to capture and search patient-reported outcomes and in the future will assist in capturing everyday activities, which, in combination with improved informatics to sort the meaningful and actionable information, will reduce the time commitment for both patients and providers.


Altered Balance of Activity in the Striatal Direct and Indirect Pathways in Mouse Models of Huntington's Disease.
Imbalance in the activity of striatal direct and indirect pathway neurons contributes to motor disturbances in several neurodegenerative diseases. In Huntington's disease (HD), indirect pathway [dopamine (DA) D2 receptor-expressing] medium-sized spiny neurons (MSNs) are believed to show earlier vulnerability than direct pathway MSNs. We examined synaptic activity and DA modulation in MSNs forming the direct and indirect pathways in YAC128 and BACHD mouse models of HD. To visualize the two types of MSNs, we used mice expressing enhanced green fluorescent protein under the control of the promoter for the DA D1 or D2 receptor. Experiments were performed in early symptomatic (1.5 months) and symptomatic (12 months) mice. Behaviorally, early symptomatic mice showed increased stereotypies while symptomatic mice showed decreased motor activity. Electrophysiologically, at the early stage, excitatory and inhibitory transmission onto D1-YAC128 and D1-BACHD MSNs were increased, while there was no change in D2 MSNs. DA modulation of spontaneous excitatory postsynaptic currents (sEPSCs) in slices was absent in YAC128 cells at the early stage, but was restored by treating the slices with the DA depleter tetrabenazine (TBZ). In BACHD mice TBZ restored paired-pulse ratios and a D1 receptor antagonist induced a larger decrease of sEPSCs than in D1-WT cells, suggesting increased DA tone. Finally, TBZ decreased stereotypies in BACHD mice. These results indicate that by reducing DA or antagonizing D1 receptors, increases in inhibitory and excitatory transmission in early phenotypic direct pathway neurons can be normalized. In symptomatic YAC128 mice, excitatory synaptic transmission onto D1 MSNs was decreased, while inhibitory transmission was increased in D2 MSNs. These studies provide evidence for differential and complex imbalances in glutamate and GABA transmission, as well as in DA modulation, in direct and indirect pathway MSNs during HD progression.


Ethanol Extract of Chaenomeles sinensis Inhibits the Development of Benign Prostatic Hyperplasia by Exhibiting Anti-oxidant and Anti-inflammatory Effects.
Chaenomeles sinensis is known to inhibit the development and progression of many age-related diseases, but the underlying molecular mechanisms are largely unclear. In the present study, we observed that the ethanol extract of Chaenomeles sinensis scavenged 2,2'-diphenylpicrylhydrazyl and 2,2'-azinobis diammonium radicals in vitro. The ethanol extract of Chaenomeles sinensis activated antioxidant response element-luciferase activity and induced expression of NRF2 target genes in HaCaT cells. The ethanol extract of Chaenomeles sinensis also suppressed LPS-induced expression of COX-2 and iNOS proteins, and mRNA expression of TNF-α and IL-2 in RAW264.7 cells. Finally, the ethanol extract of Chaenomeles sinensis significantly suppressed testosterone propionate-induced benign prostatic hyperplasia in mice. Together, our study provides the evidence that the ethanol extract of Chaenomeles sinensis inhibits the development of benign prostatic hyperplasia by exhibiting anti-oxidant and anti-inflammatory effects.


The association between ankle-brachial index and cardiovascular or all-cause mortality in metabolic syndrome of elderly Chinese.
The ankle-brachial index (ABI) is a non-invasive, reliable measurement of lower-extremity ischemia. A low ABI is associated with increased risk of coronary heart disease, stroke and death. However, the relationship between ABI and all-cause mortality or cardiovascular disease (CVD) mortality in patients with metabolic syndrome (MetS) has not been well studied. Accordingly, we here investigated the association between ABI and all-cause and CVD mortality in an elderly Chinese population with MetS. A total of 2,274 MetS patients diagnosed under the criteria proposed by the International Diabetes Federation were divided into two groups based on repeated ABI measurement over a period of 13.6 months: ABI<or=0.9 (n=525) and ABI 0.91-1.4 (n=1,749). Each of the baseline characteristics of age, systolic blood pressure, diabetes mellitus morbidity, and smoking history were significantly different between the two groups (p<0.05 or p<0.01). All-cause mortality and CVD mortality decreased gradually as the ABI increased from 0.4 to 1.4. In Cox regression analysis, the relative ratio of all-cause mortality to CVD mortality also showed a tendency to decrease with increasing ABI. In elderly patients with MetS, ABI is one of the most important indexes for determining the possible prognosis and predicting all-cause and CVD mortality. People with relatively older age, higher systolic blood pressure, diabetes mellitus morbidity and smoking history may be at risk of lower ABI (<or=0.9) and higher all-cause and CVD mortality. Our results suggest the urgent need for repeated ABI measurement in clinical practice, both during individual visits and also over time, before diagnosing peripheral artery disease and making a therapeutic decision, especially in certain high-risk populations such as patients with MetS.


[NPM1 High Mutant Allele Burden is an Adverse Prognostic Factor for AML Patients with Mutated NPM1].
To investigate the clinical features, accompanying gene mutation characteristics and prognostic factors of adult patients with acute myeloid leukemia with mutated NPM1 (NPM1+AML). Seventy-three patients with newly diagnosed adult NPM1+AML were selected. The mutations of 22 genes were detected by second generation sequencing and 43 fusion genes of AML were detected by real-time fluorescent quantitative PCR. The Kaplan-Meier survival curve and Cox multivariate regression analysis were used to study the prognostic factors. A total of 74 NPM1 site mutations were detected in 73 patients with NPM1+AML. The incidence rates were 92.0% L287fs, 2.7% Q289fs and W288fs, 1.4% L258fs and Q289H, among which 1 patient had 2 NPM1 mutations; the different mutation sites had no effect on the prognosis of NPM1+AML. The median value of NPM1 variant allele frequency (VAF) was 35.4% (1.8%-56.6%). Based on the uppermost quartile of 38.4%, the patients were classified as NPM1 VAF>38.4% (NPM1highAML) and NPM1 VAF≤38.4% (NPM1lowAML). Compared with NPM1lowAML, the early mortality rate was statistically significantly higher (33.3% vs 7.3%, P<0.05), and median EFS (148 d,95%CI 58-238 d vs 372 d,95%CI 264-480 d) (P<0.01) and median OS (179 d 95%CI 6-352 d vs 444 d) (P<0.01) were significantly shorter in NPM1high AML. A total of 126 accompanying gene mutation sites were detected in 87.7% of patients with NPM1+AML. The patients with NRAS gene mutation displayed a higher rate of complete remission (100% vs 58%) (P<0.05) and longer median OS (not reached to 320 d, 95%CI 150-490 d) (P<0.05). The 43 fusion genes were examined in 65 out of 73 cases of NPM1+AML, and in all the patients the fusion gene test was negative. Multivariate analysis showed that NPM1 VAF>38.4% was an independent prognostic factor for EFS (HR=3.1, 95% CI 1.6-6.4, P<0.01) and OS (HR=3.0, 95% CI 1.4-6.2, P<0.01). The NPM1 gene mutation in AML patients often is accompanied by other gene mutations, while the coexistence of fusion genes is rare; high NPM1 mutant allele burden is an independent prognostic factor for adult AML patients with mutated NPM1.


Paleoclimatic evidence for future ice-sheet instability and rapid sea-level rise.
Sea-level rise from melting of polar ice sheets is one of the largest potential threats of future climate change. Polar warming by the year 2100 may reach levels similar to those of 130,000 to 127,000 years ago that were associated with sea levels several meters above modern levels; both the Greenland Ice Sheet and portions of the Antarctic Ice Sheet may be vulnerable. The record of past ice-sheet melting indicates that the rate of future melting and related sea-level rise could be faster than widely thought.


Optimizing the fabrication process and interplay of device components of polymer solar cells using a field-based multiscale solar-cell algorithm.
Both the device composition and fabrication process are well-known to crucially affect the power conversion efficiency of polymer solar cells. Major advances have recently been achieved through the development of novel device materials and inkjet printing technologies, which permit to improve their durability and performance considerably. In this work, we demonstrate the usefulness of a recently developed field-based multiscale solar-cell algorithm to investigate the influence of the material characteristics, like, e.g., electrode surfaces, polymer architectures, and impurities in the active layer, as well as post-production treatments, like, e.g., electric field alignment, on the photovoltaic performance of block-copolymer solar-cell devices. Our study reveals that a short exposition time of the polymer bulk heterojunction to the action of an external electric field can lead to a low photovoltaic performance due to an incomplete alignment process, leading to undulated or disrupted nanophases. With increasing exposition time, the nanophases align in direction to the electric field lines, resulting in an increase of the number of continuous percolation paths and, ultimately, in a reduction of the number of exciton and charge-carrier losses. Moreover, we conclude by modifying the interaction strengths between the electrode surfaces and active layer components that a too low or too high affinity of an electrode surface to one of the components can lead to defective contacts, causing a deterioration of the device performance. Finally, we infer from the study of block-copolymer nanoparticle systems that particle impurities can significantly affect the nanostructure of the polymer matrix and reduce the photovoltaic performance of the active layer. For a critical volume fraction and size of the nanoparticles, we observe a complete phase transformation of the polymer nanomorphology, leading to a drop of the internal quantum efficiency. For other particle-numbers and -sizes, we observe only a local perturbation of the nanostructure, diminishing the number of continuous percolation paths to the electrodes and, therefore, reducing the device performance. From these investigations, we conclude that our multiscale solar-cell algorithm is an effective approach to investigate the impact of device materials and post-production treatments on the photovoltaic performance of polymer solar cells.


[About meta-analyses].
. Based on the publication in this issue of AI&R of a metanalytic assessment of the degree and the quality of the available evidences on the clinical efficacy of an otherwise diffuse utilization of nutritional integration on a spectrum of fragile patients, the methodological comment is focused on the limitations, biases, misleading implications which are today threatening the role of metanalytical analyses of existing literature, to produce useful-reliable evidences in areas where the representativeness of the source of data is substantially scarce. The exposure to such risk appears to be specifically worrying in the field of nursing care, due to the very limited availability of randomized and other "controlled" prospective original studies with hard end-points.


Features of distamycin preferential binding sites on natural DNA predicted using differential scanning calorimetry.
The interaction of distamycin with ColE1 DNA was examined by using differential scanning calorimetry (DSC) taking the helix-coil transition theory of DNA into consideration. Our results here strongly indicate that the affinity of distamycin to DNA, at a low distamycin concentration, depends highly on the DNA sequence, and preferential binding occurs to the sites of four to six successive A-T pairs having two or more successive G-C pairs on both their ends.


Modification of beta-lactoglobulin by microbial transglutaminase under high hydrostatic pressure: localization of reactive glutamine residues.
Microbial transglutaminase (mTG) mediated modification of bovine beta-lactoglobulin (bLG) at ambient and high hydrostatic pressure was investigated in order to characterize preferred sites of the crosslinking reaction by identifying reactive glutamine residues. bLG was labeled with triglycine (GGG) by incubation with mTG at ambient pressure or at 400 MPa, respectively, and was subjected to an enzymatic digestion with trypsin. The resulting peptides were separated and those containing glutamine residues modified with GGG were unambiguously identified using RP-HPLC with ESI-TOF-MS. For bLG treated with mTG at ambient pressure for 1 h at 40 degrees C, no labeling was observed, thus confirming that the native protein is no substrate for mTG. After incubation of the protein with mTG at 400 MPa for 1 h at 40 degrees C, four out of nine glutamine residues, namely at positions 5, 13, 35, and 59 were identified as accessible for the mTG catalyzed reaction, indicating partial unfolding of bLG under pressure and exposure of previously unaccesible glutamine residues. Thus, only a limited number of glutamine residues were substrates for mTG, which points to a pronounced substrate specificity of mTG toward individual glutamine residues within a protein.


Colloid formation in Hanford sediments reacted with simulated tank waste.
Solutions of high pH, ionic strength, and aluminum concentration have leaked into the subsurface from underground waste storage tanks atthe Hanford Reservation in Washington State. Here, we test the hypothesis that these waste solutions alter and dissolve the native minerals present in the sediments and that colloidal (diameter < 2 microm) feldspathoids form. We reacted Hanford sediments with simulated solutions representative of Hanford waste tanks. The solutions consisted of 1.4 or 2.8 mol/kg NaOH, 0.125 or 0.25 mol/kg NaAlO4, and 3.7 mol/kg NaNO3 and were contacted with the sediments for a period of 25 or 40 days at 50 degrees C. The colloidal size fraction was separated from the sediments and characterized in terms of mineralogy, morphology, chemical composition, and electrophoretic mobility. Upon reaction with tank waste solutions, native minerals released Si and other elements into the solution phase. This Si precipitated with the Al present in the waste solutions to form secondary minerals, identified as the feldspathoids cancrinite and sodalite. The solution phase was modeled with the chemical equilibrium model GMIN for solution speciation and saturation indices with respect to sodalite and cancrinite. The amount of colloidal material in the sediments increased upon reaction with waste solutions. At the natural pH found in Hanford sediments (pH 8) the newly formed minerals are negatively charged, similar to the unreacted colloidal material present in the sediments. The formation of colloidal material in Hanford sediments upon reaction with tank waste solutions is an important aspect to consider in the characterization of Hanford tank leaks and may affect the fate of hazardous radionuclides present in the tank waste.


Screening of Humic Substances Extracted from Leonardite for Free Radical Scavenging Activity Using DPPH Method.
Humic substances (HSs) have been researched for a long time and still manage to surprise humanity today. According to the latest research, in addition to their previously well-known effects, they also have antioxidant properties. However, this previous research does not examine the difference in the antioxidant effect of the fractions extracted/produced in different processes; they do not consider the light absorption of the HSs, which falsifies analysis based on the measurement of color change over time. In the present work, HS fractions were obtained from leonardite, the extraction processes can also be implemented on an industrial scale. The fractions were characterized by elementary analysis, UV-Vis and FT-IR spectroscopies, to prove that our self-extracted samples have similar characteristics to the International Humic Substances Society (IHSS) standard samples. The different methods of HS fractionation affected the elemental composition, and the spectral characteristics. The antioxidant effect was investigated using the DPPH method to screen the antioxidant efficiency of humic, fulvic, and himatomelanic acids. In addition, we compared our results with the IHSS standard samples to obtain a more comprehensive picture of the antioxidant effect of HSs extracted in different ways according to the DPPH method. Based on our results, the extraction method affects not only the physico-chemical properties but also the free radical scavenging activity of the fractions.


Specific removal of digoxin by hemoperfusion through agarose polyacrolein microsphere polyacrolein microsphere beads-antidigoxin antibodies (APAMB-AD).
The efficacy of a new, biocompatible, specific immunosorbent for hemoperfusive removal of digoxin is described. The sorbent contains antidigoxin antibodies covalently bound to polyacrolein microspheres, 0.2 mu diam. Thousands of microspheres are matrix-encapsulated in crosslinked agarose to form beads of 500 to 800 mu diam. Digoxin intoxicated dogs showed heart block, ventricular and atrial tachycardia and extended runs of PVCs. During hemoperfusion the abnormal ECG abated; at 2 h of hemoperfusion the ECG tracings returned to normal. Up to 25% of the total digoxin burden was removed. The numbers of the blood cells and the content of a battery of relevant soluble components of the blood remained constant. Dogs were alive and well after the hemoperfusion. Non hemoperfused dogs, which received antiarrythmic agents, did not survive the intoxication. This is the first report of a practical hemoperfusive system for the specific removal of digoxin from whole blood.


Effects of cigarette smoke on N-nitrosobis(2-oxopropyl)amine-induced pancreatic and respiratory tumorigenesis in hamsters.
Influences of cigarette smoke on N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic duct and respiratory tract tumorigenesis were investigated using a hamster two-stage carcinogenesis model. Male 5-week-old hamsters were divided into 5 groups. Group 1 was s.c. injected with BOP at a dose of 10 mg/kg once a week for 3 weeks as an initiation treatment together with cigarette smoke exposure over the same 4-week period. Group 2 was exposed to cigarette smoke for 26 weeks after the BOP-initiation. Groups 3 and 4 were respectively given the BOP-initiation alone and the 26-week cigarette smoke exposure without initiation. Group 5 served as a sham-smoked negative control. The experiment was terminated 30 weeks after the first BOP injection. The incidence of pancreatic adenocarcinomas was significantly decreased in Group 1 as compared to the Group 3 value (P < 0.01) while the Group 2 value did not show any change. In contrast, the incidence of laryngeal and tracheal proliferative lesions (hyperplasias and papillomas) was significantly increased in Group 2 over Group 3 (P < 0.01). The incidence of pulmonary hyperplasias was also increased in Group 2 over Group 3 (P < 0.05), although that of pulmonary adenomas or adenocarcinomas was decreased in Group 2 as compared to the Group 3 value (P < 0.01). Cigarette smoke exposure in the BOP-initiation phase (Group 1) did not affect the development of respiratory proliferative lesions. No animals in Groups 4 and 5 developed any tumors in the pancreas or respiratory tract. Our results thus indicate that cigarette smoke exposure inhibits pancreatic carcinogenesis when given in the initiation phase, whereas it modulates (enhances or suppresses) the development of proliferative lesions in the respiratory tract if applied during the promotion stage to hamsters pretreated with BOP.


Expression and distribution of cyclooxygenase-2 in human periovulatory ovary.
Cyclooxygenase, which converts arachidonic acid into prostaglandins, has two types of isoforms, cyclooxygenase-1 and cyclooxygenase-2 (COX-2). The latter is thought to be essential for the ovulatory mechanism. However, expression or distribution of COX-2 in periovulatory human ovary has not been reported. The aim of our study was to examine COX-2 expression and distribution in pre- and postovulatory human ovary. COX-2 was detected by Western blot analysis of pre-ovulatory human ovarian follicular fluid. The levels of COX-2 in preovulatory fluid obtained from 20 subjects underwent in vitro fertilization and embryo transfer, and were assayed using enzyme immunoassay for human COX-2. The results showed 7.3+/-4.1 ng/ml (mean +/- SD) with a COX-2 level range of 2.7 to 19.5 ng/ml of follicular fluid. Detection of COX-2 is considered to reflect its production in the preovulatory follicle. Immunofluorescence microscopic examination of an ovary obtained from a woman at the postovulatory period showed distribution of COX-2 in interstitial but not in granulosa cells in a ruptured follicle. These findings collectively suggest the possibility that COX-2 is mainly produced in follicles in a preovulatory phase, while after ovulation, COX-2 is produced in interstitial cells in human ovary.


Elevation of Cardiac Troponins in Prolonged Status Epilepticus: A Retrospective Chart Analysis.
To determine the clinical significance of elevation of Troponin-I [cTn-I] during prolonged status epilepticus [pSE] SE is known to be accompanied by an increase in sympathetic outflow. Elevation of cTn-I has been linked to myocardial stress. We hypothesize that in patients with risk factors for coronary artery disease[CAD], pSE may lead to myocardial stress and an elevation of cTn-I. This is a retrospective study of patients over the age of 18 years who were presented to Virginia Commonwealth University with SE between 2005 and 2010. Data was evaluated using the 30-minute definition for SE and 30 day mortality. Risk factors for CAD and cTn-I levels within the first 24 hours of diagnosis of pSE were analyzed. There were a total of 435 patients with a confirmed diagnosis of pSE, of which 266 had cTn-I concentrations reported. Statistical analysis showed a significant association between CAD risk factors and cTn-I elevation (χ2 =12.87, p-value <0.01), with Crude Odds Ratio of 4.7. In patients with a CAD risk factor, an elevation of cTn-I is associated with a significantly increased risk of mortality, with an Odds ratio of 8.0, (χ2 =40, [95% CI 4.1-15.9] p-value < 0.01). Mortality was higher in those with an elevation of cTn-I [54.65%] as opposed to those who did not have an elevation [15.08%], irrespective of CAD risk factors. OR=6.7, (χ2 =45, [95% CI=3.7-12.2] p-value < 0.01). In patients with pSE values, elevated cTn-I values are seen four to five time more often in those with CAD risk factors, as opposed to those without the risks. An elevation of cTn-I in this subgroup of patients with CAD risk factors was associated with an eight to nine fold increase in their 30 day mortality as compared to patients with pSE, who did not have an elevation of cTn-I.


Immunization recall: effectiveness and barriers to success in an urban teaching clinic.
To examine effectiveness of immunization recall in an urban pediatric teaching clinic and to identify barriers to recall effectiveness. Randomized, controlled trial. Children aged 5 to 17 months who were not up to date (UTD) with recommended immunizations were identified and assigned to intervention (n = 294) or control groups (n = 309). The intervention consisted of a mailed postcard and up to 4 telephone calls. Two months after intervention, UTD status, visit, and probable missed opportunity rates were assessed. Of the intervention group, 30% could not be reached. In 12-month-old children in the intervention group compared with those in the control group, there was a trend toward higher UTD rates (51% vs 39%, P =.07) and a higher proportion of UTD children receiving immunizations as opposed to getting more complete documentation (25% vs 10%, P =.005). Similar differences between intervention and control children were not seen in the 7-month and 19-month age categories. More children in the intervention group had a health maintenance visit (17% vs 11%, P =.03). Of children in the intervention group who were seen when not UTD, 17 of 24 (71%) of those seen for an illness visit and 5 of 24 (21%) of those seen for health maintenance probably had missed opportunities to be immunized. Recall efforts were partially successful but were undermined by inability to reach the clinic population, poor documentation of immunizations, and missed opportunities.


Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites.
The ensemble of aminoacyl tRNA synthetases is regarded as a key component of the protein translation machinery. With the progressive increase in structure-based studies on tRNA synthetase-ligand complexes, the detailed picture of these enzymes is becoming clear. Having known their critical role in deciphering the genetic code in a living system, they have always been chosen as one of the important targets for development of antimicrobial drugs. Later on, the role of aminoacyl tRNA synthetases (aaRSs) on the survivability of trypanosomatids has also been validated. It became evident through several gene knockout studies that targeting even one of these enzymes affected parasitic growth drastically. Such successful studies have inspired researchers to search for inhibitors that could specifically target trypanosomal aaRSs, and their never-ending efforts have provided fruitful results. Taking all such studies into consideration, these macromolecules of prime importance deserve further investigation for the development of drugs that cure spectrum of infections caused by trypanosomatids. In this review, we have compiled advancements of over a decade that have taken place in the pursuit of devising drugs by using trypanosomatid aaRSs as a major target of interest. Several of these inhibitors work on an exemplary low concentration range without posing any threat to the mammalian cells which is a very critical aspect of the drug discovery process. Advancements have been made in terms of using structural biology as an important tool to analyze the architecture of the trypanosomatids aaRSs and concoction of inhibitors with augmented specificities toward their targets. Some of the inhibitors that have been tested on other parasites successfully but their efficacy has so far not been validated against these trypanosomatids have also been appended.


Government and public health responses to e-cigarettes in New Zealand: vapers' perspectives.
The New Zealand (NZ) government is to lift the ban on the sale of nicotine for use in electronic cigarettes (e-cigarettes). Using a naturalistic approach, we sought to understand how the current law was experienced by e-cigarette users (vapers). Twenty-nine vapers were interviewed by telephone, between May and September 2016, using a semi-structured interview schedule. Open-ended questions covered: initiating vaping, the experience of stopping smoking, technical problems encountered, reasons for vaping, acceptability of vaping, addiction to vaping and advice given to smokers about vaping. The audio recordings were transcribed and then independently coded using a general inductive thematic analysis. This paper presents the main theme which was that vapers employed a range of reactionary strategies to the ban on the sale of nicotine e-liquid in NZ. These included lobbying government, spreading the word, establishing vaper support groups, helping people stop smoking by switching to vaping and advocating for e-cigarettes to be incorporated into smoking cessation practice. Vapers' experience and observations form a popular or lay epidemiology--one that identified that e-cigarettes were helping people stop smoking and could thus deliver public health benefits. Public health researchers and workers, and government fears about vaping, and proposals to strengthen restrictions contributed to the growth of the vaper community who reacted by forming self-help groups and providing alternative cessation support to smokers. For a significant switch from smoking to vaping to occur, the health sector needs to have a change of attitude towards vaping that is positive, and the public needs evidence-based information on vaping. A first step could be for the health sector to collaborate with the vaping community to reorient current tobacco control and cessation practice to encourage smokers to switch to less harmful smoke-free alternatives to smoking.


The Impact of a Mobile Shading System and a Phase-Change Heat Store on the Thermal Functioning of a Transparent Building Partition.
The article presents the results of multi-month field tests and numerical analyses describing the thermal functioning of mobile shading systems for building windows containing a phase-change heat accumulator. The experiments were conducted in the summer period with temperate climate conditions in Rzeszów (Poland). The tested shading system was dedicated to the daily life cycle of residents, taking into account both the need to illuminate the rooms with natural light and reducing the undesirable overheating of the rooms in the summer. The obtained empirical results showed a reduction in room overheating in the summer period by 29.4% from composite windows with a phase-change heat accumulator and a mobile shading system as compared to the reference composite window with an analogous mobile shading system. The database of empirical results allowed for the creation and verification of a numerical model of heat conversion, storage and distribution within the composite window containing phase change material and a mobile shading system. The verified model made it possible to analyse the thermal functioning of the modified transparent partitions in cool temperate, temperate and subtropical climates. The article is a solution to the problem of undesirable overheating of transparent building partitions by efficient storage and distribution of solar radiation energy thanks to the use of a mobile shading system and a phase change material, while presenting a useful tool enabling the prediction of energy gains in different climatic conditions.


Implementation of an institution-specific antimicrobial stewardship smartphone application.
Smartphones are increasingly used to access clinical decision support, and many medical applications provide antimicrobial prescribing guidance. However, these applications do not account for local antibiotic resistance patterns and formularies. We implemented an institution-specific antimicrobial stewardship smartphone application and studied patterns of use over a 1-year period.


A First Implementation of Underwater Communications in Raw Water Using the 433 MHz Frequency Combined with a Bowtie Antenna.
In 2016, there were 317 serious water pollution incidents in the UK, with 78,000 locations where businesses discharge controlled quantities of pollutants into rivers; therefore, continuous monitoring is vital. Since 1998, the environment agency has taken over 50 million water samples for water quality monitoring. The Internet of Things has grown phenomenally in recent years, reaching all aspects of our lives, many of these connected devices use wireless sensor networks to relay data to internet-connected nodes, where data can be processed, analyzed and consumed. However, Underwater wireless communications rely mainly on alternative communication methods such as optical and acoustic, with radio frequencies being an under-exploited method. This research presents real world results conducted in the Leeds and Liverpool Canal for the novel use of the 433 MHz radio frequency combined with a bowtie antenna in underwater communications in raw water, achieving distances of 7 m at 1.2 kbps and 5 m at 25 kbps.


[Bacterial cellular communication in relation to pathogenicity].
The authors briefly summarize data on cell-cell communication (quorum sensing) as well as principles of simple methods for detection of N-acyl homoserine lactones.


Systematic studies on structure and physiological activity of cyclic alpha-keto enamines, a novel class of "cooling" compounds.
3-Methyl- and 5-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one were recently identified as intense cooling compounds in roasted dark malt. To gain more insights into the molecular requirements of these compounds for imparting a cooling sensation, 26 cyclic alpha-keto enamine derivatives were synthesized, and their physiological cooling activities were evaluated. Any modification of the amino moiety, the carbocyclic ring size, or incorporation of additional methyl groups led to a significant increase of the cooling threshold. Insertion of an oxygen atom into the 2-cyclopenten-1-one ring, however, increased the cooling activity, e.g., the cooling threshold of the 5-methyl-4-(1-pyrrolidinyl)-3(2H)-furanone was found to be 16-fold below the threshold concentration determined for the 3-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one. Shifting the oxygen atom from the 4- into the 5-position of the cyclopentenone ring resulted in a even more drastic increase in cooling activity, e.g., the 4-methyl-3-(1-pyrrolidinyl)-2(5H)-furanone exhibited the strongest cooling effect at the low oral threshold concentration of 0.02-0.06 mmol/L, which is 35-fold below the value determined for (-)-menthol. In contrast to the minty smelling (-)-menthol, most of the alpha-keto enamines were found to be virtually odorless but impart a sensation of "cooling" to the oral cavity as well as to the skin, thus illustrating that there is no physiological link between cooling activity and mint-like odors.


Cryptotanshinone Inhibits the Growth of HCT116 Colorectal Cancer Cells Through Endoplasmic Reticulum Stress-Mediated Autophagy.
Among cancers, colorectal cancer (CRC) has one of the highest annual incidence and death rates. Considering severe adverse reactions associated with classical chemotherapy medications, traditional Chinese medicines have become potential drug candidates. In the current study, the effects of cryptotanshinone (CPT), a major component of Salvia miltiorrhiza Bunge (Danshen) on CRC and underlying mechanism were explored. First of all, data from in vitro experiments and in vivo zebrafish models indicated that CPT selectively inhibited the growth and proliferation of HCT116 and SW620 cells while had little effect on SW480 cells. Secondly, both ER stress and autophagy were associated with CRC viability regulation. Interestingly, ER stress inhibitor and autophagy inhibitor merely alleviated cytotoxic effects on HCT116 cells in response to CPT stimulation, while have little effect on SW620 cells. The significance of apoptosis, autophagy and ER stress were verified by clinical data from CRC patients. In summary, the current study has revealed the anti-cancer effects of CPT in CRC by activating autophagy signaling mediated by ER stress. CPT is a promising drug candidate for CRC treatment.


Blends of rABS and SEBS: Influence of In-Situ Compatibilization on the Mechanical Properties.
In this study, the in-situ compatibilization reaction between recycled acrylonitrile-butadiene-styrene copolymer (rABS) and functional styrene-ethylene-butylene-styrene block maleic anhydride (SEBS-g-MAH) was confirmed, which contributed to the toughening phenomenon of rABS, especially the notched impact strength. As mechanical test that manifested, the rABS/SEBS-g-MAH blends are stronger and more ductile than the rABS/SEBS blends. Prominently, the former has great advantage over the latter in terms of improving the impact performance. Scanning electron microscope (SEM) images showed that the compatible segments that were generated by reaction not only improve the interface adhesion of rABS/SEBS-g-MAH blends but also promote the evolution of co-continuous structures, which can be evidently observed after etching. Furthermore, the SEM micrographs of tensile fracture surfaces indicated that the formation of the co-continuous phase and the improvement of interface adhesion are the most profound reasons for the excellent tensile properties of the rABS/SEBS-g-MAH blends. The impact fracture surface revealed that two-phase interface affects crack propagation and shear yielding absorbs more impact energy than simple interface debonding does at higher deformation rates. Meanwhile, rheological analysis demonstrated that the complex viscosity of the rABS/SEBS-g-MAH (80/20 wt%) blend with a co-continuous structure exhibits a maximum positive deviation at low frequencies from the theoretical value calculated using the rule of logarithmic sum, which indicated a connection between co-continuous structure and complex viscosity. In addition, the storage modulus vs. loss modulus curves of the blends revealed that the viscoelastic behavior of rABS/SEBS-g-MAH blends is very similar to that of rABS.


Real-time detection of linear and angular displacements with a modified DVD optical head.
Here we demonstrate that an astigmatic detection system (ADS), constructed with a modified digital-versatile-disk (DVD) optical head, can achieve real-time measurement of a linear displacement and two-dimensional (2D) tilt angles with a high sensitivity. An atomic force microscope (AFM), using our detection system to sense the deflection of microfabricated cantilevers, can resolve single atomic steps on graphite surfaces with a noise level less than 0.04 nm in topographic images. This astigmatic detection system can even detect mechanical resonances due to thermal vibrations of microfabricated cantilevers. The high sensitivity, small detecting size and high bandwidth of this detection system is suitable for dynamic characterization of elements in micromachined components. Further optimization of the system will promise many other applications in diverse technological fields.


Synchronizing rock clocks in the late Cambrian.
The Cambrian is the most poorly dated period of the past 541 million years. This hampers analysis of profound environmental and biological changes that took place during this period. Astronomically forced climate cycles recognized in sediments and anchored to radioisotopic ages provide a powerful geochronometer that has fundamentally refined Mesozoic-Cenozoic time scales but not yet the Palaeozoic. Here we report a continuous astronomical signal detected as geochemical variations (1 mm resolution) in the late Cambrian Alum Shale Formation that is used to establish a 16-Myr-long astronomical time scale, anchored by radioisotopic dates. The resulting time scale is biostratigraphically well-constrained, allowing correlation of the late Cambrian global stage boundaries with the 405-kyr astrochronological framework. This enables a first assessment, in numerical time, of the evolution of major biotic and abiotic changes, including the end-Marjuman extinctions and the Steptoean Positive Carbon Isotope Excursion, that characterized the late Cambrian Earth.


Clinical and immunologic spectrum of plasmacytoid lymphocytic lymphoma without serum monoclonal IgM.
As first suggested by Lukes & Collins (1975), and recently confirmed in the literature, the pathological lesion associated with Waldenström's macroglobulinaemia can be found in patients with serum IgG or IgA monoclonal proteins. To expand upon the clinical and immunologic spectrum of this lesion, we reviewed the records of 12 patients with identical tumour morphology, though lacking an IgM paraprotein. The median age of the patients was 62 years. In five patients the tumour secreted monoclonal IgG, while one secreted monoclonal IgA. One patient had normal serum protein electrophoresis, although monoclonal light chains were demonstrated on urinary protein electrophoresis. The remaining patients had no detectable monoclonal protein. Marker studies demonstrated the B cell origin of tumour, these findings were consistent with the monoclonal protein secreted. Clinically, these cases varied, from peripheral blood involvement resembling chronic lymphocytic leukaemia, to typical lymphomatous processes, to presentations resembling multiple myeloma, reflecting the similarity of all of these conditions as varying expressions of neoplasia of the B cell system.


Triterpenoids from Schisandra lancifolia with anti-HIV-1 activity.
A new trinorcycloartane triterpenoid, lancifodilactone H (1), and a new A ring-secocycloartane triterpenoid, lancifoic acid A (2), together with a known compound, nigranoic acid (3), were isolated from the leaves and stems of Schisandra lancifolia. Their structures were elucidated by spectroscopic data analysis. Compound 1 features a biosynthetically modified seven-membered lactone ring, which was confirmed by single-crystal X-ray diffraction. Compounds 1-3 exhibited weak anti-HIV-1 activity in vitro.


Negative Cooperativity in Guest Binding of a Ditopic Self-Folding Biscavitand.
A brand-new self-folding biscavitand was synthesized from a feet-to-feet-connected bisresorcinarene. The X-ray crystal structure of the biscaivtand showed that the two cavities are tightly connected with four butylene linkages. The conformationally coupled two cavities accommodated two cationic guests, showing a homotropic negative cooperativity in nonpolar solvents (toluene and chloroform). A polar tetrahydrofuran solvent weakened the cyclic hydrogen bonding interactions of the biscavitand, which resulted in noncooperative guest binding.


Simultaneous determination of atenolol and amiloride in pharmaceutical preparations by capillary zone electrophoresis with capacitively coupled contactless conductivity detection.
Capillary zone electrophoresis coupled with a capacitively coupled contactless conductivity detector (CE-C(4)D) has been employed for the determination of atenolol and amiloride in pharmaceutical formulations. Acetic acid (150 mm) was used as background electrolyte. The influence of several factors (detector excitation voltage and frequency, buffer concentration, applied voltage, capillary temperature and injection time) was studied. Non-UV-absorbing L-valine was used as internal standard; the analytes were all separated in less than 7 min. The separation was carried out in normal polarity mode at 28 degrees C, 25 kV and using hydrodynamic injection (25 s). The separation was effected in an uncoated fused-silica capillary (75 microm, i.d. x 52 cm). The CE-C(4)D method was validated with respect to linearity, limit of detection and quantification, accuracy, precision and selectivity. Calibration curves were linear over the range 5-250 microg/mL for the studied analytes. The relative standard deviations of intra- and inter-day migration times and corrected peak areas were less than 6.0%. The method showed good precision and accuracy and was successfully applied to the simultaneous determination of atenolol and amiloride in different pharmaceutical tablet formulations.


Health status and costs of exacerbations of chronic bronchitis and COPD: how to improve antibiotic treatment.
Up to 10% of the adult population in most countries may be affected by chronic bronchitis or chronic obstructive pulmonary disease. The course of the disease is characterized by frequent exacerbations with increased respiratory symptoms. Exacerbations are the most important cause of morbidity and mortality, and significantly impair the health status of chronic bronchitis and chronic obstructive pulmonary disease patients. It has been observed that impairment in health status associated with exacerbations may not recover completely if recurrent exacerbations occur. Therefore, strategies to prolong the time free of exacerbations are a cornerstone of therapy. Antibiotics have demonstrated additional benefits to bronchodilators and corticosteroids in the treatment of exacerbations. Furthermore, the possible role of antibiotics in preventing exacerbations and reducing the costs of chronic bronchitis and chronic obstructive pulmonary disease patients is discussed.


Normal data of left ventricular parameters in non-hypertensive patients using 320-slice cardiac CT: a study on intra- and interobserver variability.
Delineate normal data in a Thai population for global left ventricular function, left ventricular mass (LVM), and LV mass index (LVMI) by gated volumetric CT angiography (CTA). Two hundred twenty seven patients with intermediate risk factors for CAD were referred for CT coronary angiography. The non-hypertensive and non-diabetic asymptomatic group was selected with negative coronary CTA. Pre-condition of mild stenosis or less than 50% area stenosis was consistently met for inclusion in the present study. One hundred fifteen patients were included (31 males, 84 females, age range 38-76 years, mean 54.6 +/- 7.2 for males and 54.0 +/- 6.8 for females respectively). Mean EDV, ESV, SV, CO, and EF in male and females were EDV 122.6 +/- 17.3 vs. 94.9 +/- 16.6ml, ESV 48.2 +/- 9.9 vs. 34.1 +/- 9.1 ml, SV 74.5 +/- 14.2 vs. 60.8 +/- 10.6 ml, CO 4.2 +/- 0.8vs. 3.6 +/- 0.7 Land EF 60.6 +/- 6.6 vs. 64.3 +/- 5.6% respectively The mean LVM and LVMI were higher in males than females (LVM 134.6 +/- 21.4 vs. 96 9 +/- 20.3 g, and LVMI 76.8 +/- 12.4 vs. 61.1 +/- 11.56 g/m2). Altman and Bland plot for each of them showed that the mean and standard deviation of the differences was constant throughout the range of measurements. Each histogram of differences showed that these differences correspond to approximately normal distribution, indicating that the required assumptions held for the use of 95% limits of agreement are valid. Data from this group represents healthy volunteers and this may serve as an important source of information representing normal reference values to be used for Thai patients.


Expression and function of the bHLH genes ALCATRAZ and SPATULA in selected Solanaceae species.
The genetic mechanisms underlying fruit development have been identified in Arabidopsis and have been comparatively studied in tomato as a representative of fleshy fruits. However, comparative expression and functional analyses on the bHLH genes downstream the genetic network, ALCATRAZ (ALC) and SPATULA (SPT), which are involved in the formation of the dehiscence zone in Arabidopsis, have not been functionally studied in the Solanaceae. Here, we perform detailed expression and functional studies of ALC/SPT homologs in Nicotiana obtusifolia with capsules, and in Capsicum annuum and Solanum lycopersicum with berries. In Solanaceae, ALC and SPT genes are expressed in leaves, and all floral organs, especially in petal margins, stamens and carpels; however, their expression changes during fruit maturation according to the fruit type. Functional analyses show that downregulation of ALC/SPT genes does not have an effect on gynoecium patterning; however, they have acquired opposite roles in petal expansion and have been co-opted in leaf pigmentation in Solanaceae. In addition, ALC/SPT genes repress lignification in time and space during fruit development in Solanaceae. Altogether, some roles of ALC and SPT genes are different between Brassicaceae and Solanaceae; while the paralogs have undergone some subfunctionalization in the former they are mostly redundant in the latter.


Blood pressure, 5-OH indoleacetic acid, and vanilmandelic acid excretion and blood platelet aggregation in hypertensive patients treated with ketanserin.
Ketanserin, a new selective 5-HT2-serotonergic antagonist, was used to: confirm its hypotensive efficacy in acute and long-term treatment, determine its influence on the influence on the metabolism of serotonin (5-HT) and catecholamines, and elucidate their mutual relationship. Ketanserin was given intravenously to 10 patients with hypertensive crisis or resistant hypertension and orally to 15 patients with mild to severe hypertension for 1 year. Blood pressure, heart rate, 24-h urinary excretion of vanilmandelic acid (VMA; the major endproduct of catecholamines) and of 5-hydroxyindoleacetic acid (HIAA; the endproduct of serotonin metabolism), and platelet aggregation were measured. In doses normalizing blood pressure and platelet aggregation, ketanserin administered to hypertensive patients either intravenously in acute treatment or orally in chronic treatment caused: (a) decreased HIAA excretion (more marked in chronic than in acute treatment) and (b) simultaneous decrease in VMA excretion. It is concluded that the decisive sites of ketanserin action are the 5-HT2 receptors of platelets. The compound reduces platelet aggregation and the release of 5-HT, its metabolism, and, hence, the excretion of HIAA. The action of ketanserin on 5-HT2 receptors of vascular smooth muscle participates in the hypotensive effect of the drug but does not explain the decreased excretion of HIAA and VMA.


Role Played by Receptors for Advanced Glycosylation End Products in Corneal Endothelial Cells after HSV-1 Infection.
Senescence, sterile inflammation, and infection cause dysfunction of corneal endothelial cells, leading to visual morbidity that may require corneal transplantation. With increasing age, the extracellular matrix is modified by non-enzymatic glycation forming advanced glycation end products (AGEs). The modifications are primarily sensed by the receptors for the AGEs (RAGE) and are manifested as a type I interferon response. Interestingly, in our study, human corneal endothelial cells (HCEn) cells did not respond to the typical RAGE ligands, including the AGEs, high mobility group box 1 (HMGB1), and serum amyloid-A (SAA). Instead, HCEn cells responded exclusively to the CpG DNA, which is possessed by typical corneal pathogen, herpes simplex virus-1 (HSV-1). Upon HSV-1 infection, the surface expression of RAGE was increased, and endocytosed HSV-1 was associated with RAGE and CpG DNA receptor, TLR9. RAGE DNA transfection markedly increased interferon-β secretion by CpG DNA or HSV-1 infection. HSV-1 infection-induced interferon-β secretion was abolished by TLR9 inhibition and partially by RAGE inhibition. Global transcriptional response analysis confirmed that RAGE and TLR9 were both significantly involved in type I interferon responses. We conclude that RAGE is a sensor of HSV-1 infection and provokes a type I interferon response.


Morphology of menstrual hemostasis in essential menorrhagia.
We performed a morphologic and morphometric study with light and electron microscopy on early menstrual hemostasis in five menorrhagic uteri and one control uterus, related the data to measured menstrual blood loss and compared the data with our previous study on normal menstruation. Menstrual blood loss ranged from 39 to 234 ml. Menorrhagic uteri contained large hemostatic plugs, protruding with a large part into the extravascular space. These plugs often consisted of loosely packed, poorly degranulated platelets with few fibrin fibers. Recanalized plugs, consisting of fibrin fibers and platelet remnants at the periphery of the vessel, were also observed in menorrhagic uteri. Using morphometry, we demonstrated a positive correlation between menstrual blood loss and the number of occlusive and nonocclusive hemostatic plugs, but not with other aspects of hemostatic plug formation such as the vessel area occluded by the plug, plug transformation, or intra- or extravascular localization of the plug. Vasodilation or endometrial height were not correlated with the amount of menstrual blood loss. These data suggest that essential menorrhagia is associated with fragile hemostatic plugs or with more extensive vessel damage.


Transcranial Doppler monitoring during percutaneous transluminal aortic valvuloplasty.
Cerebral blood flow was studied in 12 elderly patients with severe calcific aortic stenosis by means of transcranial Doppler sonography (TCD) during percutaneous transluminal aortic valvuloplasty (PTAV). In 8 of these 12 patients duplex sonography revealed a stenosis of the internal carotid artery (ICA) exceeding 50%. Frequency spectra of 10 patients showed a satisfactory quality and were analyzed. In 7 subjects balloon inflation was well tolerated and systolic blood pressure did not drop below 75 mmHg. In these patients, whether they had a stenosis of the ICA or not, blood flow velocity in the middle cerebral artery (MCA) did not decrease to a critical level. The authors defined "critical" as a reduction of mean blood flow velocity in the MCA exceeding 50% or a decrease below 35 cm/sec. Three patients showed a rapid decrease of systolic aortic pressure below 75 mmHg. In these subjects mean blood flow velocity in the MCA dropped to levels below 35 cm/sec. Deflation and retraction of the balloon resulted in a rapid increase of systemic blood pressure and flow velocity in the MCA. This report demonstrates TCD to be a useful monitoring method of determining residual perfusion in patients with aortic stenosis during PTAV.


Spontaneous Post-Transplant Disorders in NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) Mice Engrafted with Patient-Derived Metastatic Melanomas.
Patient-derived tumor xenograft (PDTX) approach is nowadays considered a reliable preclinical model to study in vivo cancer biology and therapeutic response. NOD scid and Il2rg-deficient mice represent the "gold standard" host for the generation of PDTXs. Compared to other immunocompromised murine lines, these mice offers several advantages including higher engraftment rate, longer lifespan and improved morphological and molecular preservation of patient-derived neoplasms. Here we describe a spectrum of previously uncharacterized post-transplant disorders affecting 14/116 (12%) NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) mice subcutaneously engrafted with patient-derived metastatic melanomas. Affected mice exhibited extensive scaling/crusting dermatitis (13/14) associated with emaciation (13/14) and poor/unsuccessful tumor engraftment (14/14). In this context, the following pathological conditions have been recognized and characterized in details: (i) immunoinflammatory disorders with features of graft versus host disease (14/14); (ii) reactive lymphoid infiltrates effacing xenografted tumors (8/14); (iii) post-transplant B cell lymphomas associated with Epstein-Barr virus reactivation (2/14). We demonstrate that all these entities are driven by co-transplanted human immune cells populating patient-derived tumor samples. Since the exploding interest in the utilization of NOD scid and Il2rg-deficient mice for the establishment of PDTX platforms, it is of uppermost importance to raise the awareness of the limitations associated with this model. The disorders here described adversely impact tumor engraftment rate and animal lifespan, potentially representing a major confounding factor in the context of efficacy and personalized therapy studies. The occurrence of these conditions in the NOG model reflects the ability of this mouse line to promote efficient engraftment of human immune cells. Co-transplanted human lymphoid cells have indeed the potential to colonize the recipient mouse initiating the post-transplant conditions here reported. On the other hand, the evidence of an immune response of human origin against the xenotransplanted melanoma opens intriguing perspectives for the establishment of suitable preclinical models of anti-melanoma immunotherapy.


Characterization of the Goose CAPN3 Gene and its Expression Pattern in Muscle Tissues of Sichuan White Geese at Different Growth Stages.
Calpain 3 (CAPN3), also known as p94, is associated with multiple production traits in domestic animals. However, the molecular characteristics of the CAPN3 gene and its expression profile in goose tissues have not been reported. In this study, CAPN3 cDNA of the Sichuan white goose was cloned, sequenced, and characterized. The CAPN3 full-length cDNA sequence consists of a 2,316-bp coding sequence (CDS) that encodes 771 amino acids with a molecular mass of 89,019 kDa. The protein was predicted to have no signal peptide, but several N-glycosylation, O-glycosylation, and phosphorylation sites. The secondary structure of CAPN3 was predicted to be 38.65% α-helical. Sequence alignment showed that CAPN3 of Sichuan white goose shared more than 90% amino acid sequence similarity with those of Japanese quail, turkey, helmeted guineafowl, duck, pigeon, and chicken. Phylogenetic tree analysis showed that goose CAPN3 has a close genetic relationship and small evolutionary distance with those of the birds. qRT-PCR analysis showed that in 15-day-old animals, the expression level of CAPN3 was significantly higher in breast muscle than in thigh tissues. These results serve as a foundation for further investigations of the function of the goose CAPN3 gene.


EAACI guidelines on environmental science in allergic diseases and asthma - Leveraging artificial intelligence and machine learning to develop a causality model in exposomics.
Allergic diseases and asthma are intrinsically linked to the environment we live in and to patterns of exposure. The integrated approach to understanding the effects of exposures on the immune system includes the ongoing collection of large-scale and complex data. This requires sophisticated methods to take full advantage of what this data can offer. Here we discuss the progress and further promise of applying artificial intelligence and machine-learning approaches to help unlock the power of complex environmental data sets toward providing causality models of exposure and intervention. We discuss a range of relevant machine-learning paradigms and models including the way such models are trained and validated together with examples of machine learning applied to allergic disease in the context of specific environmental exposures as well as attempts to tie these environmental data streams to the full representative exposome. We also discuss the promise of artificial intelligence in personalized medicine and the methodological approaches to healthcare with the final AI to improve public health.


Quality control of validity of data collected in clinical trials. EORTC Study Group on Data Management (SGDM).
In a study initiated by the EORTC Study Group on Data Management, 15 site visits to main participating centers in ongoing cancer clinical trials have been carried out over a 1 year period. The aim was to evaluate the quality level of EORTC clinical trial data, to find out the order of magnitude of possible problems encountered and to test a technique to objectively assess the quality of data. The process of data collection and the quality of data transfer from hospital charts to EORTC case report forms (CRF) were checked. The data quality was scored and the causes of incorrectness were evaluated. Percentages of correct data ranged from 78% up to 98%; 11/15 centers had greater than 90% correct data. The median rate of error encountered in key data was 2.8% (range 0.5-7%). The main source of error was incorrect transfer of the information recorded in the patient chart to the CRF. Equally good overall results have been observed in the centers where data managers fill in the forms (DM) and those centers without an administrative trial structure (PH). The mean percentage of correct data for both types of centers is 91.4%. The wider range in percentage for incorrect data (DM mean value 3.0%, range 0.5-7%; PH mean value 2.3%, range 1.4-3.1) suggests the important impact of the knowledge and experience of the people involved in data management. The data quality evaluation was hampered by the impossibility of checking part of the data present on the CRF, 0.4-14.5%. Besides knowledge and experience, the main aspects influencing good data quality appeared to be the efficacy of the internal organization and good local data monitoring. The importance of the design of CRFs was also highlighted. As this study was run for on-going protocols, the site visiting team had the opportunity to point out and report to the trial coordinator all shortcomings and controversial points that could thus be corrected during the course of the trial.


Clinical analysis of 12 patients caused by long-acting anticoagulant rodenticide occult poisoning.
To explore the clinical characteristics and diagnosis and treatment of occult poisoning caused by long-acting anticoagulant rodenticides. Records of 12 patients from July 2008 to April 2011 diagnosed as anticoagulant rodenticide occult poisoning, who had been misdiagnosed initially at other hospitals were analyzed retrospectively. Elements from the records included clinical symptoms and signs, laboratory findings for prothrombin time (PT) and activated partial prothrombin time (APTT), and initial misdiagnosis and treatment outcome at our hospital. The clinical presentations of patients were insidious and serious, often presented as skin ecchymose, hematuria, menorrhagia and gastrointestine bleeding. Laboratory examinations showed prolonged PT and APTT; bleeding was controlled effectively by administoring vitamin K1 daily. There were statistical difference between PT and APTT before and after the treatment (P<0.01). Coagulation disorders might be caused by the reduced acquisition in vitamin K dependent coagulation factors, which tends to be neglected due to a hidden medical history, delayed signs of poisoning, and various organs involved. A detailed patient history and systematic review may improve the diagnostic accuracy. Once diagnosed is made, vitamin K1 should be given as soon as possible.


The roles of antimicrobial peptide, rip-thanatin, in the midgut of Riptortus pedestris.
Recently, we have reported the structural determination of antimicrobial peptides (AMPs), such as riptocin, rip-defensin, and rip-thanatin, from Riptortus pedestris. However, the biological roles of AMPs in the host midgut remain elusive. Here, we compared the expression levels of AMP genes in apo-symbiotic insects with those of symbiotic insects. Interestingly, the expression level of rip-thanatin was only significantly increased in the posterior midgut region of symbiotic insects. To further determine the role of rip-thanatin, we checked antimicrobial activity in vitro. Rip-thanatin showed high antimicrobial activity and had the same structural characteristics as other reported thanatins. To find the novel function of rip-thanatin, rip-thanatin was silenced by RNA interference, and the population of gut symbionts was measured. When rip-thanatin was silenced, the symbionts' titer was increased upon bacterial infection. These results suggest that rip-thanatin functions not only as an antimicrobial peptide but also in controlling the symbionts' titer in the host midgut.


Use of a media intervention to increase positive attitudes toward transgender and gender diverse individuals.
As issues related to transgender and gender diverse individuals gain more national media attention, professional organizations that promote mental health and LGBTQ + rights continue to advocate for equality and inclusion. Barriers to equality and inclusion for transgender and gender diverse individuals can include a variety of factors including discrimination in educational and workplace settings, and issues related to housing, poverty, and homelessness. To examine the impact of a media intervention on changing attitudes toward transgender and gender diverse individuals. A total of 223 students from a large, Midwestern university in the USA participated and received a 45-minute media intervention along with pre- and post-testing. A split-plot factorial ANOVA to investigate potential differences in attitudes and beliefs toward transgender and gender diverse individuals using the Transgender Attitude and Beliefs Scale indicated a statistically significant interaction based on a media intervention where F(1, 109) = 7.042, p = .009. A split-plot factorial ANOVA to investigate potential differences in willingness to engage in social action on behalf of this population measured by the Social Justice Scale did not indicate a statistically significant interaction based on the media intervention where F(1, 109) = .881, p = .350. These findings suggest that a variety of potential media interventions can increase positive attitudes and beliefs toward marginalized groups, but a stronger and/or additional intervention is needed for participants to engage in social action on behalf of the group. Implications and limitations of the study are discussed.


Extrapulmonary pneumocystosis: the first 50 cases.
Over the last 35 years, 50 cases of extrapulmonary infection with Pneumocystis carinii have been reported in the literature throughout the world. Use of prophylactic aerosolized pentamidine may have facilitated the relative prevalence of extrapulmonary disease because of its inadequate systemic distribution. An increase in reported cases of infections due to P. carinii has been seen in conjunction with AIDS, but extrapulmonary pneumocystosis represents less than 1% of all cases of infection with P. carinii. Several organs or tissues may be involved, but the most common sites are lymph nodes, spleen, liver, and bone marrow. Extrapulmonary spread of P. carinii infection occurs via both lymphatic and hematogenous routes. While all patients with disseminated forms of this infection die rapidly, survival for patients with AIDS is possible if systemic treatment is provided, if a single extrapulmonary site is involved, and if no concomitant pneumonia is present. Because of the increasing frequency of this condition in patients who do not have pneumonia due to P. carinii, extrapulmonary pneumocystosis should be included among the AIDS-defining criteria.


Resting-sate functional reorganization of the rat limbic system following neuropathic injury.
Human brain imaging studies from various clinical cohorts show that chronic pain is associated with large-scale brain functional and morphological reorganization. However, how the rat whole-brain network is topologically reorganized to support persistent pain-like behavior following neuropathic injury remains unknown. Here we compare resting state fMRI functional connectivity-based whole-brain network properties between rats receiving spared nerve injury (SNI) vs. sham injury, at 5 days (n = 11 SNI; n = 12 sham) and 28 days (n = 11 SNI; n = 12 sham) post-injury. Similar to the human, the rat brain topological properties exhibited small world features and did not differ between SNI and sham. Local neural networks in SNI animals showed minimal disruption at day 5, and more extensive reorganization at day 28 post-injury. Twenty-eight days after SNI, functional connection changes were localized mainly to within the limbic system, as well as between the limbic and nociceptive systems. No connectivity changes were observed within the nociceptive network. Furthermore, these changes were lateralized and in proportion to the tactile allodynia exhibited by SNI animals. The findings establish that SNI is primarily associated with altered information transfer of limbic regions and provides a novel translational framework for understanding brain functional reorganization in response to a persistent neuropathic injury.


Modulation of P-glycoprotein function and multidrug resistance in cancer cells by Thai plant extracts.
The effects of ethanol extracts from Thai plants belonging to the families of Annonaceae, Rutaceae, and Zingiberaceae on P-glycoprotein (P-gp) function and multidrug resistance were examined in paclitaxel-resistant HepG2 (PR-HepG2) cells. All the extracts tested, significantly increased the accumulation of [3H]paclitaxel, a P-gp substrate, in the cells. Among nine extracts, Z01 and Z02, extracts from Curcuma comosa and Kaempferia marginata (Zingiberaceae family), respectively, potently increased the accumulation. In addition, Z01 and Z02 increased the accumulation of other P-gp substrates, rhodamine 123 and doxorubicin, in PR-HepG2 cells in a concentration-dependent manner. Increased accumulation of rhodamine 123 and doxorubicin by Z01 and Z02 was also confirmed by confocal laser scanning microscopy. The effect of Z01 and Z02 pretreatment on the expression of MDR1 mRNA was also examined. The expression of MDR1 mRNA was not affected by the treatment of PR-HepG2 cells with these extracts for 48 hours. Cytotoxicity of paclitaxel was examined by XTT and protein assays in the absence and presence of Z02. Z02 potentiated the cytotoxicity of paclitaxel in PR-HepG2 cells. These results suggest that Curcuma comosa and Kaempferia marginata belonging to Zingiberaceae are useful sources to search for new P-gp modulator(s) that can be used to overcome multidrug resistance of cancer cells.


Essential oil composition and antioxidant capacity of Lippia schomburgkiana.
The leaves and fine stems of Lippia schomburgkiana recorded an essential yield of 1.8%, the main constituents of which were 1,8-cineole (64.1%) and alpha-terpineol (12.0%). The methanol extract of L. schomburgkiana inhibited the DPPH radical, resulting in an EC50 value of 16.1 +/- 0.7 microg x mL(-1), which is only three times lower than that of trolox (4.7 +/- 0.4 microg x mL(-1)), signifying a high antioxidant activity for the species. The amount of total phenolics (376.7 +/- 35.5 mg GAE/g) and the trolox equivalent antioxidant capacity (327.0 +/- 24.8 mg TE/g) of the methanol extract confirmed the significant antioxidative capacity of this plant. The brine shrimp bioassay carried out on the oil (49.6 +/- 0.4 microg x mL(-1)) showed high toxicity, providing important evidence of its biological activity. The sensory evaluation of the leaves of L. schomburgkiana showed a percentage acceptance value very close to commercial oregano, indicating that the plant can be used in spice and condiment products.


An approach to growth of Fe-Si multilayers with controlled composition profile-a way to exchange coupled thin films.
The growth, composition and structure of sandwich structures (Fe-rich layer/Si-rich layer/Fe-rich silicide layer) grown on a Si(111) surface were studied by a few complementary microscopic and spectroscopic techniques with high spatial resolution. Intermixing at the Fe/Si and Si/Fe interfaces is demonstrated. Fe-rich layers grown directly on the Si(111) surface are crystalline and have abrupt but rough interfaces at both sides. The succeeding layers are disordered and their interfaces are fuzzy. The distributions of Fe and Si within the layers are laterally non-uniform. The reproducible fabrication of thin non-magnetic silicide spacers of predetermined thickness is demonstrated. Sandwich structures with such spacers exhibit exchange coupling between ferromagnetic Fe-rich layers.


Modeling individual differences in perceptual and attentional processes related to bulimic symptoms.
Attentional and perceptual differences between women with high and low levels of bulimic symptoms were studied with techniques adapted from cognitive science. Stimuli were pictures of young women varying in body size and facial affect. A multidimensional scaling analysis showed that the high-symptom women were significantly more attentive to information about body size and significantly less attentive to information about affect. In prototype classification tasks, the high-symptom women used significantly more information about body size and significantly less information about affect. There were strong associations between individual differences in attention in the similarity task and decision making in the classification tasks. The study shows the potential utility of cognitive science methods for the study of cognitive factors in psychopathology.


Identification of Na+/H+ exchange as a new target for toxic polycyclic aromatic hydrocarbons.
The ubiquitous environmental pollutants polycyclic aromatic hydrocarbons are responsible for important carcinogenic and apoptotic effects, whose mechanisms are still poorly understood, owing to the multiplicity of possible cellular targets. Among these mechanisms, alterations of ionic homeostasis have been suggested. In this work, the effects of benzo(a)pyrene [B(a)P] on pHi were tested in the rat liver F258 epithelial cell line, using the fluoroprobe carboxy-SNARF-1. After a 48-h treatment, B(a)P (50 nM) induced an alkalinization, followed by an acidification after 72 h and the development of apoptosis. Determinations of pH(i) recovery following an acid load showed an increased acid efflux at 48 h. Cariporide inhibited both the early alkalinization and the increased acid efflux, thus suggesting the involvement of Na+/H+ exchanger 1 (NHE1). Besides, alpha-naphtoflavone (alpha-NF), an inhibitor of CYP1A1-mediated B(a)P metabolism, prevented all pH(i) changes, and NHE1 activation was blocked by the antioxidant thiourea, which inhibited CYP1A1 metabolism-dependent H2O2 production. Regarding B(a)P-induced apoptosis, this was prevented by alpha-NF and bongkrekic acid, an inhibitor of mitochondria-dependent apoptosis. Interestingly, apoptosis was significantly reduced by cariporide. Taken together, our results indicate that B(a)P, via H2O2 produced by CYP1A1-dependent metabolism, induces an early activation of NHE1, resulting in alkalinization; this appears to play a significant role in mitochondria-dependent B(a)P-induced apoptosis.


[Coding of stimulus movement parameters in cat visual system].
The principal component analysis of matrices composed of spike numbers generated by visual neurons of cats in response to motion of simple and complex stimuli revealed vector encoding. Responses of detectors of moving dot direction and detectors of oblique line orientation are encoded independently in V1 and V2 cortices by excitation of two cardinal neurons. Each pair of these neurons generates sine and cosine functions. Responses of detectors in the association cortex selective to specific orientation of moving stripes depend on the activity of four cardinal neurons which sum up the excitation incoming from the direction and orientation channels.


Is prolonged stem cell mobilization detrimental for hematopoiesis?
Multiple hematological side effects have been reported to result from treatment with psychoactive phenothiazines. These reported toxicities include leucopenia, granulocytopenia, thrombocytopenia, agranulocytosis, and bone marrow aplasia. The physiological mechanism causing these potentially life-threatening blood dyscrasias is unknown. Recently, we discovered that phenothiazines exhibit antagonistic properties towards the VLA-4 integrin, an adhesion molecule that is responsible for homing and retention of hematological stem/progenitor cells (HSPCs) in the bone marrow. After administration of thioridazine we detected rapid mobilization of HSPCs into the peripheral blood. We propose that in patients receiving phenothiazines over a prolonged time period, continuous mobilization of stem cells out of the stem cell niche, results in a disorder of hematopoiesis. Furthermore, we also postulate that such cytopenias are caused by a loss of the niche environment, which is known to be essential for stem cell maintenance.


Spontaneous Age-Related Histopathological Changes in Microminipigs.
Microminipigs have become an attractive animal model for toxicology and pharmacology studies and for human disease models, owing to their manageable size. Although there are numerous reports of spontaneous age-related lesions in mice, rats, dogs, and monkeys, those in minipigs are scarce. In the present study, spontaneous age-related histopathological changes were investigated using 37 microminipigs (20 males and 17 females) that were 6 months to 10 years of age. Abnormal deposits of materials were evident in several animals from 6 years of age, and these deposits included amyloid in the renal medulla, thyroid gland, and adrenal gland, hyaline droplets in glomeruli, and fibrillar inclusions in neurons. Arterial sclerosing changes (intimal thickening, intimal proliferation, and medial mineralization) and proliferative lesions (hyperplasia of hepatocytes, follicular cells, Leydig cells, and uterine endometrial glands) were present at 4 years of age and beyond. Renal adenoma, uterine leiomyoma, and Leydig cell tumor were observed in several microminipigs. Moreover, glomerulosclerosis, renal interstitial fibrosis, thymic involution, and adrenocortical cell vacuolation were common in aging microminipigs. Since knowledge of age-related changes is helpful for pathologists, the basic information obtained in this study will be a useful reference for all future toxicity evaluations in microminipigs.


[Metabolic Characteristics of WBC-deplted RBC suspension during Different Storage Stage in MAP Based on UPLC-MS/MS].
To explore the metabolic characteristics and metabolic markers of WBC-depleted RBCs in MAP preservation solution and to analyzed the metabolic profile of RBC in MAP preservation solution by using metabolomics. The changes of metabolitcs in 10 U WBC-depleted RBC suspension at 3-different storage period (D 0, D 14 and D 35) were detected by using the UPLC-MS/MS, the charaeteristic ions and metabolic markers of RBC stored in preservation sblution for 0 d, 14 d and 35 days were analyzed by using the principal component analysis(PCA). The number of characteristic ions in RBC and supernatant extracts detected during the initial, middle and final storage could be clearly distinguiseed. The 5 metabolism-related substamces such as lact-c acid, nicotinamide, glucose, 5-htdroxyproline and malic acid showed statistically significant difference in 3 storage period. The UPLC-MS/MS method combined with statistical analysis of multivariate data can be used to study the metabolic characteristics of RBC, the different metabolites of RBC in different storage stages can be used as the potential markers for evaluation of guality of RBC in storag period. The results of this study provide a basis for studing the RBC guality changes in storage period.


FBN1 Splice-Altering Mutations in Marfan Syndrome: A Case Report and Literature Review.
Marfan syndrome (MFS) is a life-threatening autosomal dominant genetic disorder of connective tissue caused by the pathogenic mutation of FBN1. Whole exome sequencing and Sanger sequencing were performed to identify the pathogenic mutation. The transcriptional consequence of the splice-altering mutation was analyzed via minigene assays and reverse-transcription PCR. We identified a novel pathogenic mutation (c.8051+1G>C) in the splice site of exon 64 of the FBN1 gene in an MFS-pedigree. This mutation was confirmed to cause two different truncated transcripts (entire exon 64 skipping; partial exon 64 exclusion). We also systematically summarized previously reported transcriptional studies of pathogenic splice-altering mutations in the FBN1 gene to investigate the clinical and transcriptional consequences. In conclusion, we reported for the first time that a splice-altering mutation in the FBN1 gene leads to two abnormal transcripts simultaneously.


Survival of civilian and prisoner drug-sensitive, multi- and extensive drug- resistant tuberculosis cohorts prospectively followed in Russia.
A long-term observational study was conducted in Samara, Russia to assess the survival and risk factors for death of a cohort of non-multidrug resistant tuberculosis (non-MDRTB) and multidrug resistant tuberculosis (MDRTB) civilian and prison patients and a civilian extensive drug-resistant tuberculosis (XDRTB) cohort. MDRTB and XDRTB rates of 54.8% and 11.1% were identified in the region. Half (50%) of MDRTB patients and the majority of non-MDRTB patients (71%) were still alive at 5 years. Over half (58%) of the patients died within two years of establishing a diagnosis of XDRTB. In the multivariate analysis, retreatment (HR = 1.61, 95%CI 1.04, 2.49) and MDRTB (HR = 1.67, 95%CI 1.17, 2.39) were significantly associated with death within the non-MDR/MDRTB cohort. The effect of age on survival was relatively small (HR = 1.01, 95%CI 1.00, 1.02). No specific factor affected survival of XDRTB patients although median survival time for HIV-infected versus HIV-negative patients from this group was shorter (185 versus 496 days). The majority of MDRTB and XDRTB strains (84% and 92% respectively) strains belonged to the Beijing family. Mutations in the rpoB (codon 531 in 81/92; 88.8%), katG (mutation S315T in 91/92, 98.9%) and inhA genes accounted for most rifampin and isoniazid resistance respectively, mutations in the QRDR region of gyrA for most fluroquinolone resistance (68/92; 73.5%). Alarmingly high rates of XDRTB exist. Previous TB treatment cycles and MDR were significant risk factors for mortality. XDRTB patients' survival is short especially for HIV-infected patients. Beijing family strains comprise the majority of drug-resistant strains.


Coming to Grips-How Nurses Deal With Restlessness, Confusion, and Physical Restraints on a Neurological/Neurosurgical Ward.
Physical restraints are viewed as potentially dangerous objects for patient safety. Contemporary efforts mainly focus on preventing bad outcomes in restraint use, while little attention is paid under what circumstances physical restraints are applied harmlessly. The aim of this research was to understand how physical restraints are used by neurology/neurosurgery ward nurses in relation to the protocol. In ethnographic action research, the Functional Resonance Analysis Method (FRAM) was used to map and compare physical restraints as part of daily ward care against the protocol of physical restraints. Comparison between protocol and actual practice revealed that dealing with restlessness and confusion is a collective nursing skill vital in dealing with physical restraints, while the protocol failed to account for these aspects. Supporting and maintaining this skillset throughout this and similar nursing teams can prevent future misguided application physical restraints, offering valuable starting point in managing patient safety for these potentially dangerous objects.


Mussel-inspired dendritic polymers as universal multifunctional coatings.
A rapid and universal approach for multifunctional material coatings was developed based on a mussel-inspired dendritic polymer. This new kind of polymer mimics not only the functional groups of mussel foot proteins (mfps) but also their molecular weight and molecular structure. The large number of catechol and amine groups set the basis for heteromultivalent anchoring and crosslinking. The molecular weight reaches 10 kDa, which is similar to the most adhesive mussel foot protein mfp-5. Also, the dendritic structure exposes its functional groups on the surface like the folded proteins. As a result, a very stable coating can be prepared on virtually any type of material surface within 10 min by a simple dip-coating method, which is as fast as the formation of mussel byssal threads in nature.


Perioperative mortality and long-term outcome of infective endocarditis.
Infective endocarditis (IE) is a disease with a high morbidity and mortality during the active phase and a considerable risk of complications during follow-up. The aim of this study is to describe the clinical features of IE associated with perioperative mortality in patients undergoing surgery and the short- and long-term prognosis of this disease after surgical treatment. The clinical files of 150 patients (pts) admitted to our institution between 1989 and 2001 and whose final diagnosis was IE (Duke criteria) were retrospectively reviewed. Thus all patients included underwent at least 1 transthoracic examination, and a transesophageal examination if indicated. The study population was 69 patients with IE, 62 of whom (90%) underwent prosthetic valve replacement and 7 (10%) underwent explanation of pacemaker electrocatheter. In the statistical analysis, quantitative variables are expressed as means +/- SD and qualitative variables as proportions (percentages). Differences in survival were determined using the Kaplan-Meier log rank method. Associations were considered statistically significant when the p value was < 0.05. The mean age was 56 +/- 15 years. Thirty-five cases (51%) had prosthetic valve endocarditis, 30 (39%) had native valve IE and 7 (10%) pacemaker electrocatheter IE. Fifty-two patients (75%) had positive blood cultures. The most frequent agents were S. epidermidis (14.5%), S. aureus (14.5%), Enterococci (13%) and S. viridans (10%). Total perioperative mortality was 17.4% (n = 12), and surgical mortality was 19.4%. Our study shows a statistical tendency for higher mortality in diabetic patients (50% vs. 14%, p = 0.052) and in women (29% vs. 11%, p = 0.065). In multivariate analysis, the presence of heart failure was an independent predictor of perioperative mortality (OR = 11.4; 95% CI: 2.0-215.2; p = 0.024). Accumulated mortality in the first year was 28% and 5-year mortality was 48%. Prosthetic valve replacement in patients with IE is associated with high perioperative mortality (17.4%). Despite good early postoperative results, the mortality rate increases during the first year as well as the need for reoperation.


Platelet scintigraphy in cerebrovascular diseases.
The benefit of platelet scintigraphy using 99mTc-phytate as a method to detect atherosclerotic lesions in extracranial neck vessels was tested on 143 patients. 29 patients had an abnormal scan of the neck vessels. The scintigraphic results were critically evaluated, taking clinical observations and the angiograms performed on 88 patients into consideration. Platelet scintigraphy can be useful as an additional examination in some patients. Generally, however, the value and reliability of platelet scintigraphy must be seen as insufficient, making further prospective studies with histological examinations imperative.


Multimorbidity Profiles and Infection Severity in COVID-19 Population Using Network Analysis in the Andalusian Health Population Database.
Identifying the population at risk of COVID-19 infection severity is a priority for clinicians and health systems. Most studies to date have only focused on the effect of specific disorders on infection severity, without considering that patients usually present multiple chronic diseases and that these conditions tend to group together in the form of multimorbidity patterns. In this large-scale epidemiological study, including primary and hospital care information of 166,242 patients with confirmed COVID-19 infection from the Spanish region of Andalusia, we applied network analysis to identify multimorbidity profiles and analyze their impact on the risk of hospitalization and mortality. Our results showed that multimorbidity was a risk factor for COVID-19 severity and that this risk increased with the morbidity burden. Individuals with advanced cardio-metabolic profiles frequently presented the highest infection severity risk in both sexes. The pattern with the highest severity associated in men was present in almost 28.7% of those aged ≥ 80 years and included associations between cardiovascular, respiratory, and metabolic diseases; age-adjusted odds ratio (OR) 95% confidence interval (1.71 (1.44-2.02)). In women, similar patterns were also associated the most with infection severity, in 7% of 65-79-year-olds (1.44 (1.34-1.54)) and in 29% of ≥80-year-olds (1.35 (1.18-1.53)). Patients with mental health patterns also showed one of the highest risks of COVID-19 severity, especially in women. These findings strongly recommend the implementation of personalized approaches to patients with multimorbidity and SARS-CoV-2 infection, especially in the population with high morbidity burden.


Continuum versus discrete model: a comparison for multicellular tumour spheroids.
We study multicellular tumour spheroids with a continuum model based on partial differential equations (PDEs). The model includes viable and necrotic cell densities, as well as oxygen and glucose concentrations. Viable cells consume nutrients and become necrotic below critical nutrient concentrations. Proliferation of viable cells is contact-inhibited if the total cellular density locally exceeds volume carrying capacity. The model is discussed under the assumption of spherical symmetry. Unknown model parameters are determined by simultaneously fitting the cell number to several experimental growth curves for different nutrient concentrations. The outcome of the PDE model is compared with an analogous off-lattice agent-based model for tumour growth. It turns out that the numerically more efficient PDE model suffices to explain the macroscopic growth data. As in the agent-based model, we find that the experimental growth curves are only reproduced when a necrotic core develops. However, evaluation of morphometric properties yields differences between the models and the experiment.


Effects of age and type of picture on visuospatial working memory assessed with a computerized jigsaw-puzzle task.
We investigated the effect of age and color in a computerized version of the jigsaw-puzzle task. In Experiment 1, young and older adults were presented with puzzles in color and black-and-white line drawings, varying in difficulty from 4 to 9 pieces. Older adults performed the task better with the black-and-white stimuli and younger adults performed better with the color ones. In Experiment 2, new older and young adults identified the same fragmented pictures as fast and accurately as possible. The older group identified the black-and-white stimuli faster than those presented in color, while the younger adults identified both similarly. In Experiment 3A, new older and young groups performed the puzzle task with the same color pictures and their monochrome versions. In Experiment 3B, participants performed a speeded identification task with the two sets. The findings of these experiments showed that older adults have a memory not a perceptual difficulty.


Photophysics and photochemistry of dyes bound to human serum albumin are determined by the dye localization.
The photophysics and photochemistry of rose bengal (RB) and methylene blue (MB) bound to human serum albumin (HSA) have been investigated under a variety of experimental conditions. Distribution of the dyes between the external solvent and the protein has been estimated by physical separation and fluorescence measurements. The main localization of protein-bound dye molecules was estimated by the intrinsic fluorescence quenching, displacement of fluorescent probes bound to specific protein sites, and by docking modelling. All the data indicate that, at low occupation numbers, RB binds strongly to the HSA site I, while MB localizes predominantly in the protein binding site II. This different localization explains the observed differences in the dyes' photochemical behaviour. In particular, the environment provided by site I is less polar and considerably less accessible to oxygen. The localization of RB in site I also leads to an efficient quenching of the intrinsic protein fluorescence (ascribed to the nearby Trp residue) and the generation of intra-protein singlet oxygen, whose behaviour is different to that observed in the external solvent or when it is generated by bound MB.


Mechanism of Anticancer Action of Novel Imidazole Platinum(II) Complex Conjugated with G2 PAMAM-OH Dendrimer in Breast Cancer Cells.
Transition metal coordination compounds play an important role in the treatment of neoplastic diseases. However, due to their low selectivity and bioavailability, as well as the frequently occurring phenomenon of drug resistance, new chemical compounds that could overcome these phenomena are still being sought. The solution seems to be the synthesis of new metal complexes conjugated with drug carriers, e.g., dendrimers. Numerous literature data have shown that dendrimers improve the bioavailability of the obtained metal complexes, solving the problem of their poor solubility and stability in an aqueous environment and also breaking down inborn and acquired drug resistance. Therefore, the aim of this study was to synthesize a novel imidazole platinum(II) complex conjugated with and without the second-generation PAMAM dendrimer (PtMet2-PAMAM and PtMet2, respectively) and to evaluate its antitumor activity. Cell viability studies indicated that PtMet2-PAMAM exhibited higher cytotoxic activity than PtMet2 in MCF-7 and MDA-MB-231 breast cancer cells at relatively low concentrations. Moreover, our results indicated that PtMet2-PAMAM exerted antiproliferative effects in a zebrafish embryo model. Treatment with PtMet2-PAMAM substantially increased apoptosis in a dose-dependent manner via caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) activation along with pro-apoptotic protein expression modulation. Additionally, we showed that apoptosis can be induced by activating POX, which induces ROS production. Furthermore, our results also clearly showed that the tested compounds trigger autophagy through p38 pathway activation and increase Beclin-1, LC3, AMPK, and mTOR inhibition. The high pro-apoptotic activity and the ability to activate autophagy by the imidazole platinum(II) complex conjugated with a dendrimer may be due to its demonstrated ability to reverse multidrug resistance (MDR) and thereby increase cellular accumulation in breast cancer cells.


Preventing high-order multiple pregnancies during controlled ovarian hyperstimulation and intrauterine insemination: 3 years' experience using low-dose recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonists.
To employ protocols of mild ovarian stimulation to prevent an excessively elevated rate of high-order multiple pregnancies. Case series. University hospital. Six hundred and twenty one consecutive patients undergoing 1,259 controlled ovarian hyperstimulation and intrauterine insemination cycles. Patients received 50 IU per day of recombinant follicle-stimulating hormone (FSH) starting the third day of the cycle, then a gonadotropin-releasing hormone (GnRH) antagonist on the day in which a follicle > or =13 mm was visualized. Cycles were canceled if three or more follicles > or =16 mm and/or five or more follicles > or =11 mm were detected. Rate of high-order multiple pregnancies. The clinical pregnancy rate per initiated cycle was 9.2% (95% confidence interval, 7.5-11.1%). The incidence of twins and high-order multiple pregnancies was 9.5% (95% CI, 5.3-16.2%) and 0 (0.0-3.2%), respectively. In controlled ovarian hyperstimulation and intrauterine insemination cycles, a protocol of 50 IU of recombinant FSH daily combined with the use of GnRH antagonists and a policy of strict cancellation based on echographic criteria are associated with a satisfactory pregnancy rate per initiated cycle and a low risk of high-order multiple pregnancies.