Influence of type of aortic valve prosthesis on coronary blood flow velocity.
Severe aortic valve stenosis is associated with high resting and reduced hyperemic coronary blood flow. Coronary blood flow increases after aortic valve replacement (AVR); however, the increase depends on the type of prosthesis used. The present study investigates the influence of type of aortic valve prosthesis on coronary blood flow velocity. The blood flow velocity in the left anterior descending coronary artery (LAD) and the right coronary artery (RCA) was measured intraoperatively before and after AVR with a stentless bioprosthesis (Sorin Freedom Solo; n = 11) or a bileaflet mechanical prosthesis (St. Jude Medical Regent; n = 11). Measurements were made with an X-Plore epicardial Doppler probe (Medistim, Oslo, Norway) following induction of hyperemia with an adenosine infusion. Preoperative and postoperative echocardiography evaluations were used to assess valvular and ventricular function. Velocity time integrals (VTI) were measured from the Doppler signals and used to calculate the proportion of systolic VTI (SF), diastolic VTI (DF), and normalized systolic coronary blood flow velocities (NSF) and normalized diastolic coronary blood flow velocities (NDF). The systolic proportion of the LAD VTI increased after AVR with the St. Jude Medical Regent prosthesis, which produced higher LAD SF and NSF values than the Sorin Freedom Solo prosthesis (SF, 0.41 ± 0.09 versus 0.29 ± 0.13 [P = .04]; NSF, 0.88 ± 0.24 versus 0.55 ± 0.17 [P = .01]). No significant changes in the LAD velocity profile were noted after valve replacement with the Sorin Freedom Solo, despite a significant reduction in transvalvular gradient and an increase in the effective orifice area. AVR had no effect on the RCA flow velocity profile. The coronary flow velocity profile in the LAD was significantly influenced by the type of aortic valve prosthesis used. The differences in the LAD velocity profile probably reflect differences in valve design and the systolic transvalvular flow pattern.


"Rectal ears".
"Rectal ears," transitory protrusions of the rectum into the internal inguinal rings, were observed in a 16-month-old girl who also had "bladder ears." Inguinal hernias were not present. The etiology and significance of "rectal ears" has not been determined.


Effect of psychrotrophic bacteria from raw milk on milk proteins and stability of milk proteins to ultrahigh temperature treatment.
The effects of psychrotroph growth in raw milk on proteins of mils and on the response of milk proteins to heat treatments with ultrahigh temperature were studied. Ten gram-negative psychrotrophs isolated from raw milk readily attacked raw milk proteins. Kappa- and beta-casein were most susceptible although some of the isolates also attacked the whey proteins. Detectable proteolysis did not require large psychrotroph populations. A 10 to 20% decrease in kappa-casein during 2 days at 5 C accompanied growth of one isolate to a population of only 10,000/ml. Growth of psychrotrophs in raw milk predisposed the proteins to deleterious effects of ultrahigh temperature treatments. Ultrahigh temperature treatment by direct steam injection had little effect on raw milk caseins and decreased alpha-lactalbumin and beta-lactoglobulin by 21% and 34%, respectively. Milk that had undergone proteolysis exhibited decreased detectable kappa-, beta-, and alphas-caseins and increased loss of beta-lactoglobulin as a result of ultrahigh temperature treatment. Milk suffering extensive kappa-casein degradation coagulated during ultrahigh temperature treatment. Coagulation during or shortly after heating increased with severity of heat treatment and size of psychrotroph population.


[Reducing heart rate to treat angina pectoris].
Elevated heart rate induces an increase in myocardial oxygen consumption as well as a decrease in oxygen delivery. Myocardial ischemia is double in patients with resting heart rate above 80 bpm, compared to those with heart rate below 60 bpm. In addition, angina during effort increases the risk of mortality, directly depending on the degree of angina. Thus, in patients with myocardial angina, reducing heart rate could decrease symptoms and improve cardiovascular prognosis. A recent retrospective analysis of the results from the BEAUTIFUL study provides new evidence on this topic and is discussed in this article.


[How I explore... Hair loss in cancer patients].
Increased hair loss followed, in some instances by an acute focal or total alopecia, can develop in some cancer patients. The surgical stress or procedure, radiotherapy and some chemotherapy regimens can be responsible for these disturbing events. The alopecia is transient or permanent according to its origin. Diverse diagnostic and prognostic methods are available for assessing alopecias. The trichogram is a rewarding one.


Improved Field-Based Soybean Seed Counting and Localization with Feature Level Considered.
Developing automated soybean seed counting tools will help automate yield prediction before harvesting and improving selection efficiency in breeding programs. An integrated approach for counting and localization is ideal for subsequent analysis. The traditional method of object counting is labor-intensive and error-prone and has low localization accuracy. To quantify soybean seed directly rather than sequentially, we propose a P2PNet-Soy method. Several strategies were considered to adjust the architecture and subsequent postprocessing to maximize model performance in seed counting and localization. First, unsupervised clustering was applied to merge closely located overcounts. Second, low-level features were included with high-level features to provide more information. Third, atrous convolution with different kernel sizes was applied to low- and high-level features to extract scale-invariant features to factor in soybean size variation. Fourth, channel and spatial attention effectively separated the foreground and background for easier soybean seed counting and localization. At last, the input image was added to these extracted features to improve model performance. Using 24 soybean accessions as experimental materials, we trained the model on field images of individual soybean plants obtained from one side and tested them on images obtained from the opposite side, with all the above strategies. The superiority of the proposed P2PNet-Soy in soybean seed counting and localization over the original P2PNet was confirmed by a reduction in the value of the mean absolute error, from 105.55 to 12.94. Furthermore, the trained model worked effectively on images obtained directly from the field without background interference.


[Efficacy of the combination of 5 fluorouracil, adriamycin and cisplatin (FAP protocol) in the treatment of metastatic cylindroma. Apropos of a case with review of the literature].
We report the case of a 43 year-old woman who was submitted to a complete surgical resection of an Adenoid Cystic Carcinoma (ACC) of the submandibular salivary gland which was associated with diffuse lung metastases. Combination chemotherapy with fluoro-5-uracil, adriamycin, and cisplatin (FAP) induced an almost complete disappearance of the chest lesions. The literature about ACC and its chemotherapy is reviewed.


Immunoperoxidase staining of trichomonas vaginalis in cytologic material.
In the course of studies on the histopathology and pathogenesis of trichomonal infections, specific antisera to Trichomonas vaginalis were produced. Using these antisera, conventional immunocytochemical techniques were modified and applied to a variety of cytologic specimens. With this methodology, trichomonal organisms were identified in specimens from usual and unexpected locations. These findings plus the potential applications of similar methodologies to other areas of cytopathology are reported.


Identification of PTP1C mutation as the genetic defect in motheaten and viable motheaten mice: a step toward defining the roles of protein tyrosine phosphatases in the regulation of hemopoietic cell differentiation and function.
Homozygosity for the motheaten (me) or viable motheaten (mev) mutations causes severe dysregulation of murine hematopoiesis with the consequent development of both immunodeficiency and systemic autoimmunity. Expression of this phenotype has now been linked to loss-of-function mutations in the gene encoding PTP1C, an intracellular tyrosine phosphatase predominantly expressed in cells of hemopoietic origin. As discussed in this article, the association of PTP1C mutation with the multiple hemopoietic defects found in motheaten mice indicates that this tyrosine phosphatase is critical to normal hematopoiesis and is consistent with the recognized importance of protein tyrosine phosphorylation in modulating the cell signaling pathways governing proliferation and differentiation. The motheaten mouse therefore provides a powerful model of delineating the precise function of PTP1C and thereby elucidating the specific molecular mechanisms whereby this tyrosine phosphatase participates in the control of hemopoietic cell differentiation and function.


Pro-peptide as an intramolecular chaperone: renaturation of denatured subtilisin E with a synthetic pro-peptide [corrected].
The amino-terminal pro-sequence consisting of 77 amino acid residues is required to guide the folding of secreted subtilisin E, a serine protease, into active, mature enzyme (ikemura et al., 1987). Furthermore, denatured subtilisin E can be folded to active enzyme in an intermolecular process with the aid of an exogenously added pro-subtilisin E, the active site of which was mutated (Zhu et al., 1989). In this report, we have synthesized the pro-peptide of 77 residues (corresponding to -1 to -77 in the sequence, where residue +1 is the N-terminal amino acid residue of the mature protein), and have found that it could intermolecularly complement the folding of denatured subtilisin E to active enzyme. Furthermore, we have found that the synthetic pro-peptide exhibits specific strong binding to the active mature enzyme by inhibiting it competitively at its active centre with an upper limit to a Ki of 5.4 x 10(-7). In contrast, synthetic pro-peptides corresponding to -44 to -77, -1 to -64 and -1 to -43 inhibited the enzyme with Ki values weaker by two orders of magnitude. The results indicate that the sequence extending from -1 to -77 is essential for specificity of interaction, perhaps generating a conformation that accounts for both roles found hitherto, i.e. specific binding to the active centre, and guiding of the refolding to active enzyme. Thus these results suggest that the pro-peptide functions as an intramolecular chaperone [corrected].


The Study of Biomechanics and Clinical Anatomy on a Novel Plate Designed for Posterolateral Tibial Plateau Fractures via Anterolateral Approach.
There is no consensus about the optimal internal fixation selection for treatment of posterolateral tibial plateau fracture. This study described a novel plate through an anterolateral approach for posterolateral tibial plateau fractures (PTPFs). We evaluated the biomechanical performance of a novel plate and two conventional internal implants and investigated the anatomic feasibility of the novel plate. The fracture models were randomly assigned into six groups: Groups A-C were the model groups of posterolateral split fracture, fixed with the posterior buttress plate, the lateral locking plate, and the novel plate, respectively. Groups D-E were the model groups of posterolateral depression fracture, fixed with the posterior buttress plate, the lateral locking plate, and the novel plate, respectively. We evaluated the biomechanical performance of six model groups by the biomechanical testing and finite element analysis. Progressively increasing axial compressive loads were applied to each synthetic fracture model by using a customized indentor under 250-750 N loads. Meanwhile, we dissected 12 fresh frozen knee specimens and fixed them with the novel plate through the anterolateral approach. We recorded the adjacency of the novel plate to important anatomic structures. Biomechanical testing showed that the novel plate had the least displacement, followed by the posterior buttress plate, and the lateral plate had the most displacement in posterolateral split fracture. There was no significant difference in the displacement between the novel plate and the lateral plate at different loads in posterolateral depression fractures. And the posterior buttress plate showed the most displacement. In the finite element analysis, the maximum stress values of Groups A, B, and C were 383.76, 414.63, and 305.07 MPa under the load of 750 N, respectively. The maximum stress values of Groups D, E, and F were 474.28, 436.31, and 413.4 MPa under the load of 750 N, respectively. In the anatomic study, the placement of the novel plate had a low risk of damage to the important anatomic structures of knee posterolateral corner. The novel plate could be a great choice for the treatment of PTPFs due to better biomechanical performance and easy manipulation.


Ethnopharmacological studies on antispasmodic and antiplatelet activities of Ficus carica.
The ripe dried fruit of Ficus carica Linn. (Moraceae) commonly known as "Fig" has medicinal value in traditional system of medicine for its use in gastrointestinal and inflammatory disorders. To rationalize the medicinal use of Fig (Ficus carica) in gastrointestinal and inflammatory disorders. The aqueous-ethanolic extract of Ficus carica (Fc.Cr) was studied for antispasmodic effect on the isolated rabbit jejunum preparations and for antiplatelet effect using ex vivo model of human platelets. Fc.Cr tested positive for alkaloids, flavonoids, coumarins, saponins, sterols and terpenes. When tested in isolated rabbit jejunum, Fc.Cr (0.1-3.0mg/mL) produced relaxation of spontaneous and low K(+) (25 mM)-induced contractions with negligible effect on high K(+) (80 mM) similar to that caused by cromakalim. Pretreatment of the tissue with glibenclamide caused rightward shift in the curves of low K(+)-induced contractions. Similarly, cromakalim inhibited the contractions induced by low K(+), but not of high K(+), while verapamil equally inhibited the contractions of K(+) at both concentrations. Fc.Cr (0.6 and 0.12 mg/mL) inhibited the adenosine 5'-diphosphate and adrenaline-induced human platelet aggregation. This study showed the presence of spasmolytic activity in the ripe dried fruit of Ficus carica possibly mediated through the activation of K(+)(ATP) channels along with antiplatelet activity which provides sound pharmacological basis for its medicinal use in the gut motility and inflammatory disorders.


Geometric optics-based multiband cloaking of large objects with the wave phase and amplitude preservation.
The geometric optics principles are used to develop a unidirectional transmission cloak for hiding objects with dimensions substantially exceeding the incident radiation wavelengths. Invisibility of both the object and the cloak is achieved without metamaterials, so that significant widths of the cloaking bands are provided. For the preservation of wave phases, the λ-multiple delays of waves passing through the cloak are realized. Suppression of reflection losses is achieved by using half-λ multiple thicknesses of optical elements. Due to periodicity of phase delay and reflection suppression conditions, the cloak demonstrates efficient multiband performance confirmed by full-wave simulations.


EEG dynamics of the frontoparietal network during reaching preparation in humans.
Visuomotor transformation processes are essential when accurate reaching movements towards a visual target have to be performed. In contrast, those transformations are not needed for similar, but non-visually guided, arm movements. According to previous studies, these transformations are carried out by neuronal populations located in the parietal and frontal cortical areas (the so-called "dorsal visual stream"). However, it is still debated whether these processes are mediated by the sequential and/or parallel activation of the frontoparietal areas. To investigate this issue, we designed a task where the same visual cue could represent either the target of a reaching/pointing movement or the go-signal for a similar but non-targeting arm movement. By subtracting the event-related potentials (ERPs) recorded from healthy subjects performing the two conditions, we identified the brain processes underlying the visuomotor transformations needed for accurate reaching/pointing movements. We then localized the generators by means of cortical current density (CCD) reconstruction and studied their dynamics from visual cue presentation to movement onset. The results showed simultaneous activation of the parietal and frontal areas from 140 to 260 ms. The results are interpreted as neural correlates of two critical phases of visuomotor integration, namely target selection and movement selection. Our findings suggest that the visuomotor transformation processes required for correct reaching/pointing movements do not rely on a purely sequential activation of the frontoparietal areas, but mainly on a parallel information processing system, where feedback circuits play an important role before movement onset.


Rapid, Direct, Noninvasive Method to Determine the Amount of Immobilized Protein.
Protein immobilization is of utmost importance in many areas, where various proteins are used for selective detection of target compounds. Despite the importance given to determine the amount of immobilized protein, there is no simple method that allows direct, noninvasive detection. In this work, a method based on pH transition, occurring during change of solution ionic strength, was developed. The method utilized the ionic character of the immobilized protein while implementing biologically compatible buffers. Five different proteins, namely, glucose oxidase, horseradish peroxidase, bovine serum albumin, lysozyme, and protein A, were immobilized in different amounts on a porous polymeric matrix, and their pH transition was measured using lactate buffer of various concentrations and pH values. A linear correlation was found between the amount of immobilized protein and the amplitude of the pH transition, allowing the detection down to 2 nmol of immobilized protein. By changing the buffer concentration and pH, the sensitivity of the method could be tailored. Criteria based on the symmetry of the pH transition peak have been developed to determine if a particular measurement is within a linear range. In addition, a mathematical model was developed enabling prediction of pH transition profiles based solely on the protein amino acid sequence, the buffer pKa value(s), and the amount of immobilized protein.Hence, it can be used to design pH transition method experiments to achieve the required sensitivity for a target sample. Since the proposed method is noninvasive, it can be routinely applied during optimization of the immobilization protocol, for quality control, and also as an in-process monitoring tool.


PhotoModPlus: A web server for photosynthetic protein prediction from genome neighborhood features.
A new web server called PhotoModPlus is presented as a platform for predicting photosynthetic proteins via genome neighborhood networks (GNN) and genome neighborhood-based machine learning. GNN enables users to visualize the overview of the conserved neighboring genes from multiple photosynthetic prokaryotic genomes and provides functional guidance on the query input. In the platform, we also present a new machine learning model utilizing genome neighborhood features for predicting photosynthesis-specific functions based on 24 prokaryotic photosynthesis-related GO terms, namely PhotoModGO. The new model performed better than the sequence-based approaches with an F1 measure of 0.872, based on nested five-fold cross-validation. Finally, we demonstrated the applications of the webserver and the new model in the identification of novel photosynthetic proteins. The server is user-friendly, compatible with all devices, and available at bicep.kmutt.ac.th/photomod.


Concerning the application of phenomenology to caring research.
When phenomenology is adopted as a framework for conducting nursing research, confusions sometimes arise because the researchers do not clarify their understanding of phenomenology. One of the biggest confusions is whether to follow philosophical phenomenological guidelines or scientific guidelines. While phenomenology began as a philosophy, it is argued here that the guidelines of scientific practice should be followed when conducting caring research. This article sharpens the distinction between philosophical and scientific phenomenology and demonstrates the confusion that can ensue when philosophical phenomenology is uncritically used as the model for scientific research. It does so by examining the work of Crotty.


Simulation of pulsed ultrasonic diffraction in viscous fluids using transmission line matrix method.
Ultrasonic fields propagating in viscous media undergo changes in shape due to diffraction, attenuation, and dispersion. Until now, some implementations in the transmission line matrix (TLM) method has been developed to simulate either diffraction or attenuation but never both. In this work, the quadratic frequency dependence of the absorption coefficient as well as the dispersive effect of a viscous fluid are introduced in the TLM method. The idea is to decompose the emitted wave into its components at different frequencies using Fourier transform. Then, dispersion and attenuation effects are considered for each wave component separately before superposing them to get the required acoustic response. This is possible because each one of them is characterized by a constant absorption coefficient and propagates at a single speed. This TLM model has been applied to the diffracted ultrasonic field by a circular transducer radiating a short pulse in a viscous fluid. The obtained waveforms are interpreted in terms of plane and edge waves. A study of the influence of the most important parameters on the waveform of the detected ultrasonic pulses is performed. The numerical results obtained highlight the attenuation effect on the waves' shapes and the influence of the dispersion on their arrival times.


Detection of HPV infection in head and neck cancers: Promise and pitfalls in the last ten years: A meta-analysis.
The current controversial discussion on the disease-specific survival of patients with human papillomavirus (HPV)-positive (+) and -negative (-) squamous cell carcinoma (SCC) of the head neck region was the motivation for the present meta-analysis. Different detection methods for HPV are available, though these often lack sensitivity. As a consequence, there may be false interpretation of HPV positivity. A bias concerning HPV status and therefore also survival rates is serving a non-durable relevance in the discussion of tailored therapies. A literature search was performed via the online database PubMed/NCBI, and data extraction and statistical analysis were conducted. A total of 139 studies published between 2004 and 2014 were evaluated in the present meta-analysis. The HPV detection methods, patient characteristics, tumor localizations and stages, as well as (neo-) adjuvant therapies and survival times were analyzed. The average incidence rates of HPV+ patients with oropharyngeal tumors were higher than those of patients with cancers of other regions of the head and neck. Upon evaluating the results of different detection methods no significant differences were identified. We have compared the HPV incidence rates of each detection method, when studies have used more than one. Regarding overall survival, the pooled adjusted hazard ratio (HR) for oropharyngeal SCC was 0.31 [95% confidence interval (CI)=0.27-0.36]. Unfortunately, only 3 equivalent studies were available on nonoropharyngeal tumors, for which the pooled adjusted HR was 1 (95% CI=0.73-1.36). Overall, the evaluation demonstrated that the survival rates reported in numerous studies were not evaluated multifactorially and important confounders were excluded from the statistics. The HPV detection methods used were often not sufficient in representing HPV positivity. In addition, oropharyngeal and oral SCCs were assessed together in the localization. The widely differing number of HPV+ patients in each of the various studies may be explained by insufficient detection methods and by a lack of localization distinction. The considerations of a tailored therapy according to HPV status should be rejected based on the present information. The previously published studies should be read critically and do not represent a basis for therapeutic decisions.


Does OKT3 monoclonal antibody react with an antigen-recognition structure on human T cells?
OKT3 monoclonal antibody to human T cells inhibits the target cell lysis mediated by allogeneic cytotoxic T cells and the generation of these effector cells in mixed lymphocyte culture. This marked inhibition of cell-mediated lysis is not found with other monoclonal antibodies also reactive with cell surface antigens of human T cells (OKT1, OKT4, OKT5, OKT6, OKT8, and OKT11). OKT3 antibody is mitogenic and this effect appears to require receptor activation in that it occurs at low concentrations (10(-12) M range) of OKT3 antibody, requires intact OKT3 IgG, and is inhibited by a factor(s) in human plasma. By contrast, the inhibition of allogeneic cell-mediated lysis by OKT3 antibody appears to be due to steric hindrance in that it requires higher concentrations of OKT3 antibody (10(-8) M range), Fab fragments retain approximately 10% activity, and inhibition is demonstrable in the presence of human plasma. These findings are consistent with the suggestion that OKT3 antibody reacts with the human T-cell antigen-recognition structure.


The pathophysiological function of peroxisome proliferator-activated receptor-gamma in lung-related diseases.
Research into respiratory diseases has reached a critical stage and the introduction of novel therapies is essential in combating these debilitating conditions. With the discovery of the peroxisome proliferator-activated receptor and its involvement in inflammatory responses of cardiovascular disease and diabetes, attention has turned to lung diseases and whether knowledge of this receptor can be applied to therapy of the human airways. In this article, we explore the prospect of peroxisome proliferator-activated receptor-gamma as a marker and treatment focal point of lung diseases such as asthma, chronic obstructive pulmonary disorder, lung cancer and cystic fibrosis. It is anticipated that peroxisome proliferator-activated receptor-gamma ligands will provide not only useful mechanistic pathway information but also a possible new wave of therapies for sufferers of chronic respiratory diseases.


Arterial gene transfer to rabbit endothelial and smooth muscle cells using percutaneous delivery of an adenoviral vector.
Previous investigations in live animals convincingly established that arterial gene transfer, while feasible, was compromised by a low transfection efficiency. More recent studies have shown that transfection efficiency may be substantially augmented by the use of recombinant adenoviral vectors. Most in vivo transfections reported to date, however, have used direct (operative) administration of the adenoviral vector. Clinical applications of arterial gene transfer (such as prevention of restenosis), however, would require local percutaneous delivery of the transgene. The present study was designed to extend in vivo intraoperative findings to percutaneous delivery system and to assess whether gene transfer remains site specific. A recombinant, replication-defective adenovirus modified to include an expression cassette for nucleus-targeted beta-galactosidase was introduced into rabbit iliac arteries in vivo using either a double-balloon catheter (DBC, n = 27) or a hydrogel-coated balloon catheter (HBC, n = 27). Contralateral arteries-normal, endothelium-denuded, or sham-transfected with a control adenoviral vector-served as controls. beta-Galactosidase expression was assessed by X-Gal staining. Cell-transduction efficiency was measured by morphometric analysis. Polymerase chain reaction (PCR) and histochemistry were used to detect the presence and/or expression of viral DNA in remote organs. Transgene expression was detected in all cases (46 of 46) between 3 and 14 days after transfection but was in no case detectable 28 days after transfection. In the DBC group, transgene expression was limited to endothelial cells when the endothelium was left intact and to rare medial cells (< 2.2%) when it had been removed. In contrast, HBC delivery resulted in transduction of up to 9.6% of medial smooth muscle cells (P = .0001). Optimized PCR and histochemistry failed to detect evidence of extra-arterial transfection except in a small number of cells (between 1 in 3 x 10(2) and 1 in 3 x 10(5) cells) in the livers of 2 animals in the DBC group. (1) Efficient, adenovirus-mediated, arterial gene transfer to endothelial and/or smooth muscle cells is feasible by percutaneous, clinically applicable techniques. (2) Consistent transfection of medial smooth muscle cells may be achieved when the endothelial layer is abraded. (3) Medial transfection is more efficient when an HBC, rather than a DBC, is used. (4) Percutaneous delivery of the adenoviral vector via HBC results in site-specific arterial gene transfer. Very-low-level extra-arterial transfection may occur, however, when the DBC is used.


Multimeric analysis in diagnosis of vWD variants in Indians.
von Willebrand disease is a common inherited bleeding disorder and the problem is undefined in developing countries due to limitation of its diagnostic facilities. The aim of the study was to diagnose vWD in patients with history of muco - cutaneous bleeding and characterization into its variants by multimeric analysis. 224 patients presenting with history of muco - cutaneous bleeding were selected. In all patients, platelet count, BT, PT, APTT, PF3 availability, clot solubility and factor VIII assay were done. Diagnosis of vWD was confirmed by RIPA, vWF: Ag, and vWF: RCo and its sub-characterization was done by multimeric analysis. 64 patients were diagnosed to have vWD. Of these, 21.9% were of type 1 vWD, 43.7% type 2 vWD, 1.6% acquired vWD and 32.8% type 3 vWD. By multimeric analysis, 2 patients had supranormal HMW multimers and two patients had normal distribution of vWF multimers were diagnosed as type 2M 'Vicenza'; and type 2M vWD respectively. It is concluded, that vWD is not an uncommon condition amongst Indian population.


Estimates of global research productivity in using nicotine replacement therapy for tobacco cessation: a bibliometric study.
Tobacco use is a major healthcare problem worldwide. Tobacco smoking remains the most important risk factor for both cancer and heart diseases. This study was initiated due to the lack of published data concerning the real progress in research output in the use of nicotine replacement therapy (NRT) for tobacco cessation. This study was aimed to use bibliometric analysis to estimate the NRT literature indexed in Scopus database at global level. Core of the search strategy was the documents that contained specific words or phrases regarding NRT as keywords in the title. Publication output of most prolific countries was adjusted to the gross domestic product and population size. All citations analysis were accomplished on December 22, 2017. A total of 2138 references were retrieved and published from 56 countries, which were published between 1970 and 2016. The USA has the most number of published articles accounted to 986, followed by the UK (312 publications) and then Australia (102 publications), and Sweden (102 publications). No data related to NRT were published from 156 countries. No significant correlation was found between the country population size or 2016 gross domestic product values and the number of publications of the top-10 most prolific countries in the field of NRT (r = - 0.156, P = 0.664; and r = - 0.173, P = 0.632, respectively). Furthermore, there is no correlation between prevalence of tobacco smoking and number of publications of the top-10 most prolific countries in the field of NRT (r = - 0.235, P = 0.514). The present data reveal a solid mass of research activity on NRT. The USA was by far the predominant country in the amount of NRT-based research activity. NRT-based research activities were low or not available in most countries. The results of this study delineate a framework for better understanding the situations of current NRT research and prospective directions of the research in this field which could be applied for managing and prioritizing future research efforts in NRT research.


Pima Indian males have lower beta-adrenergic sensitivity than Caucasian males.
The sympathetic nervous system controls cardiovascular homeostasis and regulates energy metabolism. Pima Indians, a population with a low prevalence of hypertension and a high prevalence of obesity, have low sympathetic nervous activity, compared with Caucasians. Preliminary findings suggest that they may also have a low beta-adrenergic sensitivity. We studied beta-adrenergic sensitivity in 87 nondiabetic normotensive individuals [52 Pima Indians (35 males/17 females) and 35 Caucasians (24 males/11 females)], matched for age and body weight. Chronotropic sensitivity to beta-adrenergic stimulation was assessed by the dose of isoproterenol necessary to increase heart rate by 25 beats per minute [chronotropic dose-25 (CD25)]. Despite a similar basal heart rate and arterial blood pressure, Pimas tended to have lower beta-adrenergic sensitivity than Caucasians (CD25 = 2.37 +/- 2.27 vs. 1.57 +/- 1.38 microg, P = 0.07; mean +/- SD). This difference was significant in males (CD25 = 3.03 +/- 2.39 vs. 1.85 +/- 1.56 microg, P = 0.02) but not in females (CD25 = 1.01 +/- 1.17 vs. 0.96 +/- 0.61 microg, P = 0.99). In males only, CD25 was positively correlated to percent body fat (r = 0.36, P < 0.01). After adjustment for percent body fat, beta-adrenergic sensitivity was still significantly lower in Pima than in Caucasian males (CD25 = 3.44 +/- 2.24 vs. 2.57 +/- 1.60 microg, P = 0.05). In conclusion, our data suggest that increased adiposity is accompanied by decreased beta-adrenergic sensitivity in males only. However, at each level of adiposity, Pima Indian males have lower beta-adrenergic sensitivity than Caucasian males. In combination with a low sympathetic nervous system activity, a reduced beta-adrenergic sensitivity may contribute to the low prevalence of hypertension and the high prevalence of obesity observed in Pima Indians.


Mycobacterium abscessus felon complicated with osteomyelitis: not an ordinary nail salon visit.
Mycobacterium abscessus is an environmental organism that has been implicated in pulmonary and extrapulmonary infections. Cases of furunculosis have been described in patients who underwent footbaths in nail salons; however, no cases of severe soft tissue infections or osteomyelitis have been reported following manicures. Here, we present the case of a 50-year-old woman who developed a felon in right index finger one week after having a manicure. She underwent incision and drainage of affected area. Cultures from purulence grew Mycobacterium abscessus. Imaging revealed osteomyelitis of distal phalanx. She was successfully treated with a prolonged course of antibiotics that included imipenem, linezolid, tigecycline, and clarithromycin. We highlight the importance of recognizing this uncommon complication and advocate the use of combined antibiotic regimens for an adequate treatment of this infection.


IgG4-related disease: a clinical perspective.
IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder that can affect almost any organ. Common presentations include major salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. The main histopathological features are a dense, polyclonal, lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform fibrosis and obliterative phlebitis. The precise pathogenic mechanisms of IgG4-RD are still unclear. CD4+ T and B cells, including IgG4-expressing plasmablasts, constitute the major inflammatory cell populations and are believed to cause organ damage and tissue fibrosis. The diagnosis of the disease may be challenging and should be based on specific histopathological findings, typical laboratory and radiological aspects and an appropriate clinical context. The first-line treatment of IgG4-RD is based on glucocorticoids, which are usually efficacious. However, B cell depletion induced by rituximab has also been found to induce remission in steroid-resistant disease or has been used as steroid-sparing agent for relapsing disease. This review provides an update on clinical and therapeutic aspects of IgG4-RD.


3-Hydroxybutyrate aids the recovery of the energy state from aglycaemic hypoxia of adult but not neonatal rat brain slices.
The level of phosphocreatine (PCr) and the intracellular pH (pHi) of superfused cortical brain slices from adult or 10-day-old rats were monitored using 31P NMR. When the glucose in the superfusing medium was replaced by 3-hydroxybutyrate (3HB), there was a significant reduction in PCr of the adult but not the neonatal slices. The level of PCr of the adult slices was reduced by a greater amount by aglycaemic hypoxia compared with the neonatal brain slices and pHi was decreased by the same amount. After aglycaemic hypoxia, the levels of PCr of the neonatal slices recovered to the same extent when perfused with glucose or 3HB alone or a mixture of glucose and 3HB. The recovery of the PCr was significantly more in the neonatal than the adult brain slices with glucose alone after aglycaemic hypoxia, whereas pHi returned to control levels in both tissue types and with all substrates. The relative recovery of the PCr of the adult slices after aglycaemic hypoxia was the same with either 3HB or glucose. However, if glucose and 3HB were applied together, recovery of PCr was significantly improved compared with glucose alone.


Crystallization and preliminary X-ray analysis of the two domains of glucosamine-6-phosphate synthase from Escherichia coli.
The glutamine amidohydrolase and fructose 6-phosphate binding domains of glucosamine-6-phosphate synthase from Escherichia coli have been overexpressed, purified and crystallized for X-ray diffraction analysis. The crystals of the glutamine amidohydrolase domain belong to the orthorhombic space group P2(1)2(1)2(1) with cell dimensions a = 70.4 A, b = 82.5 A, c = 86.1 A, with two molecules in the asymmetric unit, and diffract to 1.9 A resolution. The native Patterson indicated pseudo c-face centering of the unit cell. The fructose 6-phosphate binding domain was crystallized in the hexagonal space group P6(1) or P6(5) with cell dimensions a = b = 63.5 A, c = 334.3 A and with two molecules in the asymmetric unit. Diffraction data to 2.6 A resolution have been collected.


Amplitude death and synchronized states in nonlinear time-delay systems coupled through mean-field diffusion.
We explore and experimentally demonstrate the phenomena of amplitude death (AD) and the corresponding transitions through synchronized states that lead to AD in coupled intrinsic time-delayed hyperchaotic oscillators interacting through mean-field diffusion. We identify a novel synchronization transition scenario leading to AD, namely transitions among AD, generalized anticipatory synchronization (GAS), complete synchronization (CS), and generalized lag synchronization (GLS). This transition is mediated by variation of the difference of intrinsic time-delays associated with the individual systems and has no analogue in non-delayed systems or coupled oscillators with coupling time-delay. We further show that, for equal intrinsic time-delays, increasing coupling strength results in a transition from the unsynchronized state to AD state via in-phase (complete) synchronized states. Using Krasovskii-Lyapunov theory, we derive the stability conditions that predict the parametric region of occurrence of GAS, GLS, and CS; also, using a linear stability analysis, we derive the condition of occurrence of AD. We use the error function of proper synchronization manifold and a modified form of the similarity function to provide the quantitative support to GLS and GAS. We demonstrate all the scenarios in an electronic circuit experiment; the experimental time-series, phase-plane plots, and generalized autocorrelation function computed from the experimental time series data are used to confirm the occurrence of all the phenomena in the coupled oscillators.


The mutual effect of extracellular Ca2+, abscisic acid, and pH on the rate of stomatal closure.
An analysis of the rate of stomatal closure in epidermal strips of Commelina communis L. induced by different calcium concentrations (10 nM to 1 mM) demonstrated a biphasic dependency, the initial process of closure being more calcium dependent. This dependency was more evident at pH 7 than pH 5 of the bathing medium. Addition of low concentrations of abscisic acid (10 nM) induced a broadening of the Ca(2) dependency, while 10 microM abscisic acid increased the rate of stomatal closure in the whole Ca(2+) range and to a large extent abolished the calcium-induced effects. Such results indicate an interaction of external protons, Ca(2+), and abscisic acid, and possible competition for the membrane associated binding sites of the mechanism(s) responsible for the regulation of stomatal closure.


Foreign body ingestions in a schizophrenic patient.
The topic of foreign body ingestion has received extensive coverage in the areas of surgery, emergency medicine and pediatrics. A subset of this topic, the intentional ingestion of foreign bodies, however, is much less common, and involves subtleties in evaluation and management not usually seen in accidental ingestions. Here, we report a case of ingestion of a rolled, metal tuna can lid in a male prison inmate previously diagnosed with depression and paranoid schizophrenia. Following evaluation by the surgical team, the foreign body was removed by laparotomy and the patient was discharged back to the prison without complication. In many cases, ingestions ofthis type involve a command hallucination ordering the patient to swallow the foreign body. Interestingly, the patient in the present case reported auditory hallucinations commanding him not to swallow the can lid.


Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters: Cross-sectional study.
The objective of the present study was to assess the effect of cyclosporine (CsA) on the pharmacokinetic parameters of mycophenolic acid (MPA), an active mycophenolate mofetil (MMF) metabolite, and to compare with the effect of everolimus (EVR).Anonymized medical records of 404 kidney recipients were reviewed. The main MPA pharmacokinetic parameters (AUC(0-12) and Cmax) were evaluated.The patients treated with a higher mean dose of CsA displayed higher MPA AUC(0-12) exposure in the low-dose MMF group (1000 mg/day) (40.50 ± 10.97 vs 28.08 ± 11.03 h mg/L; rs = 0.497, P < 0.05), medium-dose MMF group (2000 mg/day) (43.00 ± 6.27 vs 28.85 ± 11.08 h mg/L; rs = 0.437, P < 0.01), and high-dose MMF group (3000 mg/day) (56.75 ± 16.78 vs 36.20 ± 3.70 h mg/L; rs = 0.608, P < 0.05).A positive correlation was also observed between the mean CsA dose and the MPA Cmax in the low-dose MMF group (Cmax 22.83 ± 10.82 vs 12.08 ± 5.59 mg/L; rs = 0.507, P < 0.05) and in the medium-dose MMF group (22.77 ± 8.86 vs 13.00 ± 6.82 mg/L; rs = 0.414, P < 0.01).The comparative analysis between 2 treatment arms (MMF + CsA and MMF + EVR) showed that MPA AUC(0-12) exposure was by 43% higher in the patients treated with a medium dose of MMF and EVR than in the patients treated with a medium dose of MMF and CsA.The data of the present study suggest a possible CsA versus EVR influence on MMF pharmacokinetics. Study results show that CsA has an impact on the main MPA pharmacokinetic parameters (AUC(0-12) and Cmax) in a CsA dose-related manner, while EVR mildly influence or does not affect MPA pharmacokinetic parameters. Low-dose CsA (lower than 180 mg/day) reduces MPA AUC(0-12) exposure under the therapeutic window and may lead to ineffective therapy, while a high-dose CsA (>240 mg/day) is related to greater than 10 mg/L MPA Cmax and increases the likelihood of adverse events.


[Grapefruit juice as a contraindication? An approach in psychiatry].
The authors investigated in this preliminary study the influence of grapefruit juice on the metabolism of two tricyclic antidepressants. An increase of plasma concentrations is observed indeed for many drugs when administered concomitantly with grapefruit juice. This effect was mainly attributed to inhibition of cytochrome P450 1A2 and 3A4 enzymes by naringenin. These isoenzymes are involved too in the metabolism of many psychotropic drugs. Only two benzodiazepines (midazolam and triazolam) were studied in the conditions of grapefruit juice association. All these studies are performed in healthy subjects and with a study design very different from the clinical conditions. On the basis of these considerations, the authors hypothesized that grapefruit juice should inhibit tricyclic antidepressant metabolism and thus increase the bioavailability of these drugs. They want to precise if this possible drug plasma level increase could be clinically important for depressed patients. Fourteen depressed inpatients were selected for the study. Seven of them received amitriptyline (100 to 150 mg/d) and the seven others clomipramine (112.5 to 225 mg/d). Tricyclic antidepressant and desmethylated metabolite plasma levels were determined on four occasions. The first and second day samples were obtained to determined the plasma level intraindividual variability of antidepressants. On the third and fourth days, plasma levels were determined after an oral coadministration of the antidepressant and 250 ml of pure and fresh grapefruit juice. One patient was excluded from the study due to the coadministration of clomipramine and fluvoxamine. There is indeed a major drug-interaction between these two drugs, and the tricyclic antidepressant plasma levels of this patient were in the toxic range, without side effect. In this group of patients, there was no metabolic interaction between amitriptyline and grapefruit juice. But the mean plasma levels of clomipramine and desmethylclomipramine increased after coadministration of this juice (+4.5% and +10.5% respectively). The authors concluded that with these preliminary results, the potential clinical relevance of this interaction cannot be estimated.


Sequential Tandem Addition to a Tungsten-Trifluorotoluene Complex: A Versatile Method for the Preparation of Highly Functionalized Trifluoromethylated Cyclohexenes.
The effects of an electron-withdrawing group on the organic chemistry of an η2-bound benzene ring are explored using the complex TpW(NO)(PMe3)(η2-PhCF3). This trifluorotoluene complex was found to undergo a highly regio- and stereoselective 1,2-addition reaction involving protonation of an ortho carbon followed by addition of a carbon nucleophile. The resulting 1,3-diene complexes can undergo a second protonation and nucleophilic addition with a range of nucleophiles including hydrides, amines, cyanide, and protected enolates. Interestingly, the addition of the second proton and nucleophile occurs in a 1,4-fashion, again with a high degree of regio- and stereocontrol. Oxidation of the metal allows for the isolation of highly substituted trifluoromethylcyclohexenes with as many as four stereocenters set by the metal. The ability to synthesize enantio-enriched organics was also demonstrated for a diene and a trisubstituted cyclohexene. Substitution from an enantio-enriched η2-dimethoxybenzene complex in neat trifluorotoluene yielded enantio-enriched trifluorotoluene complex, which was elaborated into cyclohexadienes and cyclohexenes with ee's ranging from 92 to 99%.


The Effect of Training in the Preparatory and Competitive Periods on Trunk Rotational Power in Canoeists, Ice-Hockey Players, and Tennis Players.
This study evaluates changes in trunk rotational power at different weights and velocities after the preparatory and competitive periods in ice-hockey players, tennis players, and canoeists. The subjects performed trunk rotations to each side with a barbell of different weights placed on the shoulders (6, 10, 12, 16, 20, 22, and 26 kg) prior to and after 6 weeks of the preparatory period and 6 weeks of the competitive period. The results showed that mean power produced in the acceleration phase of trunk rotations increased significantly at weights from 10 to 26 kg or 6 to 26 kg after the preparatory and competitive periods in tennis players. The values obtained during trunk rotations with weights ≥12 kg also increased significantly after the preparatory period in ice-hockey players, whereas there were no significant changes after the competitive period. Similarly, the mean power during trunk rotations with weights ≥10 kg increased significantly only after the preparatory period in canoeists. Similar changes were observed for the peak power. These findings demonstrate that changes in trunk rotational power reflect the specificity of their training programs. This information may provide a basis for designing exercises focused on improvements of power produced during trunk rotations under loading conditions.


Iranian Nurses' Experiences of Workplace Violence in Prehospital Emergency Care: A Qualitative Study.
Prehospital emergency care nurses experience severe workplace violence. However, despite the widespread violence they experience, this phenomenon has not been well studied among these nurses. Therefore, the purpose of this study was to explore the experiences of Iranian nurses working in prehospital setting regarding workplace violence with a focus on the factors leading to such violence. In this qualitative descriptive study, 23 prehospital nurses participated purposefully. The data were collected by individual face-to-face semistructured interviews and analyzed using content analysis methodology. Data analysis led to the identification of 4 main themes, including job competency mismatch, inadequate resources, criticality of the situation and circumstances, and inadequate awareness and misplaced expectations of society. These nurses have not completed specialized training courses, work in a system that is in a critical situation, and face many barriers and deficiencies in terms of intra- and interorganizational coordination. On the other hand, people in the community do not have sufficient awareness about the duties and services provided by prehospital nurses and thus have unrealistic expectations to receive services. The results showed that there was a deep gap between the prehospital emergency realities and public expectations, leading to workplace violence. Therefore, efforts to improve the working conditions of nurses with an emphasis on teaching specialized prehospital emergency courses, especially violence control courses, promoting intra- and interorganizational coordination, and increasing the equipment and personnel of ambulances for special missions, as well as raising the public awareness and outlining more realistic expectations, may reduce the prevalence of violence against prehospital nurses.


Surface Fe(II)/Fe(III) Cycle Promoted Ultra-Highly Sensitive Electrochemical Sensing of Arsenic(III) with Dumbbell-Like Au/Fe3O4 Nanoparticles.
Developing a new ultrasensitive interface to detect As(III) is highly desirable because of its seriously toxic and low concentration in drinking water. Recently, Fe3O4 nanoparticles of high adsorption toward As(III) become very promising to be such an interface, which is still limited by the poor understanding of their surface physicochemical properties. Herein, we report that dumbbell-like Au/Fe3O4 nanoparticles, when being modified the screen-printed carbon electrode, can serve as an efficient sensing interface for As(III) detection with an excellent sensitivity of 9.43 μA ppb-1 and a low detection limit of 0.0215 ppb. These outstanding records were attributed to the participation of Fe(II)/Fe(III) cycle on Fe3O4 surface in the electrochemical reaction of As(III) redox, as revealed by X-ray photoelectron spectroscopy, X-ray absorption near edge structure, and extended X-ray absorption fine structure. This work provides new insight into the mechanism of electroanalysis from the viewpoint of surface active atoms, and also helps to predict the construction of ultrahighly sensitive electrochemical sensors for other heavy metal ions with nonprecious redox active materials.


Developing seventh grade students' systems thinking skills in the context of the human circulatory system.
Developing systems thinking skills in school can provide useful tools to deal with a vast amount of medical and health information that may help learners in decision making in their future lives as citizen. Thus, there is a need to develop effective tools that will allow learners to analyze biological systems and organize their knowledge. Here, we examine junior high school students' systems thinking skills in the context of the human circulatory system. A model was formulated for developing teaching and learning materials and for characterizing students' systems thinking skills. Specifically, we asked whether seventh grade students, who studied about the human circulatory system, acquired systems thinking skills, and what are the characteristics of those skills? Concept maps were used to characterize students' systems thinking components and examine possible changes in the students' knowledge structure. These maps were composed by the students before and following the learning process. The study findings indicate a significant improvement in the students' ability to recognize the system components and the processes that occur within the system, as well as the relationships between different levels of organization of the system, following the learning process. Thus, following learning students were able to organize the systems' components and its processes within a framework of relationships, namely the students' systems thinking skills were improved in the course of learning using the teaching and learning materials.


Determination of flux through different metabolite pathways in Saccharomyces cerevisiae by 1H-NMR and 13C-NMR spectroscopy.
We propose an experimental approach combining 1H-NMR and 13C-NMR spectroscopy to investigate metabolite flux in cells under physiological conditions and present a mathematical model giving the relationships between the following different parameters. 13C fractional enrichment, fluxes in competing pathways, metabolite concentration and experimental time. This model has been used for determining the absolute and/or relative values of five fluxes involving pyruvate, ethanol, acetyl-CoA and glutamate via the Krebs cycle in glucose-grown repressed Saccharomyces cerevisiae cells fed with [1-13C]glucose and/or unlabeled ethanol. The glucose consumption and the production of various compounds such as ethanol, glycerol, trehalose etc. were studied qualitatively and/or quantitatively as a function of time. The 13C fractional enrichment of [2-13C]ethanol was determined by observing the proton resonance of the methyl group. Addition of 25 mM unlabeled ethanol shows no significant effect on the glucose consumption or the production of any metabolites. However unlabeled ethanol exerts a strong influence on the enrichment of glutamate C4, but only induces an insignificant change on glutamate C2 and C3. Apart from the fact that ethanol is a potential precursor of acetyl-CoA as expected, these results indicate that (a) the probability for citrate and 2-oxoglutarate to make one turn or more in the Krebs cycle is negligible and (b) the scrambling between C4 and C3 via the glyoxylate shunt is virtually absent. The flux of ethanol formation from pyruvate is about three-times and nine-times greater than that of ethanol consumption and acetyl-CoA formation, respectively, from pyruvate via pyruvate dehydrogenase. Without addition of unlabeled ethanol, the ratio of the integrated resonance of glutamate (C2 + C3)/C4 reflecting the activity of pyruvate carboxylase relative to that of citrate synthase, is about 1.1. By comparing the absolute values of the different fluxes, it was found that 88% of the glucose was used to synthetize ethanol but the observed concentration of ethanol in the supernatant represents only 58% of the glucose consumption. The validity of the present model was supported by the data obtained from similar experiments using unlabeled ethanol and non-NMR techniques.


Persistent measles virus infection and otosclerosis.
The cause of otosclerosis is still unknown. Recently, measles virus involvement has been implicated. The aim of this study was to analyze the presence of measles virus RNA within the otosclerotic focus and to evaluate the perilymphatic antibody pattern. Bone and perilymph specimens from 40 patients with the spontaneous form of otosclerosis and from control patients were investigated by reverse transcription polymerase chain reaction (RT-PCR), Western blot techniques, and cell culture. By the use of RT-PCR, measles virus RNA could be detected in 32 patients, but not in controls. Analysis of perilymph revealed the presence of antibodies to N, F1, and M measles virus proteins in all cases, and antibodies against H protein in 2 additional cases. In preosteoblasts cultured from otosclerotic bone chips, no measles virus RNA could be amplified. We conclude that the spontaneous form of otosclerosis is, in the vast majority of cases, a measles virus-associated disease of the otic capsule.


Detrusor underactivity: Clinical features and pathogenesis of an underdiagnosed geriatric condition.
Urinary incontinence and other lower urinary tract symptoms exert a major influence on the health and independence of frail older people. Detrusor underactivity (DU) is defined as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span. DU may influence the clinical presentation and impede the therapy of disorders as common and as disparate as detrusor overactivity, urinary retention, and benign prostatic hyperplasia. Urodynamically, nearly two-thirds of incontinent nursing home residents exhibit DU. The clinical diagnosis of DU when present alone or in association with other bladder conditions such as detrusor overactivity (detrusor hyperactivity with impaired contractility (DHIC)) is challenging, because symptoms lack adequate precision. A catheterized and increasingly noninvasive ultrasound-based postvoid residual assessment allows a bedside diagnosis of retention and may suggest the presence of DU in individuals (mostly women) with a low likelihood of bladder outlet obstruction (BOO). Nevertheless, it cannot differentiate primary DU from retention secondary to BOO. The management of individuals with DHIC remains unsatisfactory, because antispasmodic anticholinergic medications may worsen retention, whereas bethanechol does not improve bladder emptying. Human detrusor biopsies reveal axonal degeneration, muscle loss, and fibrosis in DU. Animal studies suggest that multiple risk factors, including retention itself, lack of estrogen, infection, inflammation, and aging, may contribute to DU. Priority areas for future research include efforts to facilitate clinical nonurodynamic diagnosis of probable DU plus translational research designed to address the pathogenesis of this complex multifactorial geriatric syndrome.


Patient factors and the influence of nephrologists, social workers, and nurses on patient decisions to choose continuous peritoneal dialysis.
To determine which members of the health care team are viewed by ESRD patients as the most helpful in giving information and deciding on a dialysis modality, we surveyed 42 outpatients after they toured the dialysis facility. The tour included discussions with a social worker, PD and HD nurses, watching a videotape, and receipt of written materials. Nephrologists referred patients for tours. Multiple responses were accepted. Patients felt that social workers (70%) and nurses (71%) gave the most useful information. Fifty per cent of patients thought the nurse, 43% the social worker, 21% the nephrologist, and 21% family or friend most helpful in deciding on PD versus HD. Twenty-three patients chose PD, 16 chose in-center HD. Patients choosing PD were more likely to be white (20/29 versus 3/10, p less than 0.05) and employed (11/23 versus 3/16 choosing HD, p less than 0.10). Patients choosing PD were also better educated but this was not independent of race. No differences in gender, age, or the presence of diabetes were seen among those choosing PD versus HD. Social workers and nurses are more influential than nephrologists in helping patients select a dialysis modality. PD patient recruitment efforts should focus on social workers' and nurses' input.


Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.
Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.


Suppression of Jab1 expression inhibits proliferation and promotes apoptosis of AMC-HN-8 cells.
c-Jun activation domain-binding protein-1 (Jab1) is a multifunctional protein involved in cell proliferation and apoptosis, DNA damage and repair and genome stability. In a number of types of human carcinoma, the abnormal expression of Jab1 is associated with poor prognosis, suggesting that Jab1 serves a vital function in tumorigenesis. However, the functional effects and the underlying molecular mechanisms of Jab1 in laryngeal squamous cell carcinoma (LSCC) progression remain poorly understood. The results of the present study demonstrate that downregulating Jab1 expression promotes LSCC apoptosis while inhibiting the proliferation of LSCC cells. Furthermore, Jab1 inhibition results in decreased protein kinase B phosphorylation accompanied by increased caspase-3 cleavage and p53 expression. It has been identified that the increased expression of Jab1 is markedly associated with LSCC progression, therefore Jab1 may be used as a novel target for the treatment of laryngeal cancer.


Prevalence and treatment of anemia with once-weekly epoetin alfa in patients with diabetes and chronic kidney disease.
To describe the characteristics and prevalence of anemia in patients with diabetes and chronic kidney disease (CKD) not receiving dialysis and to evaluate the efficacy and safety of once-weekly (QW) epoetin alfa for the treatment of anemia in these patients. Post hoc subset analyses were conducted for 2 studies: a prospective, multicenter survey evaluating the prevalence of anemia in patients with CKD (the Prevalence of Anemia in Early Renal Insufficiency [PAERI] study) and a prospective, multicenter, open-label trial evaluating the efficacy and safety of QW epoetin alfa for the treatment of anemia associated with CKD (the Clinical Evaluation of Procrit Dosed Once Weekly in Patients With Anemia Due to Early Renal Insufficiency [POWER] study). Patients in the POWER study received epoetin alfa, 10,000 U subcutaneously QW for up to 16 weeks. Each study subset consisted of patients with type 1 or type 2 diabetes. More than 60% of patients in both studies had diabetes. In the PAERI study, 52.4% of the patients with diabetes (N = 3,361) had a hemoglobin (Hb) level < or = 12 g/dL, and 10.5% had Hb < or = 10 g/dL. Female sex, African American race, reduced kidney function, reduced transferrin saturation, and diabetes as the cause of CKD were strongly associated with anemia. In the POWER study, the mean Hb level in the patients with diabetes (N = 816) increased from 9.1 g/dL (baseline) to 11.6 g/dL (final); the mean increase in Hb from baseline was 2.4 g/dL (P<0.0001). Epoetin alfa therapy was associated with significant quality of life improvements and was well tolerated. Diabetes is prevalent in patients with CKD not receiving dialysis, and anemia is prevalent among these patients. Epoetin alfa QW is safe and effective in treating anemia in these patients.


[The main metabolites ferrokinetics in differential diagnostic of anemic syndrome with microcytic, hypochromic characteristics of erythrocytes in patients with colorectal cancer.]
The clinical analysis of blood and main metabolites of ferrokinetics was implemented before treatment in 46 patients with colorectal cancer mainly in stage III-IV. The analysis of obtained results demonstrated that the technique of detection of hepcidin 25 can be used as an additional diagnostic criterion of anemic syndrome in complex with ferritin, soluble receptors of transferrin and expanded clinical analysis of blood. This is especially important in differential diagnostic of anemia of chronic diseas combined with iron-deficiency anemia and anemia of chronic disease with functional iron deficiency because treatment differs in the main. The perspective consists in pathogenic approach to treatment of anemia of chronic disease in oncologic patients using anti-hepcidin medications on the basis of antibodies to hormone, inhibitors and blockers of its expression under control of concentration of hepcidin.


Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma.
A lack of disease-specific symptoms and good tumour markers makes early detection and diagnosis of pancreatic ductal adenocarcinoma (PDAC) challenging. To analyse the tissue expression and circulating levels of four stroma-derived substances (type IV collagen, endostatin/type XVIII collagen, osteopontin and tenascin C) and four conventional tumour markers (CA 19-9, TPS, CEA and Ca 125) in a PDAC cohort. Tissue expression of markers in normal pancreas and PDAC tissue was analysed with immunofluorescence. Plasma concentrations of markers were measured before and after surgery. Patients with non-malignant disorders served as controls. The conventional and stromal substances were expressed in the cancer cell compartment and the stroma, respectively. Although most patients had increased levels of many markers before surgery, 2/12 (17%) of patients had normal levels of Ca 19-9 at this stage. High preoperative endostatin/type XVIII collagen, and postoperative type IV collagen was associated with short survival. Neither the pre- nor postoperative levels of TPS, Ca 125 or CA 19-9 were associated to survival. PDAC is characterized by an abundant stroma. These initial observations indicate that the stroma can be a source of PDAC tumour markers that are found in different compartments of the cancer, thus reflecting different aspects of tumour biology.


High-Throughput Screening and Analysis of Charge Variants of Monoclonal Antibodies in Multiple Formulations.
Among different biopharmaceutical products, monoclonal antibodies (mAbs) show a high level of complexity, including heterogeneity due to differences in size, hydrophobicity, charge, and so forth. Such heterogeneity can be related to both cell-based production and any of the stages of purification, storage, and delivery that the mAb is subjected to. Choosing the right formulation composition providing both physical and chemical stabilities can be a very challenging process, especially when done in the limited time frame required for a typical drug development cycle. Charge variants, a common type of heterogeneity for mAbs, are easy to detect by ion exchange, specifically cation exchange chromatography (CEX). We have developed and implemented a high-throughput CEX-based approach for the rapid screening and analysis of charge modifications in multiple formulation conditions. In this work, 96 different formulations of antistreptavidin IgG1 and IgG2 molecules were automatically prepared and analyzed after incubation at high temperature. Design of experiment and statistical analysis tools have been utilized to determine the major formulation factors responsible for chemical stability of antibodies. Regression models were constructed to find the optimal formulation conditions. The methodology can be applied to different stages of preformulation and formulation development of mAbs.


Neurodevelopmental Disorders and Environmental Toxicants: Epigenetics as an Underlying Mechanism.
The increasing prevalence of neurodevelopmental disorders, especially autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), calls for more research into the identification of etiologic and risk factors. The Developmental Origin of Health and Disease (DOHaD) hypothesizes that the environment during fetal and childhood development affects the risk for many chronic diseases in later stages of life, including neurodevelopmental disorders. Epigenetics, a term describing mechanisms that cause changes in the chromosome state without affecting DNA sequences, is suggested to be the underlying mechanism, according to the DOHaD hypothesis. Moreover, many neurodevelopmental disorders are also related to epigenetic abnormalities. Experimental and epidemiological studies suggest that exposure to prenatal environmental toxicants is associated with neurodevelopmental disorders. In addition, there is also evidence that environmental toxicants can result in epigenetic alterations, notably DNA methylation. In this review, we first focus on the relationship between neurodevelopmental disorders and environmental toxicants, in particular maternal smoking, plastic-derived chemicals (bisphenol A and phthalates), persistent organic pollutants, and heavy metals. We then review studies showing the epigenetic effects of those environmental factors in humans that may affect normal neurodevelopment.


Identification of novel and conserved microRNAs in Coffea canephora and Coffea arabica.
As microRNAs (miRNAs) are important regulators of many biological processes, a series of small RNAomes from plants have been produced in the last decade. However, miRNA data from several groups of plants are still lacking, including some economically important crops. Here microRNAs from Coffea canephora leaves were profiled and 58 unique sequences belonging to 33 families were found, including two novel microRNAs that have never been described before in plants. Some of the microRNA sequences were also identified in Coffea arabica that, together with C. canephora, correspond to the two major sources of coffee production in the world. The targets of almost all miRNAs were also predicted on coffee expressed sequences. This is the first report of novel miRNAs in the genus Coffea, and also the first in the plant order Gentianales. The data obtained establishes the basis for the understanding of the complex miRNA-target network on those two important crops.


Protein kinase C beta II upregulates intercellular adhesion molecule-1 via mitochondrial activation in cultured endothelial cells.
Activation of protein kinase C (PKC) is closely linked with endothelial dysfunction. However, the effect of PKCβII on endothelial dysfunction has not been characterized in cultured endothelial cells. Here, using adenoviral PKCβII gene transfer and pharmacological inhibitors, the role of PKCβII on endothelial dysfucntion was investigated in cultured endothelial cells. Phorbol 12-myristate 13-acetate (PMA) increased reactive oxygen species (ROS), p66shc phosphorylation, intracellular adhesion molecule-1, and monocyte adhesion, which were inhibited by PKCβi (10 nM), a selective inhibitor of PKCβII. PMA increased the phosphorylation of CREB and manganese superoxide dismutase (MnSOD), which were also inhibited by PKCβi. Gene silencing of CREB inhibited PMA-induced MnSOD expression, suggesting that CREB plays a key role in MnSOD expression. Gene silencing of PKCβII inhibited PMA-induced mitochondrial ROS, MnSOD, and ICAM-1 expression. In contrast, overexpression of PKCβII using adenoviral PKCβII increased mitochondrial ROS, MnSOD, ICAM-1, and p66shc phosphorylation in cultured endothelial cells. Finally, PKCβII-induced ICAM-1 expression was inhibited by Mito-TEMPO, a mitochondrial ROS scavenger, suggesting the involvement of mitochondrial ROS in PKC-induced vascular inflammation. Taken together, the results suggest that PKCβII plays an important role in PMA-induced endothelial dysfunction, and that the inhibition of PKCβII-dependent p66shc signaling acts as a therapeutic target for vascular inflammatory diseases.


Circular RNA hsa_circ_0005046 and hsa_circ_0001791 May Become Diagnostic Biomarkers for Breast Cancer Early Detection.
Breast cancer (BC) is one of the most common lethal diseases in women worldwide. Recent evidence has shown that covalently closed Circular RNA (circRNA) deregulation is observed in different human malignancies and cancers. Lately, circRNAs are being considered as a new diagnostic biomarker; however, the mechanism and the correlation of action between circRNAs and BC are still unclear. In the present study, we try to investigate the expression level of hsa_circ_0005046 and hsa_circ_0001791 in BC. By using quantitative real-time polymerase chain reaction (qRT-PCR), expression profiles of candidate circRNAs were detected in 60 BC tissue and paired adjacent normal tissues. Furthermore, the clinicopathological relation and diagnostic value were estimated. Our results showed the higher expression levels of hsa_circ_0005046 and hsa_circ_0001791 in BC tissues compared to paired adjacent normal tissues with P value (P < 0.0001) for both circRNAs, and the area under the receiver operating characteristic (ROC) curve was 0.857 and 1.0, respectively; in addition, a total 10 miRNAs that can be targeted by each candidate circRNAs was predicted base on bioinformatics databases. Taken together, for the first time, the results of our study presented high expression levels of hsa_circ_0005046 and hsa_circ_00017916 in BC; although there was no direct correlation between the high expression level of both circRNAs with clinic pathological factors, except hsa_circ_0001791 association with estrogen receptors (ER), high ROC curve in expressed samples indicated that both circRNAs could be used as a new diagnostic biomarker for BC. Moreover, miRNAs selection tools predicted that miR-215 and mir-383-5p which have a tumor suppressor role in BC can be targeted by our candidate circRNAs to affect the PI3K/AKT pathway; in conclusion, further studies are required to validate the oncogene role of our candidate circRNAs through the PI3k pathway.


Evolution of parent-of-origin effects on placental gene expression in house mice.
The mammalian placenta is a hotspot for the evolution of genomic imprinting, a form of gene regulation that involves the parent-specific epigenetic silencing of one allele. Imprinted genes are central to placental development and are thought to contribute to the evolution of reproductive barriers between species. However, it is unclear how rapidly imprinting evolves or how functional specialization among placental tissues influences the evolution of imprinted expression. We compared parent-of-origin expression bias across functionally distinct placental layers sampled from reciprocal crosses within three closely related lineages of mice ( Mus ). Using genome-wide gene expression and DNA methylation data from fetal and maternal tissues, we developed an analytical strategy to minimize pervasive bias introduced by maternal contamination of placenta samples. We corroborated imprinted expression at 42 known imprinted genes and identified five candidate imprinted genes showing parent-of-origin specific expression and DNA methylation. Paternally-biased expression was enriched in the labyrinth zone, a layer specialized in nutrient transfer, and maternally-biased genes were enriched in the junctional zone, which specializes in modulation of maternal physiology. Differentially methylated regions were predominantly determined through epigenetic modification of the maternal genome and were associated with both maternally- and paternally-biased gene expression. Lastly, comparisons between lineages revealed a small set of co-regulated genes showing rapid divergence in expression levels and imprinted status in the M. m. domesticus lineage. Together, our results reveal important links between core functional elements of placental biology and the evolution of imprinted gene expression among closely related rodent species.


Cardiovascular toxicity of dihydroxytryptamines.
A comparison of the acute toxicity and a histological examination of the toxic effects in mouse of 4,7-; 5,6-; 5,7- and 6,7-dihydroxytryptamines and related compounds are present. A time and dose dependent induction of subepicardial lesions by 5,6-dihydroxytryptamine is demonstrated. The development of ischemic necrosis of the vaculature of the tail following 6,7-dihydroxytryptamine is described. The toxic effects of these tryptamines are discussed with regard to the phenomena of specific neurodegeneration induced by 5,6- and 5,7-dihydroxytryptamines.


Hyaluronidase activity in lysosomes of bone tissue.
1. The distribution pattern of hyaluronidase in subcellular fractions of bone-tissue homogenates is closely similar to that reported by Vaes & Jacques (1965b) for the other acid hydrolases of this tissue. The highest specific activity of hyaluronidase is also found in the light-mitochondrial fraction. 2. In cytoplasmic extracts of bone, about 60% of the activity of hyaluronidase is latent, and is unmasked by a number of treatments (digitonin, low osmotic pressure, freezing and thawing, Waring Blendor) that unmask the lysosomal beta-glucuronidase in a closely parallel manner. Low concentrations of Triton X-100 render a larger proportion of beta-glucuronidase than of hyaluronidase accessible to external substrates, but release the same proportion of both enzymes in unsedimentable form. 3. These results support the concept of an association of hyaluronidase with lysosomes in bone.


Hematological response to the new synthetic muramyl dipeptide derivative muroctasin after chemotherapy in patients with malignant lymphoma. A randomized crossover trial.
A randomized crossover trial was performed in 20 patients receiving chemotherapy for malignant lymphoma. N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine (MDP-Lys(L18), muroctasin) at a dose of 200 micrograms was subcutaneously administered after one of two cycles of the same protocol. The administration was started on day 4 after the start of chemotherapy and continued for 10 days. The mean length from the start of chemotherapy to nadir of white blood cell (WBC) was not significantly different between the control and muroctasin cycles. The mean WBC and neutrophil counts at nadir of the control cycle were significantly lower than those at the same point of muroctasin cycle, respectively. A positive effect of muroctasin cycle, defined as WBC count at nadir being increased by 1,000/mm3, WBC count being increased by 1,000/mm3 on two points examined after nadir, or faster reach to nadir and faster recovery to normal range of WBC than in the control cycle, was observed in 7 (35%) of 20 patients. On the other hand, only one (5%) patient showed a superiority of the control cycle over the muroctasin cycle. Toxic effects of muroctasin were observed in 34.8% of patients, but were tolerable for most patients. These results show that muroctasin has a clinical efficacy in the restoration of leukopenia after chemotherapy.


Long-term measurement of binaural intensity and pitch matches. II. Fluctuating low-frequency hearing loss.
Thirteen subjects made consecutive long-term recordings of binaural intensity and pitch matches in their homes using portable equipment to assess hearing fluctuations. Two groups of subjects were used; one with monaural fluctuating low-frequency hearing loss (FLFHL) without vertigo, and one with monaural Meniere's disease (i.e. FLFHL with vertigo). The subjects measured binaural pitch matches using a 0.25- or 1-kHz reference tone presented at 60 dB SPL to one ear, and a loudness-matched test tone of adjustable frequency presented to the other ear during one to several weeks. Their results were compared to those previously obtained from ten normal-hearing subjects. Both groups of subjects showed fluctuations in binaural intensity and pitch matches not seen in the normal-hearing group. We calculated the average day-to-day difference in matched intensity and frequency for each subject's test period as a measure of disease activity. This measure indicated that the group with Meniere's disease has a higher disease activity than the group with FLFHL without vertigo, and that both these groups of subjects had higher disease activity than normal-hearing subjects.


Guggulsterone, a plant-derived inhibitor of NF-TB, suppresses CDX2 and COX-2 expression and reduces the viability of esophageal adenocarcinoma cells.
Induction by bile acid of caudal type homeobox 2 (CDX2) and cyclooxygenase-2 (COX-2) expression via nuclear factor-κB (NF-κB) activation is a critical event in the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Guggulsterone (GS) is a plant sterol that inhibits NF-κB activity. Here, we evaluated whether GS has either or both chemopreventive or therapeutic effects against EAC. Two EAC cells lines were treated with deoxycholic acid (DCA) in the presence of GS or vehicle. The levels of transcription and translation of IκBα, CDX2, and COX-2 were determined. Prostaglandin E2 (PGE2) levels, cell viability, and cell cycle distribution were assessed as well. GS inhibited DCA-induced IκBα phosphorylation. GS and the NF-κB inhibitor BAY11-7085 suppressed DCA-induced CDX2 and COX-2 expression in EAC cells. GS also suppressed basal transcription levels of CDX2 and COX-2 and reduced constitutive synthesis of COX-2 and PGE2. Further, GS reduced the viability of EAC cells, increased their numbers in the apoptotic sub-G1 fraction. GS suppressed DCA-induced and NF-κB-dependent activation of CDX2 and COX-2 expression. Further, GS also reduced the viability of EAC cells. GS may serve as candidate for preventing and treating EAC and BE.


Prognostic risk of immune-associated signature in the microenvironment of brain gliomas.
Understanding the key factors in the tumor microenvironment (TME) that affect the prognosis of gliomas is crucial. In this study, we sought to uncover the prognostic significance of immune cells and immune-related genes in the TME of gliomas. We incorporated data of 970 glioma patient samples from the Chinese Glioma Genome Atlas (CGGA) database as the training set, and an additional set of 666 samples from The Cancer Genome Atlas (TCGA) database served as the validation set. From our analysis, we identified 21 immune-related differentially expressed genes (DEGs) in the TME, which holds implications for glioma prognosis. Based on these genes, we constructed a prognostic risk model on the 21 genes. The prognostic risk model demonstrated robust performance with an area under the curve (AUC) value of 0.848. Notably, the risk score derived from the model emerged as an independent prognostic factor of gliomas, with high risk scores indicative of an unfavorable prognosis. Furthermore, we observed that high infiltration levels of certain immune cells, namely, activated dendritic cells, M0 macrophages, M2 macrophages, and regulatory T cells (Tregs), correlated with an unfavorable glioma prognosis. In conclusion, our findings suggested that the TME of gliomas harbored a distinct immune-associated signature, comprising 21 immune-related genes and specific immune cells. These elements significantly influence the prognosis and present potential as novel indicators in the clinical assessment of glioma patient outcomes.


Autophagy during conidiation and conidial germination in filamentous fungi.
Filamentous fungi form aerial hyphae on solid medium, and some of these differentiate into conidiophores for asexual sporulation (conidiation). In the filamentous deuteromycete, Aspergillus oryzae, aerial hyphae are formed from the foot cells and some differentiate into conidiophores, which are composed of vesicles, phialides and conidia. Recently, we isolated the yeast ATG8 gene homologue Aoatg8 from A. oryzae, and visualized autophagy by the expression of an EGFP (enhanced green fluorescent protein)-AoAtg8 fusion protein and DsRed2 protein in this fungus. Furthermore, by constructing the Aoatg8 deletion and conditional mutants, we demonstrated that autophagy functions during the process of differentiation of aerial hyphae, conidiation and conidial germination in A. oryzae. Here, we discuss the contribution of autophagy towards the differentiation and germination processes in filamentous fungi.


An Ultrasound Simulation Model for the Pulsatile Blood Flow Modulated by the Motion of Stenosed Vessel Wall.
This paper presents an ultrasound simulation model for pulsatile blood flow, modulated by the motion of a stenosed vessel wall. It aims at generating more realistic ultrasonic signals to provide an environment for evaluating ultrasound signal processing and imaging and a framework for investigating the behaviors of blood flow field modulated by wall motion. This model takes into account fluid-structure interaction, blood pulsatility, stenosis of the vessel, and arterial wall movement caused by surrounding tissue's motion. The axial and radial velocity distributions of blood and the displacement of vessel wall are calculated by solving coupled Navier-Stokes and wall equations. With these obtained values, we made several different phantoms by treating blood and the vessel wall as a group of point scatterers. Then, ultrasound echoed signals from oscillating wall and blood in the axisymmetric stenotic-carotid arteries were computed by ultrasound simulation software, Field II. The results show better consistency with corresponding theoretical values and clinical data and reflect the influence of wall movement on the flow field. It can serve as an effective tool not only for investigating the behavior of blood flow field modulated by wall motion but also for quantitative or qualitative evaluation of new ultrasound imaging technology and estimation method of blood velocity.


Community awareness and risk of rabies associated with exposure to animals in India.
Rabies is a fatal but preventable disease. Around the world, awareness studies about rabies have been widely used to understand the disease and in its preventive measures. The present study was conducted to assess the awareness of rabies as a disease, its transmission, and prevention among the general population and also to assess the perceived health risks associated with exposure to animals. A cross-sectional study was undertaken across seven representative states in India between July and November 2017. Multistage sampling methodology was followed to select 1012 households as the primary sampling unit, and one adult responsible respondent from each household was interviewed as study participants. Six hundred and eleven (60.4%) participants had heard of rabies. Only 0.2% had extensive knowledge of rabies. Majority (440, 72.0%) of the participants considered rabies as a fatal disease; 77.3% opined that risk of rabies from dogs was high compared to 41.6% who believed that there was little or no risk of rabies from cats. Only 37 (3.7%) participants were aware about preexposure prophylaxis. The awareness on rabies and its prevention in the study population was not satisfactory.


Genetic polymorphisms and response to medications for alcohol use disorders: a systematic review and meta-analysis.
To assess whether response to medications for alcohol use disorders varies by genotype. Systematic review and meta-analysis. We found no studies that assessed the clinical utility of genotype-guided dosing strategies or genotype-guided medication selection, and none randomized by genotype. All included studies assessed the association between genotype and response to medication. Of 15 included studies, eight (n = 1365 participants) assessed variation in naltrexone response and polymorphisms of OPRM1. Our meta-analyses for return to heavy drinking found no significant difference between A allele homozygotes and those with at least one G allele, both without (risk difference: 0.26; 95% CI: -0.01-0.53; n = 174) and with inclusion of studies rated as high or unclear risk of bias (risk difference: 0.14; 95% CI: -0.03-0.3; n = 382). For all other polymorphism-medication pairs, we found just one eligible study. Estimates of effect for return to heavy drinking suggest it is possible that patients with at least one G allele of A118G polymorphism of OPRM1 might be more likely to respond to naltrexone, but confidence intervals were wide; additional studies are needed to improve confidence in the estimates.


[Using of antibodies against Microsporia Hsp70 family proteins for analysis of secretome of intracellular parasites].
Microsporidia is a large group of fungi-related unicellular parasites with obligate intracellular lifestyle. Unlike other protozoan intracellular parasites (Kinetoplastida and Apicomplexa), most microsporidian species develop in direct contact with the host cell cytoplasm. This fact, acquisition of unique transporters to exploit host metabolic system (alongside the strong minimization of own machinery) and predicted repertoire of microsporidia secretome altogether suggest an active role of parasite proteins in the control of infected cell. Lack of information about secretome of microsporidia intracellular stages is largely due to the methodological difficulties of working with the obligate intracellular parasites. An important problem of such study is the contamination of preparations of host cell cytoplasm by inner (nonsecreted) parasite proteins. Even the homogenization of infected tissue in mild conditions and removal of parasite cells by low-speed centrifugation may result in their partial disruption. We expressed the fragments of three Hsp70 family chaperones from the microsporidium Paranosema (Antonospora) locustae in bacteria Escherichia coli. Immunoblotting with proteins of microsporidia intracellular stages and infected host tissue (locust fat bodies) demonstrated that antibodies against recombinant polypeptides may be used to monitor the integrity of parasite cells during homogenization of infected host tissue and subsequent removal of parasites by centrifugation.


Characteristic angles in the wetting of an angular region: deposit growth.
Solids dispersed in a drying drop migrate to the (pinned) contact line. This migration is caused by outward flows driven by the loss of the solvent due to evaporation and by geometrical constraint that the drop maintains an equilibrium surface shape with a fixed boundary. Here, in continuation of our earlier paper, we theoretically investigate the evaporation rate, the flow field, and the rate of growth of the deposit patterns in a drop over an angular sector on a plane substrate. Asymptotic power laws near the vertex (as distance to the vertex goes to zero) are obtained. A hydrodynamic model of fluid flow near the singularity of the vertex is developed and the velocity field is obtained. The rate of the deposit growth near the contact line is found in two time regimes. The deposited mass falls off as a weak power gamma of distance close to the vertex and as a stronger power beta of distance further from the vertex. The power gamma depends only slightly on the opening angle alpha and stays roughly between -1/3 and 0. The power beta varies from -1 to 0 as the opening angle increases from 0 degrees to 180 degrees. At a given distance from the vertex, the deposited mass grows faster and faster with time, with the greatest increase in the growth rate occurring at the early stages of the drying process.


Neonatal adverse drug reactions: an analysis of reports to the French pharmacovigilance database.
Term and preterm neonates are at high risk for serious adverse drug reactions (ADRs). A descriptive study of reports registered in the French pharmacovigilance database from 1986 to 2012 were obtained. All reports concerning neonates (≤1 month of life) with direct drug exposure were retrieved. Characteristics of the reports, including reported ADR(s), drug(s) and the causality assessment using the French causality assessment method, were described. A total of 1688 reports were analyzed and more than half of them were classified as serious (n = 995). Median age at ADR occurrence was 9 days. Overall, 3127 ADRs were described in these reports in relation to 2238 suspect/interacting drugs. The most commonly reported system organ classes (SOCs) were injury, poisoning and procedural complications (16%), general disorders and administration site conditions (12.5%) and blood and lymphatic system disorders (12%). In the majority of ADRs reported (73%), infants fully recovered and less than 4% of neonates deceased as a consequence of the reported ADR. One out of five ADRs was associated with drug administration errors. Therapeutic classes commonly incriminated were anti-infectives, nervous system and alimentary tract drugs. Substances most frequently related to serious ADRs were zidovudine, ibuprofen and nevirapine. Among the 10 most frequently encountered drug-ADR pairs, two substances were mainly implicated, zidovudine in haematological adverse reactions and phytomenadione in maladministrations. Anti-infective drugs, mainly antiretroviral therapy, account for the majority of ADRs reported in neonates. The specific issue of drug maladministration and medication errors remains to be addressed in neonates.


Automated bioacoustic identification of species.
Research into the automated identification of animals by bioacoustics is becoming more widespread mainly due to difficulties in carrying out manual surveys. This paper describes automated recognition of insects (Orthoptera) using time domain signal coding and artificial neural networks. Results of field recordings made in the UK in 2002 are presented which show that it is possible to accurately recognize 4 British Orthoptera species in natural conditions under high levels of interference. Work is under way to increase the number of species recognized.


Behavioral diversity and neurochemical plasticity: selection of stress coping strategies that define social status.
Social interactions include a variety of stimulating but challenging factors that are the basis for strategies that allow individuals to cope with novel or familiar stressful situations. Evolutionarily conserved strategies have been identified that reflect specific behavioral and physiological identities. In this review we discuss a unique model for social stress in the lizard Anolis carolinensis, which has characteristics amenable to an investigation of individual differences in behavioral responses via central and sympathetic neurochemical adaptation. Profiles of proactive and reactive phenotypes of male A. carolinensis are relatively stable, yet retain limited flexibility that allows for the development of the social system over time. For male A. carolinensis, the celerity of social signal expression and response translate into future social standing. In addition, proactive aggressive, courtship, and feeding behaviors also predict social rank, but are not as important as prior interactions and memories of previous opponents to modify behavioral output and affect social status. The central neurotransmitters dopamine and serotonin, and the endocrine stress axis (HPA) appear to be the fundamental link to adaptive stress coping strategies during social interactions. Only small adaptations to these neural and endocrine systems are necessary to produce the variability measured in behavioral responses to stressful social interactions. These neuroendocrine factors are also manifest in responses to other stimuli and form the basis of heritable strategies for coping with stress.


Effect of 1,3-di-o-tolylguanidine (DTG), rimcazole and EMD 57445, the sigma receptor ligands, in the forced swimming test.
As it is known, sigma receptor ligands have been able to modulate the central neurotransmitter systems, including noradrenergic-, NMDA-ergic- and dopaminergic ones, which are essential for the mechanism of action of antidepressant drugs. Therefore, it can be assumed that some selective sigma ligands can possess antidepressant-like activity. In the present studies 1,3-di-o-tolylguanidine (DTG), rimcazole (RIM) and EMD 57445 were examined in the forced swimming test in rats and mice. DTG and RIM decreased the immobility time in mice. EMD 57445 was inactive but it antagonized the anti-immobility effects of DTG and RIM. Both latter drugs did not change the locomotor activity of mice, EMD 57445 at higher dose decreased it. In addition, DTG showed antidepressant-like activity in rats, this effect being counteracted by EMD 57445. At the same time both drugs attenuated the spontaneous motor activity in rats. Taken together, the present results suggested that DTG and RIM may possess sigma agonistic activity while EMD 57445--the antagonistic one. Further investigations are needed to support agonistic/antagonistic activities of the studied sigma ligands and to elucidate the potential involvement of sigma site subtypes in this model.