The effects of 2-aminoethoxydiphenyl borate and diphenylboronic anhydride on gap junctions composed of Connexin43 in TM₄ sertoli cells.
2-Aminoethoxydiphenyl borate (2-APB) has recently been demonstrated to inhibit gap junction (GJ) channels, whereas the underlying mechanisms are still unknown. Using mouse TM₄ Sertoli cell which expresses connexin43 (Cx43), we explored the effects of 2-APB and its analogues on dye-coupling through junctional channels formed by Cx43 and on expression of Cx43. Exposure of the cells to 2-APB (1-50 µM) and one of its analogues diphenylboronic anhydride (DPBA) (1-30 µM) for 4 h leads to a significant decrease in dye coupling of GJ in a concentration-dependent manner. The inhibitory effects of 2-APB and DPBA are reversible since decreased GJ coupling resumes after the two compounds are washed out. The disfunction of GJ induced by 2-APB and DPBA is associated with a decrease in total amount of Cx43 protein and number of GJs on the cell membrane. 2-APB and DPBA do not alter Cx43 phosphorylation state and the level of Cx43 mRNA expression. The loss of Cx43 protein is prevented by either lysosomal or proteasomal inhibitor, suggesting that the decrease in Cx43 results from a 2-APB or DPBA-enhanced degradation of Cx43. The present results indicate that 2-APB and DPBA inhibit GJ communication through decreasing Cx43 expression in TM₄ cells.


Functional regulation of adipose-derived stem cells by PDGF-D.
Platelet-derived growth factor-D (PDGF-D) was recently identified, and acts as potent mitogen for mesenchymal cells. PDGF-D also induces cellular transformation and promotes tumor growth. However, the functional role of PDGF-D in adipose-derived stem cells (ASCs) has not been identified. Therefore, we primarily investigated the autocrine and paracrine roles of PDGF-D in this study. Furthermore, we identified the signaling pathways and the molecular mechanisms involved in PDGF-D-induced stimulation of ASCs. It is of interest that PDGF-B is not expressed, but PDGF-D and PDGF receptor-β are expressed in ASCs. PDGF-D showed the strongest mitogenic effect on ASCs, and PDGF-D regulates the proliferation and migration of ASCs through the PI3K/Akt pathways. PDGF-D also increases the proliferation and migration of ASCs through generation of mitochondrial reactive oxygen species (mtROS) and mitochondrial fission. mtROS generation and fission were mediated by p66Shc phosphorylation, and BCL2-related protein A1 and Serpine peptidase inhibitor, clade E, member 1 mediated the proliferation and migration of ASCs. In addition, PDGF-D upregulated the mRNA expression of diverse growth factors such as vascular endothelial growth factor A, fibroblast growth factor 1 (FGF1), FGF5, leukemia inhibitory factor, inhibin, beta A, interleukin 11, and heparin-binding EGF-like growth factor. Therefore, the preconditioning of PDGF-D enhanced the hair-regenerative potential of ASCs. PDGF-D-induced growth factor expression was attenuated by a pharmacological inhibitor of mitogen-activated protein kinase pathway. In summary, PDGF-D is highly expressed by ASCs, where it acts as a potent mitogenic factor. PDGF-D also upregulates growth factor expression in ASCs. Therefore, PDGF-D can be considered a novel ASC stimulator, and used as a preconditioning agent before ASC transplantation.


Van der Waals supercritical fluid: exact formulas for special lines.
In the framework of the van der Waals model, analytical expressions for the locus of extrema (ridges) for heat capacity, thermal expansion coefficient, compressibility, density fluctuation, and sound velocity in the supercritical region have been obtained. It was found that the ridges for different thermodynamic values virtually merge into single Widom line only at T < 1.07T(c), P < 1.25P(c) and become smeared at T < 2T(c), P < 5P(c), where T(c) and P(c) are the critical temperature and pressure. The behavior of the Batschinski lines and the pseudo-Gruneisen parameter γ of a van der Waals fluid were analyzed. In the critical point, the van der Waals fluid has γ = 8/3, corresponding to a soft sphere particle system with exponent n = 14.


Indomethacin modulates circulating cytokine responses to strenuous exercise in humans.
Physical stress is associated with circulating cytokinemia. However the mechanisms of cytokine regulation during such stress are not clearly defined. Non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin, are widely used in countering the effects of excessive exercise, but their impact on circulating pro- and anti-inflammatory cytokine production in healthy humans also remains unclear. This study investigated the effect of five days of oral indomethacin treatment (75 mg per day) on the serum concentrations of IL-6, IL-10, IL-12, and TNF-alpha induced by exercising healthy volunteers. The results demonstrate that indomethacin does not alter resting serum cytokine concentrations. Increased circulating levels were noted, however, for all four cytokines with exercise, but with a different time-course. During and after strenuous physical exercise, indomethacin treatment blunted serum IL-6, and augmented TNF-alpha and IL-10. These findings may have important implications for both host defense and the injuries associated with excessively vigorous exercise.


[Cross-section anatomy of the subphrenic spaces].
The cross-section anatomy of the subphrenic spaces were investigated in 20 Chinese cadavers. On the horizontal sections, the subphrenic spaces consist of the perihepatic and perisplenic spaces. The fissure for ligamentum venosum was separated into two parts by the lesser omentum, the anterior part communicates with gastrohepatic recess, the posterior is the superior recess of the omental bursa into which the caudate lobe of the liver projected. The bare area of the stomach encroaches upon the posterior surface of the gastric fundus between the right and left layers of the gastrophrenic ligament and lies between the superior and splenic recesses of the omental bursa. Left subphrenic retroperitoneal space is between the bare area of the stomach and the diaphragm.


Identification and Determination of 492 Contaminants of Different Classes in Food and Feed by High-Resolution Mass Spectrometry Using the Standard Addition Method.
The methodology for the identification and determination of 492 different toxicants from a single sample in food and feed by high-resolution quadrupole time-of-flight MS in combination with HPLC has been presented. The sample preparation is easy. The analytes are pesticides of different classes, including mycotoxins, veterinary drugs, and synthetic dyes. A scheme for the identification and determination of toxicants using the standard addition method has been given. The RSDs of the analytical results presented are ≤0.15, with a 40-60 min sample screening time and a 2-3 h for the determination of the detected toxicants.


[Do arrhythmias after infarction deter patients from smoking?].
Although the short-term outcome of patients treated by thrombolysis during the acute phase of myocardial infarction is now well known, data concerning the repercussions of the coronary accident on smoking are less clearly established. This aspect is particularly important, as cessation of smoking is one of the most effective measures in the context of secondary prevention, with an excellent cost-benefit ratio. Between 1985 and 1991, 218 consecutive patients underwent thrombolysis for myocardial infarction. With a follow-up of 35 +/- 20 months, 11.5% of patients have died, including 6% while in hospital. A questionnaire was sent to 193 surviving patients with a response rate of 97.4%, 27.3% of patients continued to smoke after the myocardial infarction. Smoking patients were younger (p = 0.001) and had generally returned to work (p = 0.05). Continuation of smoking was not influenced by either the patency of the artery or the type of revascularization, and was not correlated with residual symptoms. The frequency of arrhythmias during the acute phase was not related to previous smoking. On the other hand, smoking patients who survived after an infarction appear to quit smoking twice as frequently when they had experienced a cardiac arrhythmia during the acute phase of the infarction (p = 0.005), as confirmed by multivariate analysis. Can the "stress" induced by the arrhythmia, possibly combined with the doctor's reactive anxiety explain cessation of smoking in these patients? If so, it would open new horizons in terms of secondary prevention of myocardial infarction.


Bioactive compounds in human milk and intestinal health and maturity in preterm newborn: an overview.
Premature births are increasing worldwide (about 15 millions per year) due to several reasons (an advanced maternal age, fertility treatments, stress, smoking, nutritional deficiencies) and lead to a high societal overall cost. Among neonatal care procedures, the clinical nutrition practices are essential to promote the development and to minimize the sequelae. Premature newborns are at major risk of death by infections due to the immaturity of their intestine. Human milk provides not only nutrients but also a plethora of biologically active components that are tailored to contribute to the development of the intestinal tract early in postnatal life. Among them, some bioactive molecules exhibit trophic effects (LC—PUFA, sphingomyelin, IGF—I and IGF—II, EGF, insulin, leptin, adiponectin, lactoferrin, lactadherin, probiotics, prebiotics, miRNA) or are part of the intestinal cell membranes (PUFA, LC—PUFA, phospholipids, sphingolipids, cholesterol), others educate the intestine for innate microbial recognition (sCD14, sTLR—2, miRNA), many of them display direct fighting against pathogens (some fatty acids and monoglycerides, some phospholipids and sphingolipids, BSSL, insulin, lactoferrin, sIgAs, MUC—1, lactadherin, probiotics, prebiotics), or contribute to establish the gut microbiota (LC—PUFA, lactoferrin, probiotics, prebiotics). A synergetic action exists between several bioactive molecules. All together these precious agents regulate the maturation of the intestinal mucosal barrier, and might program early in postnatal life the future adult intestinal health. This review lists the main bioactive compounds and addresses their plausible roles and mechanisms of action.


[Studies on detection of serum IgA and IgG antibodies specific for Chlamydia trachomatis in latent infections in males].
We determined the serum concentrations of IgA and IgG antibodies specific for Chlamydia trachomatis (C. trachomatis) by an indirect immunoperoxidase assay (IPAzyme kit, Savyon Diagnostics, Ltd., Bee, Shova, Israel) to evaluate their diagnostic significance in latent infections in males. Forty-five asymptomatic males whose wife or partner was suspected to be infected with C. trachomatis were studied and the incidence of serum IgA (titer greater than or equal to 16) and IgG (titer greater than or equal to 64) antibodies for C. trachomatis was compared with that in a healthy group, a group with non-gonococcal urethritis (NGU) patients. Changes in IgA titer during treatment were also examined. The incidence of IgA and IgG antibodies in the healthy group was found to be 2.4% and 11.9% in males, and 4.8% and 18.1% in females, respectively. In patients whose wife or partner who was positive to C. trachomatis, the incidence of IgA and IgG antibodies was 42.2% and 75.6%, respectively. In the NGU patients the incidence of IgA and IgG antibodies was 56.3% and 62.5%, respectively. The incidence of IgA and IgG antibodies in patients whose wife or partner was antibody-positive were significantly higher (p less than 0.01) than the corresponding value in healthy men and women, but there was no significant difference from NGU patients or the elderly group. The IgA antibody titer during treatment of C. trachomatis infection showed no reduction in some cases. This study revealed frequent latent incidence of C. trachomatis infection in male patients. Determination of C. trachomatis IgA and IgG antibodies is considered to be supplemental for diagnosis of chlamydial latent infections.


[Conceptual issues in the development of quality indicators for mental health systems].
Once the parameters to design and assess a Mental Health System have been put forward it's necessary to operationalize them into quality indicators and outcome measures. These indicators allow us to compare processes and results with other systems and services, they let us do the economic assessment and the allotment of resources, they give way to treatment guidelines and external evaluation, generating a new type of organizations evidence-based. This paper reviews the conceptual aspects of performance indicators and its use in some developed countries. It also discusses their usefulness, at the input, the process and the outcome level, to treat patients and to organize Mental Health Services and Systems. Despite therapists not benefiting directly from the use of this type of indicators, its importance should not be disregarded in order to organize a Mental Health System for large populations.


First-principles calculations on the energetics, electronic structures and magnetism of SrFeO(2).
The electronic and magnetic properties of SrFeO(2) with different magnetic configurations have been calculated via the plane-wave pseudopotential density functional theory method, using the experimental lattice parameters. The results give an antiferromagnetic ground state for SrFeO(2) with an absolute magnetic moment agreeing very well with the experimental report. In comparison with the counterparts whose magnetic moments are parallel to the c axis, the structures with spin moments parallel to the a (or b) axis exhibit no observable preference in total energy, but show different density distributions of the Fe 3d(x(2)-y(2) ) and Fe 3d(z(2) ) states. The square-planar crystal field splits the Fe 3d orbitals into a high-level d(x(2)-y(2) ), a low d(z(2) ), and intermediate d(xy) and d(xz) or d(yz) components. The exchange splitting is larger than the crystal-field splitting, resulting in the high-spin Fe 3d states. Referred to the triplet O(2), the O-vacancy formation energy from SrFeO(3) to SrFeO(2) has been deduced as well, along with its dependence on the temperature and O(2) partial pressure.


Past, Present and Future of Membrane Technology in Spain.
The following review aims at analyzing the contribution of Spanish researchers to membrane science and technology, with a historical compilation of the main milestones. We used a bibliometric analysis based on the Scopus database (1960-2020) dealing with 8707 documents covering the different disciplines and subject areas where membranes are involved. Furthermore, the information has been updated to the present moment of writing this manuscript in order to include the latest research lines and the different research groups currently active in Spain, which may lead the way to the development of the field in the coming years.


Selection of Nicotiana tabacum Haploids of High Photosynthetic Efficiency.
Anthers of Nicotiana tabacum cultivar Wisconsin 38 were treated with the mutagen ethyl methane sulfonate and cultured to obtain populations of haploid plants of high genetic variability. The selection of these populations by their photosynthetic efficiency was carried out in a hydroponic culture chamber with a CO(2) atmosphere concentration close to the compensation point. Plants that survived 45 days of treatment were grown in pots in a greenhouse and their performance was compared to a population of unselected haploids. The growth characteristics, net photosynthesis, and chlorophyll content were measured and the haploid character verified. Selected plants were propagated by in vitro culture of buds and then diploidized to obtain seeds. Growth and other characteristics of the plants obtained were compared with those of the parental variety (Wisconsin 38) in a field assay. Growth, dry weight, leaf area, and net photosynthesis of selected plants were higher than in control plants.


[MELAS syndrome: clinical, pathological and neuroimaging study].
The form of presentation of a new case of Melas Syndrome is described, together with a pathological and neuroimage study, including clinical development over a 3 year period. The usefulness of MR should be underlined here, given clinical doubts, and also normality in the EMG early phases of and the association with obstructive hypertrophic miocardiopathy.


Particles, sweat, and tears: a comparative study on bioaccessibility of ferrochromium alloy and stainless steel particles, the pure metals and their metal oxides, in simulated skin and eye contact.
Ferrochromium alloys are manufactured in large quantities and placed on the global market for use as master alloys (secondary raw materials), primarily for stainless steel production. Any potential human exposure to ferrochromium alloy particles is related to occupational activities during production and use, with 2 main exposure routes, dermal contact and inhalation and subsequent digestion. Alloy and reference particles exposed in vitro in synthetic biological fluids relevant for these main exposure routes have been investigated in a large research effort combining bioaccessibility; chemical speciation; and material, surface, and particle characteristics. In this paper, data for the dermal exposure route, including skin and eye contact, will be presented and discussed. Bioaccessibility data have been generated for particles of a ferrochromium alloy, stainless steel grade AISI 316L, pure Fe, pure Cr, iron(II,III)oxide, and chromium(III)oxide, upon immersion in artificial sweat (pH 6.5) and artificial tear (pH 8.0) fluids for various time periods. Measured released amounts of Fe, Cr, and Ni are presented in terms of average Fe and Cr release rates and amounts released per amount of particles loaded. The results are discussed in relation to bulk and surface composition of the particles. Additional information, essential to assess the bioavailability of Cr released, was generated by determining its chemical speciation and by providing information on its complexation and oxidation states in both media investigated. The effect of differences in experimental temperature, 30 degrees C and 37 degrees C, on the extent of metal release in artificial sweat is demonstrated. Iron was the preferentially released element in all test media and for all time periods and iron-containing particles investigated. The extent of metal release was highly pH dependent and was also dependent on the medium composition. Released amounts of Cr and Fe were very low (close to the limit of detection, <0.008% of particles released or dissolved as iron or chromium) for the alloy particles (ferrochromium alloy and stainless steel), the pure Cr particles, and the metal oxide particles. The released fraction of Cr (Cr/[Cr + Fe]) varied with the material investigated, the test medium, and the exposure time and cannot be predicted from either the bulk or the surface composition. Chromium was released as noncomplexed Cr(III) and in addition in very low concentrations (<3 microg/L). Nickel released was under the limit of detection (0.5 microg/L), except for ultrafine stainless steel particles (<10 microg/L). It is evident that media chemistry and material properties from a bulk and surface perspective, as well as other particle characteristics, and the chemical speciation of released metals have to be considered when assessing any potential hazard or risk induced by sparingly soluble metal or alloy particles.


Distribution of nodal metastases after chemotherapy in nonseminomatous testis cancer: a possible indication for limited dissection.
To assess the clinical and pathological findings of patients treated by bilateral retroperitoneal lymph node dissection (RPLND) after chemotherapy, to identify a subset for whom modified template nodal resection might be contemplated, as bilateral RPLND is the treatment of choice in patients with residual retroperitoneal disease after chemotherapy for nonseminomatous germ-cell tumour (GCT). The medical records were reviewed of 50 consecutive patients who had RPLND after chemotherapy between 1996 and 2005. Bilateral template RPLND was performed uniformly. Extracted lymph nodes were surgically stratified into three distinct anatomical zones by two sagittal planes running in front of the aorta and the inferior vena cava. The pathological findings were correlated with the side of the primary lesion and the extent of metastatic disease before chemotherapy. Pathological assessment of the resected lymph nodes revealed teratoma in 28 patients (56%), viable carcinoma in three (6%), and necrosis or fibrosis in 19 (38%). All clinical stage Is, IIA and IIB left-sided primary tumours followed a predictable pattern of spread constricted to a modified left-sided template. Patients with clinical stage IIC and III, or right-sided primary tumour, had a less predictable metastatic pattern, having crossover metastases to the contralateral template. Bilateral RPLND should be considered as the reference standard in patients with metastatic GCT and residual retroperitoneal mass after completing chemotherapy. However, the present data suggest that a modified template dissection might be considered even after chemotherapy in patients with left-sided primary tumours and limited nodal involvement at presentation.


Characterization of Dynamic UbR-Proteasome Subcomplexes by In vivo Cross-linking (X) Assisted Bimolecular Tandem Affinity Purification (XBAP) and Label-free Quantitation.
Proteasomes are protein degradation machines that exist in cells as heterogeneous and dynamic populations. A group of proteins function as ubiquitin receptors (UbRs) that can recognize and deliver ubiquitinated substrates to proteasome complexes for degradation. Defining composition of proteasome complexes engaged with UbRs is critical to understand proteasome function. However, because of the dynamic nature of UbR interactions with the proteasome, it remains technically challenging to capture and isolate UbR-proteasome subcomplexes using conventional purification strategies. As a result, distinguishing the molecular differences among these subcomplexes remains elusive. We have developed a novel affinity purification strategy, in vivo cross-linking (X) assisted bimolecular tandem affinity purification strategy (XBAP), to effectively isolate dynamic UbR-proteasome subcomplexes and define their subunit compositions using label-free quantitative mass spectrometry. In this work, we have analyzed seven distinctive UbR-proteasome complexes and found that all of them contain the same type of the 26S holocomplex. However, selected UbRs interact with a group of proteasome interacting proteins that may link each UbR to specific cellular pathways. The compositional similarities and differences among the seven UbR-proteasome subcomplexes have provided new insights on functional entities of proteasomal degradation machineries. The strategy described here represents a general and useful proteomic tool for isolating and studying dynamic and heterogeneous protein subcomplexes in cells that have not been fully characterized.


Receptor activation of NADPH oxidases.
Reactive oxygen species (ROS) have been implicated in many intra- and intercellular processes. High levels of ROS are generated as part of the innate immunity in the respiratory burst of phagocytic cells. Low levels of ROS, however, are generated in a highly controlled manner by various cell types to act as second messengers in redox-sensitive pathways. A NADPH oxidase has been initially described as the respiratory burst enzyme in neutrophils. Stimulation of this complex enzyme system requires specific signaling cascades linking it to membrane-receptor activation. Subsequently, a family of NADPH oxidases has been identified in various nonphagocytic cells. They mainly differ in containing one out of seven homologous catalytic core proteins termed NOX1 to NOX5 and DUOX1 or 2. NADPH oxidase activity is controlled by regulatory subunits, including the NOX regulators p47phox and p67phox, their homologs NOXO1 and NOXA1, or the DUOX1 or 2 regulators DUOXA1 and 2. In addition, the GTPase Rac modulates activity of several of these enzymes. Recently, additional proteins have been identified that seem to have a regulatory function on NADPH oxidase activity under certain conditions. We will thus summarize molecular pathways linking activation of different membrane-bound receptors with increased ROS production of NADPH oxidases.


Core-Shell Sn-Ni-Cu-Alloy@Carbon Nanorods to Array as Three-Dimensional Anode by Nanoelectrodeposition for High-Performance Lithium Ion Batteries.
We report the synthesis of a novel three-dimensional anode based on the core-shell Sn-Ni-Cu-alloy@carbon nanorods which was fabricated by pulse nanoelectrodeposition. Li ion batteries equipped with the three-dimensional anode demonstrated almost 100% capacity retention over 400 cycles at 450 mA g(-1) and excellent rate performance even up to 9000 mA g(-1) for advanced Li-ion battery. Insight of the high performance can be attributed to three key factors, Li-Sn alloys for Li-ion storage, Ni-Cu matrix for the electronic conductive and nanorods structure, and the carbon shell for the electronic/Li-ion conductive and holding stable solid electrolyte interphase (SEI), because these shells always kept stable volumes after extension of initial charge-discharge cycles.


Moxibustion for alleviating side effects of chemotherapy or radiotherapy in people with cancer.
Moxibustion, a common treatment in traditional Chinese medicine, involves burning herbal preparations containing Artemisia vulgaris on or above the skin at acupuncture points. Its intended effect is to enhance body function, and it could reduce the side effects of chemotherapy or radiotherapy and improve quality of life (QoL) in people with cancer. To assess the effects of moxibustion for alleviating side effects associated with chemotherapy, radiotherapy or both in people with cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE via Ovid, Embase via Ovid and AMED (Allied and Complementary Medicine Database) from their inception to February 2018. We also searched databases in China including the Chinese BioMedical Literature Database (CBM), Chinese Medical Current Contents (CMCC), TCMonline, Chinese Dissertation Database (CDDB), China Medical Academic Conference (CMAC) and Index to Chinese Periodical Literature from inception to August 2017. Registries for clinical trials and other resources were also searched. We included randomised controlled trials (RCTs) comparing moxibustion treatment, including moxa cone and moxa stick, versus sham, no treatment or conventional treatment. Two review authors (HWZ and FC) independently extracted data on study design, participants, treatment and control intervention, and outcome measures, and they also assessed risk of bias in the included studies. We performed meta-analyses, expressing dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean differences (MD), with 95% confidence intervals (CI). We included 29 RCTs involving 2569 participants. Five RCTs compared moxibustion versus no treatment, 15 compared moxibustion plus conventional treatment versus conventional treatment, one compared moxibustion versus sham moxibustion, and eight compared moxibustion versus conventional medicine. The overall risk of bias was high in 18 studies and unclear in 11 studies. Studies measured outcomes in various ways, and we could rarely pool data.Moxibustion versus no treatment: low-certainty evidence from single small studies suggested that moxibustion was associated with higher white blood cell counts (MD 1.77 × 109/L; 95% CI 0.76 to 2.78; 80 participants, low-certainty evidence) and higher serum haemoglobin concentrations (MD 1.33 g/L; 95% CI 0.59 to 2.07; 66 participants, low-certainty evidence) in people with cancer, during or after chemotherapy/radiotherapy, compared with no treatment. There was no evidence of an effect on leukopenia (RR 0.50, 95% CI 0.10 to 2.56; 72 participants, low-certainty evidence) between study groups. The effects on immune function (CD3, CD4, and CD8 counts) were inconsistent.Moxibustion versus sham moxibustion: low-certainty evidence from one study (50 participants) suggested that moxibustion improved QoL (measured as the score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)) compared with sham treatment (MD 14.88 points; 95% CI 4.83 to 24.93). Low-certainty evidence from this study also showed reductions in symptom scores for nausea and vomiting (MD -38.57 points, 95% CI -48.67 to -28.47) and diarrhoea (MD -13.81, 95% CI -27.52 to -0.10), and higher mean white blood cell count (MD 1.72 × 109/L, 95% CI 0.97 to 2.47), serum haemoglobin (MD 2.06 g/L, 95% CI 1.26 to 2.86) and platelets (MD 210.79 × 109/L, 95% CI 167.02 to 254.56) when compared with sham moxibustion.Moxibustion versus conventional medicines: low-certainty evidence from one study (90 participants) suggested that moxibustion improved WBC count eight days after treatment ended compared with conventional medicines (MD 0.40 × 109/L; 95% CI 0.15 to 0.65). Low-certainty evidence from two studies (235 participants) suggested moxibustion improved serum haemoglobin concentrations compared with conventional medicines (MD 10.28 g/L; 95% CI 4.51 to 16.05).Moxibustion plus conventional treatment versus conventional treatment alone: low-certainty evidence showed that moxibustion plus conventional treatment was associated with lower incidence and severity of leukopenia (WHO grade 3 to 4) (RR 0.14, 95% CI 0.01 to 2.64; 1 study, 56 participants), higher QoL scores on the EORTC QLQ-C30 (MD 8.85 points, 95% CI 4.25 to 13.46; 3 studies, 134 participants, I² = 26%), lower symptom scores for nausea and vomiting (RR 0.43, 95% CI 0.25 to 0.74; 7 studies, 801participants; I² = 19%), higher white blood cell counts (data not pooled due to heterogeneity), higher serum haemoglobin (MD 3.97 g/L, 95% CI 1.40 to 6.53; 2 studies, 142 participants, I² = 0%). There was no difference in platelet counts between the two groups (MD 13.48 × 109/L; 95% CI -16.00 to 42.95; 2 studies, 142 participants; I² = 34%).Most included studies did not report related adverse events, such as burning or allergic reactions. Limited, low-certainty evidence suggests that moxibustion treatment may help to reduce the haematological and gastrointestinal toxicities of chemotherapy or radiotherapy, improving QoL in people with cancer; however, the evidence is not conclusive, and we cannot rule out benefits or risks with this treatment. High-quality studies that report adverse effects are needed.


FuGE: Functional Genomics Experiment Object Model.
This is an interim report on the Functional Genomics Experiment (FuGE) Object Model. FuGE is a framework for creating data standards for high-throughput biological experiments, developed by a consortium of researchers from academia and industry. FuGE supports rich annotation of samples, protocols, instruments, and software, as well as providing extension points for technology specific details. It has been adopted by microarray and proteomics standards bodies as a basis for forthcoming standards. It is hoped that standards developers for other omics techniques will join this collaborative effort; widespread adoption will allow uniform annotation of common parts of functional genomics workflows, reduce standard development and learning times through the sharing of consistent practice, and ease the construction of software for accessing and integrating functional genomics data.


The detection of feigned mental disorders on specific competency measures.
Psychologists have standardized competency-to-stand-trial (CST) assessments through the development of specialized CST measures. However, their research has largely neglected the possibility that CST measures may be stymied by feigning mental disorders and concomitant impairment. The current study is the first systematic examination of (a) how feigned mental disorders may affect CST measures and (b) which scales are effective at identifying feigned cases. Bona fide patients (n = 65) were compared with suspected malingerers (n = 22) on 3 CST measures: the Georgia Court Competency Test (GCCT), the MacArthur Competence Assessment Tool--Criminal Adjudication, and the Evaluation of Competency to Stand Trial--Revised (ECST-R). Results indicated that these CST measures are vulnerable to feigning. The development of specialized GCCT and ECST-R scales yielded moderately effective screens for feigned mental disorders in the context of CST evaluations.


Patient-centeredness and empathy in a bilingual interprofessional primary care teaching clinic: a pilot study.
Utilizing the Consultation and Relational Empathy survey, this project examined the perceptions of care team empathy and patient-centeredness between English- and Spanish-speaking patients. From fall through spring semesters, patient surveys from a primary care, interprofessional student-led teaching clinic were collected and analyzed. Overall, mean scores for both English- and Spanish-speaking patients were above the reported normative average for general practitioners. While, overall, patients expressed satisfaction with the student-led teaching clinic in terms of empathy and patient-centeredness, English-speaking patients had higher median scores than Spanish-speaking patients. Analyzed individually, questions related to communication and provider attitudes were scored lower by Spanish-speaking patients. These results demonstrate that student-led clinics can deliver patient-centered care and highlight the continuing need to investigate and address disparities between English- and Spanish-speaking patients with regard to feelings of empathy and patient-centeredness.


Goblet cells in the normal adult human larynx--studies on morphology, distribution and density.
From 12 clinically and macroscopically normal larynges from adult persons all the mucosa was prepared and stained with PAS-alcian blue to study the morphology, distribution, and density of the goblet cells. In each larynx goblet cells were counted in 600 fields of 0.01768 mm2 mucosal surface, distributed on 18, 18 and 24 localities in the subglottis, glottis with the sinus of Morgagni, and supraglottis respectively. The goblet cells form a continuous pattern, comprising the entire subglottis, the anterior commissure, the sinus of Morgagni, the false vocal cords, vestibule of the larynx, and reaching to the cranial part of the laryngeal surface of the epiglottis. Another continuous, but goblet cell-free area extended from a couple of mm posterior to the anterior commissure, posteriorad on the cranial surface of the vocal cords, ary regions, aryepiglottic fold, the edge of the epiglottis, and 4-5 mm of the laryngeal surface of the epiglottic top, epiglottic vallecula, piriform recess, and the postcricoid region. Between the pseudostratified, ciliated columnar epithelium with goblet cells and the goblet cell-free stratified squamous epithelium there is a transitional epithelium in which the goblet cells alter from the 40 micron tall goblet cells characteristic of the respiratory tract epithelium to being quite flattened in order to disappear completely in the stratified squamous epithelium. The goblet cell density is significantly lower in the subglottis, viz. 125 cells per field, than in the glottis with the sinus of Morgagni and supraglottis, where the median density is 166 and 161 cells respectively per field. A possible correlation between the influence of the respiratory air upon the density of goblet cells and the complex anatomy of the larynx is discussed.


Distinct α subunit variations of the hypothalamic GABAA receptor triplets (αβγ) are linked to hibernating state in hamsters.
The structural arrangement of the γ-aminobutyric acid type A receptor (GABAAR) is known to be crucial for the maintenance of cerebral-dependent homeostatic mechanisms during the promotion of highly adaptive neurophysiological events of the permissive hibernating rodent, i.e the Syrian golden hamster. In this study, in vitro quantitative autoradiography and in situ hybridization were assessed in major hypothalamic nuclei. Reverse Transcription Reaction-Polymerase chain reaction (RT-PCR) tests were performed for specific GABAAR receptor subunit gene primers synthases of non-hibernating (NHIB) and hibernating (HIB) hamsters. Attempts were made to identify the type of αβγ subunit combinations operating during the switching ON/OFF of neuronal activities in some hypothalamic nuclei of hibernators. Both autoradiography and molecular analysis supplied distinct expression patterns of all α subunits considered as shown by a strong (p < 0.01) prevalence of α1 ratio (over total α subunits considered in the present study) in the medial preoptic area (MPOA) and arcuate nucleus (Arc) of NHIBs with respect to HIBs. At the same time α2 subunit levels proved to be typical of periventricular nucleus (Pe) and Arc of HIB, while strong α4 expression levels were detected during awakening state in the key circadian hypothalamic station, i.e. the suprachiasmatic nucleus (Sch; 60%). Regarding the other two subunits (β and γ), elevated β3 and γ3 mRNAs levels mostly characterized MPOA of HIBs, while prevalently elevated expression concentrations of the same subunits were also typical of Sch, even though this time during the awakening state. In the case of Arc, notably elevated levels were obtained for β3 and γ2 during hibernating conditions. We conclude that different αβγ subunits are operating as major elements either at the onset of torpor or during induction of the arousal state in the Syrian golden hamster. The identification of a brain regional distribution pattern of distinct GABAAR subunit combinations may prove to be very useful for highlighting GABAergic mechanisms functioning at least during the different physiological states of hibernators and this may have interesting therapeutic bearings on neurological sleeping disorders.


Lymphoid Tissue-Resident Alcaligenes Establish an Intracellular Symbiotic Environment by Creating a Unique Energy Shift in Dendritic Cells.
Lymphoid-tissue-resident commensal bacteria (LRCs), including Alcaligenes faecalis, are present in intestinal lymphoid tissue including the Peyer's patches (PPs) of mammals and modulate the host immune system. Although LRCs can colonize within dendritic cells (DCs), the mechanisms through which LRCs persist in DCs and the symbiotic relationships between LRCs and DCs remain to be investigated. Here, we show an intracellular symbiotic system in which the LRC Alcaligenes creates a unique energy shift in DCs. Whereas DCs showed low mitochondrial respiration when they were co-cultured with Escherichia coli, DCs carrying A. faecalis maintained increased mitochondrial respiration. Furthermore, E. coli induced apoptosis of DCs but A. faecalis did not. Regarding an underlying mechanism, A. faecalis-unlike E. coli-did not induce intracellular nitric oxide (NO) production in DCs due to the low activity of its lipopolysaccharide (LPS). Therefore, A. faecalis, an example of LRCs, may persist within intestinal lymphoid tissue because they elicit little NO production in DCs. In addition, the symbiotic DCs exhibit characteristic physiologic changes, including a low rate of apoptosis and increased mitochondrial respiration.


Ubiquitinated proteins activate the proteasome by binding to Usp14/Ubp6, which causes 20S gate opening.
In eukaryotic cells, ubiquitination of proteins leads to their degradation by the 26S proteasome. We tested if the ubiquitin (Ub) chain also regulates the proteasome's capacity for proteolysis. After incubation with polyubiquitinated proteins, 26S proteasomes hydrolyzed peptides and proteins 2- to 7-fold faster. Ub conjugates enhanced peptide hydrolysis by stimulating gate opening in the 20S proteasome. This stimulation was seen when this gate was closed or transiently open, but not maximally open. Gate opening requires conjugate association with Usp14/Ubp6 and also occurs if Ub aldehyde occupies this isopeptidase's active site. No stimulation was observed with 26S from Ubp6Delta mutants, but this effect was restored upon addition of Usp14/Ubp6 (even an inactive Ubp6). The stimulation of gate opening by Ub conjugates through Usp14/Ubp6 requires nucleotide binding to the gate-regulatory ATPases. This activation enhances the selectivity of the 26S proteasome for ubiquitinated proteins and links their deubiquitination to their degradation.


[Biological approach to adolescent suicide].
The high rating of suicide attempts and suicide in the general population and among adolescents justifies a lot of research studies, aiming to better define the genetic and biologic factors. The most relevant model and the most admitted is the role of serotonin which at low concentration in the brain causes more violent suicides or suicidal behaviors, as well as more aggressiveness and impulsiveness. It is not excluded that variations linked to the age could determine, among other factors, specific suicidal behaviors related to the adolescence.


Demographic effects on the Trail Making Test in marijuana abusers.
Demographic effects on the Trail Making Test (TMT), a test often used for screening for cognitive impairment, were examined in a sample of marijuana abusers in drug abuse treatment programs. A sample was drawn from electronic files of data from the Drug Abuse Treatment outcome Study (DATOS). The DATOS was a naturalistic, prospective cohort study that collected data from 1991-1993 in 96 programs in 11 cities in the United States. The number of marijuana abusers' scores available for analysis were 259. Data were analyzed to determine the effects of sex, ethnicity, age, and education variables on the two parts of the TMT in this large treatment sample of marijuana abusers. The variables of age and education level were statistically significantly related to TMT parts A and B, and ethnicity was statistically significant for part B of the TMT. R-Square values for overall models were moderate (A = .15, B = .18) suggesting that demographic effects on the TMT are weak.


Safety and clinical effectiveness of intravitreal administration of bevacizumab (Lumiere®) in patients with neovascular age-related macular degeneration.
The present study was an open-label, prospective, uncontrolled and multicenter clinical trial to investigate the safety and effectiveness of bevacizumab (Lumiere®) administered by the intravitreal route for the treatment of neovascular age-related macular degeneration (nAMD). A total of 22 patients without previous treatment with anti-vascular endothelial growth factor were recruited. Monthly therapy with 1.25 mg intravitreal bevacizumab was applied. Adverse events (AE), visual acuity (VA) and central retinal thickness (CRT) were assessed at baseline, day 1 and day 28 after each injection. A total of 87 AEs were reported; most of them were not serious (96.6%), expected (65.5%) and occurred after the third injection (56.3%). The most frequent AE was 'conjunctival hemorrhage' (29.9% of AEs), attributed to the injection procedure. Treatment was not suspended due to safety reasons in any case. After six months, a statistically significant gain of +8.2 (SD±8.8) letters and a CRT reduction of -75.50 µm (SD±120.3) were achieved with unilateral therapy. VA improvement and CRT reduction were also achieved with bilateral therapy, although to a lesser extent. The results of the present study suggested that therapy with a minimum of 3 doses of bevacizumab over a 6-month period was well tolerated and resulted in a sustained response regarding VA improvement and CRT reduction from the beginning of therapy compared with the baseline value. The study protocol was registered at clinicaltrials.gov (ref. no. NCT03668054).


Development and pH sensitivity of the respiratory rhythm of fetal mice in vitro.
In newborn and adult mammals, chemosensory drive exerted by CO(2) and H(+) provides an essential tonic input: without it the rhythm of respiration is abolished. It is not known, however, whether this chemosensory drive and the respiratory rhythm appear simultaneously during development. In isolated brainstem-spinal cord preparations from fetal mice, we determined at what stage of fetal life the respiratory rhythm appeared in third to fifth cervical ventral roots (phrenic motoneurons) and whether this fetal rhythm was sensitive to chemosensory inputs. A respiratory-like rhythm consisting of short duration bursts of discharges recurring at 2-16 min(-1) was detected in two of nine embryonic day 13 fetuses; it was abolished by transection of the spinal cord between the first to second cervical segments and was phase-related to rhythmic activity from medullary units of the ventral respiratory group. At embryonic day 13, it coexisted with a slow rhythm (0.1-2.0 min(-1)) of long duration bursts of action potentials which was generated by the spinal cord. At later fetal stages, the respiratory-like rhythm became more robust and of higher frequency, while the spinal cord rhythm became less obvious. At all fetal stages, acidification of the superfusion medium from pH 7.5-7.2 or 7.4-7.3 or 7.4 to 7.2 increased the frequency of both the respiratory-like and the spinal cord rhythms. In addition, acidification reduced the amplitude of the integrated burst activity of the spinal cord rhythm of embryonic day 13-embryonic day 16 fetuses and the respiratory-like rhythm of embryonic day 17 and older fetuses. Our results indicate that the rhythms transmitted by phrenic motoneurons during fetal development are chemosensitive from early fetal stages. Through its effects on induction and patterning of the rhythm, chemosensory drive may play a role in activity-dependent formation of respiratory neural networks.


Understanding Preferences for Humane and Cruel Treatment of Pest Rodents in Site C, Khayelitsha, South Africa.
The cruel treatment of pest rodents is a neglected area of study. This paper uses a representative survey from Khayelitsha (Cape Town) to show that a minority of residents preferred rodent control to be humane but that most did not care how rats are killed and almost a fifth said they would be 'happy' if the rats suffered. Agreeing that animal welfare is important and having become used to the presence of rats raised the probability of support for humane rodent control and decreased support for cruel rodent control. Being concerned that rats might be linked to witchcraft increased the probability of a pro-cruel stance. These results were robust to the inclusion of measures of rodent presence in the household and socio-economic status. This highlights the importance of values (notably concern about animal welfare) and cultural beliefs - in this case concerns that rodents might be linked to witchcraft - in predicting whether respondents are likely to have a pro-cruel stance on rodent control or not. Promoting the humane treatment of pest animals in this context thus requires engaging with local culture.


Context-aware dynamic filtering network for confocal laser endomicroscopy image denoising.
Objective.As an emerging diagnosis technology for gastrointestinal diseases, confocal laser endomicroscopy (CLE) is limited by the physical structure of the fiber bundle, leading to the inevitable production of various forms of noise during the imaging process. However, existing denoising methods based on hand-crafted features inefficiently deal with realistic noise in CLE images. To alleviate this challenge, we proposed context-aware kernel estimation and multi-scale dynamic fusion modules to remove realistic noise in CLE images, including multiplicative and additive white noise.Approach.Specifically, a realistic noise statistics model with random noise specific to CLE data is constructed and further used to develop a self-supervised denoised model without the participation of clean images. Secondly, context-aware kernel estimation, which improves the representation of features by similar learnable region weights, addresses the problem of the non-uniform distribution of noises in CLE images and proposes a lightweight denoised model (CLENet). Thirdly, we have developed a multi-scale dynamic fusion module that decouples and recalibrates features, providing a precise and contextually enriched representation of features. Finally, we integrated two developed modules into a U-shaped backbone to build an efficient denoising network named U-CLENet.Main Results.Both proposed methods achieve comparable or better performance with low computational complexity on two gastrointestinal disease CLE image datasets using the same training benchmark.Significance.The proposed approaches improve the visual quality of unclear CLE images for various stages of tumor development, helping to reduce the rate of misdiagnosis in clinical decision-making and achieve computer graphics-assisted diagnosis.


Extracellular siderophores of rapidly growing Aspergillus nidulans and Penicillium chrysogenum.
The highly active extracellular siderophores previously detected in young cultures of Aspergillus nidulans and Penicillium chrysogenum have been identified as the cyclic ester fusigen (fusarinine C), and its open-chain form, fusigen B (fusarinine B).


Expression of the extracellular domain of the human heat-stable enterotoxin receptor in Escherichia coli and generation of neutralizing antibodies.
The entire extracellular domain of the human heat-stable enterotoxin (ST) receptor as well as a truncated N-terminal domain were cloned as glutathione S-transferase fusion proteins and expressed in Escherichia coli. The recombinant fusion proteins were purified from both the cytosol and the inclusion body fractions by selective detergent extraction followed by glutathione-agarose affinity chromatography. The purified protein, corresponding to the entire extracellular domain, bound the stable toxin peptide with an affinity comparable to that of the native receptor characterized from the human colonic T84 cell line. No binding was observed with the N-terminal truncated fragment of the receptor under similar conditions. Polyclonal antibodies were raised to the entire extracellular domain fusion protein as well as the truncated extracellular domain fusion protein, and the antibodies were purified by affinity chromatography. Addition of the purified antibodies to T84 cells inhibited ST binding and abolished ST-mediated cGMP production, indicating that critical epitopes involved in ligand interaction are present in the N-terminal fragment of the receptor. Purified antibodies recognized a single protein of Mr 160,000 Da on Western blotting with T84 membranes, corresponding to a size of the native glycosylated receptor in T84 cells. These studies are the first report of the expression, purification, and characterization of any member of the guanylyl cyclase family of receptors in E. coli and show that binding of the toxin to the extracellular domain of the receptor is possible in the absence of any posttranslational modifications such as glycosylation. The recombinant fusion proteins as well as the antibodies that we have generated could serve as useful tools in the identification of critical residues of the extracellular domain involved in ligand interaction.


Contamination risk of the surgical team through ROBODOC's high-speed cutter.
During cutting of the femoral cavity in the ROBODOC procedure, an aerosol cloud of irrigation fluid, blood, and tissue debris was seen. This cloud potentially is contaminated with bacterial and viral vectors, which is an infection risk for the surgical team. A flat and a ball cutter were tested in four standard situations macroscopically with a colored solution. In a second experiment, the cutter was exposed to a fluid contaminated with Staphylococcus aureus, and bacterial room contamination was detected using standard cultures. The aerosol cloud was seen in a 6 x 3.6-m area. Extension and concentration varied, depending on the irrigation situation. ROBODOC's high-speed cutter produces an aerosol cloud in an area in which all members of the surgical team are affected. Sufficient protection is necessary for everyone in the operating room.


A simplified marking technique for eyebrow reconstruction using composite grafts.
Eyebrows can be damaged in facial burns, trauma, skin cancer, herpes zoster and other conditions. Some of these patients will demand eyebrow reconstruction surgery. This can be done using free composite grafts from the scalp or flaps from the temporal area. Both techniques require time-consuming planning, marking and shaping of the graft or flap in order to achieve a good cosmetic result. In an attempt to make free graft reconstructions faster and easier, we modified the technique. We describe an easy way of obtaining a template that simplifies the procedure and enhances symmetry.


Cancer Comprehensive Analysis in Gastric Carcinoma: Benefits and New Perspectives.
Gastric cancer is one of the most common and deadly cancers worldwide. Screening tests as well as tools for prediction of treatment outcomes and prognosis have been developed, but they have many limitations. The integration of liquid biopsy provided new aspects in screening and diagnosis of gastric cancer. In the present study, we used different techniques, studying the genetic and epigenetic profile of circulating tumor cells. We aimed to acquire all the available information, compare it with already existing studies, and evaluate the benefit of this approach. A blood sample was isolated from 2 gastric cancer patients at stages III-IV, followed by the isolation of CTCs. The circulating tumor cells were used for array comparative genomic hybridization, next-generation sequencing, and whole gene expression microarrays. Different variants were detected, while the microsatellite instability status was stable in both cases. The tumor mutational burden was low to medium. Gene expression assays revealed that >100 genes were overexpressed compared to noncancer samples. Amplifications of X chromosome were also observed in both cases, by using array comparative genomic hybridization. Although there are several techniques for cancer screening, prediction of therapy outcomes, and prognosis, the application of a complete comprehensive cancer panel, combining the study of variants, fusions, chromosomal abnormalities, and gene expression, is more appropriate. Information provided by the above techniques might contribute in designing more efficient treatment protocols and screening tools. Despite the limitation of samples, the data are encouraging, and further study is needed so that they can be used at clinical level.


Rechargeable Mg2+/Li+, Mg2+/Na+, and Mg2+/K+ Hybrid Batteries Based on Layered VS2.
Rechargeable Mg batteries have great potential in next-generation scalable energy-storage applications, but the electrochemical performance is limited by the Mg-intercalation cathodes. Hybrid batteries based on dual-cation (Mg2+ and alkali metal cations) electrolytes would not only improve the electrochemical performance but also induce the co-intercalation of Mg2+ with alkali metal cations. As previous reports overwhelmingly focus on Mg2+/Li+ hybrid batteries, in this work, Mg2+/Na+ and Mg2+/K+ hybrid batteries are constructed using a typical layered VS2 cathode and studied in comparison with Mg2+/Li+ batteries. It is observed that Mg2+ could co-intercalate into VS2 with Li+, Na+, or K+. However, Mg-intercalation is irreversible in the Mg2+/Li+ system, and co-intercalation of Mg2+ and K+ would cause a collapse of VS2. Comparatively, the co-intercalation of Mg2+ and Na+ into VS2 exhibits the highest reversibility, and the Mg2+/Na+ hybrid battery shows the best cycling stability without capacity fading within 1000 cycles. Our work highlights the co-intercalation reversibility of a non-pre-expanded layered disulfide cathode and delivers insights for the development of high-performance rechargeable Mg metal batteries.


Workplace and community social capital and burnout among professionals of health and welfare services for the seniors: A multilevel analysis in Japan.
Despite the potential of the social capital approach in preventing burnout, there is sparse evidence of its contextual effect. This study aimed to reveal the contextual association of workplace and community social capital on burnout among professionals of health and welfare services for seniors in Japan. We collected data from a cross-sectional questionnaire survey for all health and welfare professionals working in Community Comprehensive Support Centers (CCSCs) in the central Tokyo area in 2015. We assessed burnout using the Japanese version of the Maslach Burnout Inventory, which consists of three subscales: emotional exhaustion, depersonalization, and reduced personal accomplishment. We prepared social capital items regarding workplace (the CCSC the participants belonged to) and community (the current catchment area of the CCSC). We aggregated individual responses of workplace and community social capital within each CCSC to create group-level workplace and community social capital indicators. Among the 1771 questionnaires distributed, we analyzed 1110 from 211 CCSCs. Multilevel analysis showed that higher group-level workplace social capital was significantly associated with lower scores of all three subscales after adjusting for covariates. Moreover, we found a significant association between greater group-level community social capital and lower scores of depersonalization and reduced personal accomplishment. Working in workplaces and communities with higher social capital is related to lower burnout. The findings suggest that strategies to enhance the social capital of their workplace and community would be beneficial in the prevention of burnout among professionals in the field of health and social welfare.


N- and C-terminal halves of human annexin VI differ in ability to form low pH-induced ion channels.
Human recombinant annexin VI (AnxVI) or its N- (AnxVIA) and C-terminal (AnxVIB) fragments were expressed in E. coli. Their ability to form voltage-dependent ion channels in membranes, induced by low pH, was measured to verify the hypothesis that, upon acidification, the hydrophobicity of AnxVI at a specific domain significantly increases allowing the AnxVI interaction with lipids in a Ca(2+)-independent manner. By theoretically analyzing changes in protein hydrophobicity, we found that hydrophobicity of AnxVIA significantly differed from that of AnxVIB at low pH. These predictions were confirmed experimentally by using planar lipid bilayers and liposome pull-down assay. We found striking difference between AnxVIA and AnxVIB in the ion channel activity, as well as in the membrane binding, suggesting that the halves of AnxVI maybe functionally different. Moreover, we calculated and predicted that the ion channel activity at low pH should appear in other human annexins, as AnxII, AnxV (as known), AnxVIII, and AnxXIII. The possibility that AnxVI acts as cytosolic component of a transmembrane pH-sensing mechanism is proposed.


Treatment of a burn animal model with functionalized tridimensional electrospun biomaterials.
Laminin-functionalized poly-d,l-lactic acid scaffolds were produced. Following this, mesenchymal stem cells and keratinocytes were seeded on biomaterials for the in vivo experiments, where the biomaterials with or without cells were implanted. The analysis is comprised of the visual aspect and mean size of the lesion plus the histology and gene expression. The results showed that the cells occupied all the structure of the scaffolds in all the groups. After nine days of in vivo experiments, the defect size did not show statistical difference among the groups, although the groups with the poly-d,l-lactic acid/Lam biomaterial had the lowest lesion size and presented the best visual aspect of the wound. Gene expression analysis showed considerable increase of tumor growth factor beta 1 expression, increased vascular endothelial growth factor and balance of the BAX/Bcl-2 ratio when compared to the lesion group. Histological analysis showed well-formed tissue in the groups where the biomaterials and biomaterials plus cells were used. In some animals, in which biomaterials and cells were used, the epidermis was formed throughout the length of the wound. In conclusion, these biomaterials were found to be capable of providing support for the growth of cells and stimulated the healing of the skin, which was improved by the use of cells.


Why an extended evolutionary synthesis is necessary.
Since the last major theoretical integration in evolutionary biology-the modern synthesis (MS) of the 1940s-the biosciences have made significant advances. The rise of molecular biology and evolutionary developmental biology, the recognition of ecological development, niche construction and multiple inheritance systems, the '-omics' revolution and the science of systems biology, among other developments, have provided a wealth of new knowledge about the factors responsible for evolutionary change. Some of these results are in agreement with the standard theory and others reveal different properties of the evolutionary process. A renewed and extended theoretical synthesis, advocated by several authors in this issue, aims to unite pertinent concepts that emerge from the novel fields with elements of the standard theory. The resulting theoretical framework differs from the latter in its core logic and predictive capacities. Whereas the MS theory and its various amendments concentrate on genetic and adaptive variation in populations, the extended framework emphasizes the role of constructive processes, ecological interactions and systems dynamics in the evolution of organismal complexity as well as its social and cultural conditions. Single-level and unilinear causation is replaced by multilevel and reciprocal causation. Among other consequences, the extended framework overcomes many of the limitations of traditional gene-centric explanation and entails a revised understanding of the role of natural selection in the evolutionary process. All these features stimulate research into new areas of evolutionary biology.


Dermatology education on the Web.
Conventional dermatology teaching favours a didactic, factual approach, rather than a problem-solving approach. A Web-based education system that uses a problem-solving approach offers many advantages. Several international Websites now provide continuing education to specialist dermatologists. These are all 'discretionary' Websites, that is, they are visited by choice; 'obligatory' educational Websites are those tied to a university medical faculty or postgraduate college and which host either online tasks that must be completed or unique examinable material. An interactive education Website, named Dermconsult, has been established unofficially for fellows of the Australasian College of Dermatologists and registrars in training. However, a successful Website will require backing from certifying organizations. Continuing medical education will need to be compulsory for potential users if an educational Website is to be successful.


Fringe localization control in holographic interferometry.
The practical use of holographic interferometry in nondestructive testing leads to many situations in which the characteristics of the fringe patterns make the observation and subsequent interpretation of the fringes difficult. Fringe control may then be employed to correct the troublesome parameters, the most commonly treated of which is fringe spacing. To gain more powerful control, a novel method is presented here that also permits one to change the localization of the fringe pattern. General vectorial expressions are derived that relate a tilt in the reference beam to a change in the fringe localization. Moreover the changes introduced into the fringe vector by this tilt can be suppressed by an adequate shift of the illumination beam focus. Some illustrative examples for a plane object are presented.


Optimal size of prostheses for functioning of the aortic prosthetic valve in aortic and mitral valve replacement with annular enlargement through Manouguian's technique.
There is not yet agreement about the optimal size of the prostheses in aortic and mitral valve replacement with Manouguian's technique. In this technique, the aortic prosthetic valve can be pushed upon the mitral prosthesis which may cause dysfunction of the aortic prosthetic valve. The aim of this study was to clarify the size of the prostheses needed to avoid dysfunction of the aortic prosthetic valve. Three patients underwent aortic and mitral valve replacement through this procedure. Two of them had active aortic and mitral valve endocarditis. Aortomitral continuity involved with abscesses could be approached and completely excised using this technique. All patients survived the operation, but 1 of them suffered aortic mechanical valve dysfunction for the reason stated. Anatomical analysis of the geometrical relation of the 2 prosthetic valves suggests that the mitral annulus should be enlarged less than 25 mm to avoid dysfunction of the aortic prosthetic valve.


Clinical risks of thrombolytic therapy.
Understanding the clinical risks of intravenous thrombolytic therapy is critical to appropriate patient selection. The major risks can be classified into 5 major categories: intracranial hemorrhage, systemic hemorrhage, immunologic complications, hypotension, and myocardial rupture. Although theoretical concern exists about thromboembolic complications, they rarely occur. Although cardiac rhythm disturbances are somewhat more likely to occur at the time of reperfusion, the clinical significance of "reperfusion arrhythmias" is minimal. Intracranial hemorrhage, the most devastating complication, occurs in 0.2-1% of patients treated with thrombolytic therapy. Factors associated with incremental risk are now being identified from large clinical trials. Systemic hemorrhage is uncommon in patients without major vascular punctures and seldom leads to serious adverse outcomes. Immunologic complications--including anaphylaxis, which is rare, and immune complex disease, which is more common--occur only with streptokinase or agents with a streptokinase moiety, including anistreplase (anisoylated plasminogen--streptokinase activator complex, APSAC). Hypotension, which can be managed easily in most patients, is also observed much more frequently with streptokinase and anistreplase. Myocardial rupture is increasingly being recognized as a possible complication of late thrombolysis. A proper perspective on clinical risk can only be gained in the context of potential benefit of therapy. In many cases individual patients considered to be at highest risk for complications also stand to gain the most from treatment. Many of the questions raised by currently available data about bleeding risk are being addressed in the ongoing Global Utilization of t-PA and Streptokinase (GUSTO) Trial. A paradigm for considering this decision making problem is presented.


Geometry sensing by dendritic cells dictates spatial organization and PGE(2)-induced dissolution of podosomes.
Assembly and disassembly of adhesion structures such as focal adhesions (FAs) and podosomes regulate cell adhesion and differentiation. On antigen-presenting dendritic cells (DCs), acquisition of a migratory and immunostimulatory phenotype depends on podosome dissolution by prostaglandin E(2) (PGE(2)). Whereas the effects of physico-chemical and topographical cues have been extensively studied on FAs, little is known about how podosomes respond to these signals. Here, we show that, unlike for FAs, podosome formation is not controlled by substrate physico-chemical properties. We demonstrate that cell adhesion is the only prerequisite for podosome formation and that substrate availability dictates podosome density. Interestingly, we show that DCs sense 3-dimensional (3-D) geometry by aligning podosomes along the edges of 3-D micropatterned surfaces. Finally, whereas on a 2-dimensional (2-D) surface PGE(2) causes a rapid increase in activated RhoA levels leading to fast podosome dissolution, 3-D geometric cues prevent PGE(2)-mediated RhoA activation resulting in impaired podosome dissolution even after prolonged stimulation. Our findings indicate that 2-D and 3-D geometric cues control the spatial organization of podosomes. More importantly, our studies demonstrate the importance of substrate dimensionality in regulating podosome dissolution and suggest that substrate dimensionality plays an important role in controlling DC activation, a key process in initiating immune responses.


Male physical aggression as a function of alcohol, frustration, and subjective mood.
An experiment tested the hypothesis that alcohol intoxication will increase aggression only if the subject is experiencing the intoxicated state as displeasing. Forty males drank either 0.8 mL of pure alcohol/kg body weight or a placebo drink and were then exposed to either a pleasant or an unpleasant mood manipulation. Following this, they were given the chance to aggress in a modified version of the Buss "aggression machine" paradigm. All subjects were observed under varying levels of frustration. Results indicated that alcohol-drinking subjects were more aggressive than placebo-drinking subjects, and that both intoxicated and sober subjects increased their aggression when frustrated. Intoxicated subjects in a pleasant mood were most aggressive under both provocative and nonprovocative conditions. The hypothesis was not supported and results are discussed in relation to different theoretical models and in relation to results from other similar studies.


Pro: High dose of therapeutic plasma exchange-mind the gap!
'Mind the gap' is a recorded warning phrase used in the London Tube since 1969. The following article is meant to be a warning of an increasing knowing-doing gap in routine practice of therapeutic plasma exchange (TPE), a treatment method that is used more and more throughout the world. The American Society of Apheresis recommendations, including the most recent ones from 2016, suggest using a TPE volume of 1.0-1.5 times the actual calculated plasma volume of the patient. There are only a few exceptions to that rule, such as the recommnded exchange volume in vasculitis or mushroom poisoning. The published literature suggests that in routine clinical practice in many institutions in several countries the exchanged volume might in fact be lower than recommended by the guidelines. In the following article we argue for a high dose of exchanged plasma volume, yet sketch different scenarios on how this time-averaged high dose can be delivered in various ways depending on the underlying disease, refuting a one-size-fits-all strategy that might facilitate the procedure but may result in 'underpheresis' in many patients. Further, the objectives underlying the use of smaller exchange volumes, especially the gap between the cost of blood products and the reimbursement of TPE are discussed. Lastly, the knowing-guiding gap is described, which can only be overcome by collecting high-quality data and conducting prospective clinical trials in the field of TPE.


Targeting VEGF-VEGFR Pathway by Sunitinib in Peripheral Primitive Neuroectodermal Tumor, Paraganglioma and Epithelioid Hemangioendothelioma: Three Case Reports.
Sunitinib malate (Sutent(TM); Pfizer Inc., New York, N.Y., USA) is a small molecule kinase inhibitor with activity against a number of tyrosine kinase receptors, including vascular endothelial growth factor receptors, stem-cell factor receptor, and platelet-derived growth factor receptors alpha and beta. Sunitinib, registered for the treatment of renal cell carcinoma and gastrointestinal stromal tumors, has recently been approved for the treatment of patients with advanced pancreatic neuroendocrine tumors. Peripheral primitive neuroectodermal tumor (pPNET), paraganglioma (PGL) and epithelioid hemangioendothelioma (EHE) are rare tumors in which there is an overexpression of pro-angiogenic factors and in which a high intratumoral microvessel density is a significant poor prognostic factor. On the basis of this preclinical rationale and the lack of effective treatments in pre-treated advanced stages of these rare diseases, we report our interesting experience of pPNET, PGL and EHE treatment with sunitinib.


Feasibility and Reliability of Microvascular Reconstruction in the Vessel-depleted Previously Operated Neck.
Microvascular reconstruction of defects in the head and neck has always been a challenge in patients who have undergone previous neck dissection, owing to the prior resection of potential recipient blood vessels used for free flap perfusion. The objective of the study is to evaluate the reliability and safety of free flap reconstruction in patients who have had previous neck dissection. Twenty-four free flaps were performed in 22 patients with a previous history of neck dissection for head-and-neck squamous cell carcinoma. These included patients who underwent salvage surgery for recurrent cancer as well as patients undergoing secondary reconstruction following previous oncological resections. Flap includes 12 radial forearm free flaps, 5 fibula flaps, 1 rectus abdominis flap, and 6 anterolateral thigh flaps. In cases with the previous history of selective neck dissection, recipient vessels on the ipsilateral/same side of the previously operated neck were used, while contralateral vessels were used in patients with a history of modified radical or radical neck dissection. Vein grafts were not necessary, except for one case. In our series, we did not have any flap loss or considerable increase in operative time. Free flap reconstruction of head-and-neck defects is highly successful in patients with a history of previous neck dissection, despite a relative scarcity of recipient blood vessels. Careful planning and relying on flaps with a long vascular pedicle obviates the need to perform a suitable vein graft. In our present series, careful planning and the right choice of a free flap with a long vascular pedicle contributes to the absence of free flap failure. In our experience, previous neck dissection should not be considered as a contraindication to microvascular reconstruction of previously operated oncologic defects.


Shifting the life-history paradigm: discovery of novel habitat use by hawksbill turtles.
Adult hawksbill turtles (Eretmochelys imbricata) are typically described as open-coast, coral reef and hard substrate dwellers. Here, we report new satellite tracking data on female hawksbills from several countries in the eastern Pacific that revealed previously undocumented behaviour for adults of the species. In contrast to patterns of habitat use exhibited by their Caribbean and Indo-Pacific counterparts, eastern Pacific hawksbills generally occupied inshore estuaries, wherein they had strong associations with mangrove saltwater forests. The use of inshore habitats and affinities with mangrove saltwater forests presents a previously unknown life-history paradigm for adult hawksbill turtles and suggests a potentially unique evolutionary trajectory for the species. Our findings highlight the variability in life-history strategies that marine turtles and other wide-ranging marine wildlife may exhibit among ocean regions, and the importance of understanding such disparities from an ecological and management perspective.


L-arginine, the substrate of nitric oxide synthase, inhibits fertility of male rats.
To examine the effect of L-arginine, the substrate of nitric oxide (NO) synthase, on reproductive function of male rats. Male rats were gavaged with either L-arginine (100 or 200 mg x kg(-1) x d(-1)), D-arginine (200 mg x kg(-1) x d(-1)) or vehicle (0.9% NaCl) for seven consecutive days. Their sexual behaviour and fertility were evaluated using receptive females. L-arginine (200 mg/kg) had no significant effect on sexual competence (in terms of sexual arousal, libido, sexual vigour and sexual performance). In mating experiments, the higher dose of L-arginine effectively and reversibly inhibited fertility, whilst the lower dose and the inactive stereoisomer D-arginine had no significant effect. The antifertility effect caused by L-arginine was due to a profound elevation in the preimplantation loss mediated possibly by impairment in epididymal sperm maturation, hyperactivated sperm motility and sperm capacitation. Elevated NO production may be detrimental to male fertility.


Exploring the Role of Endothelial Cell Resilience in Cardiovascular Health and Disease.
Traditionally, much research effort has been invested into focusing on disease, understanding pathogenic mechanisms, identifying risk factors, and developing effective treatments. A few recent studies unraveling the basis for absence of disease, including cardiovascular disease, despite existing risk factors, a phenomenon commonly known as resilience, are adding new knowledge and suggesting novel therapeutic approaches. Given the central role of endothelial function in cardiovascular health, we herein provide a number of considerations that warrant future research and considering a paradigm shift toward identifying the molecular underpinnings of endothelial resilience.


Stability of hard tissue profile after mandibular setback in sagittal split osteotomies: a longitudinal and long-term follow-up study.
The aim of the study was to conduct a long-term follow-up on the stability of the hard tissues after bilateral sagittal split osteotomy (BSSO) with rigid internal fixation (RIF)to set back the mandible and to compare it with that of mandibular advancement performed by the same team of surgeons and with the same examination protocol. Seventeen consecutive patients (6 females and 11 males) could be re-examined 12.7 years (T5) after surgery. The previous examinations were before surgery (T1), 5 days (T2), and 6.6 (T3) and 14.4 (T4) months after surgery. Lateral cephalograms were traced by hand, digitized, and evaluated with the Dentofacial Planner software program. The x-axis for the system of co-ordinates ran through sella (point zero) and the line nasion-sella-line minus 7 degrees. The program determined the x- and y-values of each variable and the usual angles and distances. The effects of treatment were determined with Wilcoxon matched pairs, signed ranks test, with Bonferroni adjustment, and the relationship between variables with Spearman rank correlation coefficient. Relapse at point B was 0.94 mm or 15 per cent and at pogonion 1.46 mm or 21 per cent of the initial setback at T5. Relapse was mainly short-term (T4-T2), 13 per cent for point B and 17 per cent for pogonion. Gender correlated significantly with relapse (T5-T2) at point B (P = 0.002) and pogonion (P = 0.021), i.e. females in contrast to males showed further distalization of the mandible instead of relapse. No correlations were seen for age or the amount of surgical setback. The long-term results in mandibular setback patients were more stable when compared with the mandibular advancement patients examined previously. The initial soft tissue profile, the initial growth direction, and the remodelling processes of the hard tissues must be considered as reasons for long-term relapse. Growth direction positively influenced the long-term results in females: further distalization of the mandible occurred.


Interactions of diclazuril enantiomers with serum albumins: Multi-spectroscopic and molecular docking approaches.
In this work, multi-spectroscopic and molecular docking methods have been conducted in the investigation of enantioselective interactions between diclazuril enantiomers and human/bovine serum albumins (HSA/BSA). The binding constants between serum albumins (SAs) and diclazuril enantiomers revealed that SAs exhibited stronger binding affinity for (R)-diclazuril than (S)-enantiomer. In addition, the fluorescence quenching of SAs induced by diclazuril enantiomers was ascribed to static quenching mechanism, in which hydrogen bonds and Van der Waals forces were the main interactions. According to the thermodynamic study, binding of diclazuril enantiomers and SAs was an exothermic process driven by enthalpy change. Then, circular dichroism spectroscopy of SAs with diclazuril enantiomers revealed that the SAs conformation had changed in the presence of diclazuril. Moreover, molecular docking technology was applied in exploration of interactions between SAs and diclazuril enantiomers. The docking energy between SAs and (R)-diclazuril was larger than (S)-diclazuril, which indicated that the affinity of SAs with (R)-diclazuril was stronger than (S)-enantiomer. This work may provide valuable information for explaining differences in pharmacokinetics and residue elimination of diclazuril enantiomers in living organisms.


The factor structure and clinical utility of clinician-rated dimensions of psychosis symptom severity in patients with recent-onset psychosis: Results of a 1-year longitudinal follow-up prospective cohort study.
The classic subtype classification of schizophrenia has been removed, and DSM-5 now includes the Clinician-Rated Dimensions of Psychosis Symptom Severity (CRDPSS). In the present study, a factor analysis of the CRDPSS was performed, and we assessed whether patient classification using the derived factor structure helps predict the clinical course. The participants were 390 patients with recent-onset psychosis enrolled in the Korean Early Psychosis Cohort Study (KEPS). Two factors were identified: psychotic (including delusions, hallucinations, disorganization, and abnormal psychomotor behavior) and negative-cognitive (including negative symptoms and impaired cognition). Patients were grouped based on the factor structure and changes in clinical course were monitored over 1 year. The negative-cognitive group demonstrated longer duration of untreated psychosis, earlier onset, and a higher rate of psychiatric comorbidities. Baseline Positive and Negative Syndrome Scale (PANSS) total and Clinical Global Impression-Severity (CGI-S) scores were higher in psychotic group, but group differences were not observed after 2 months. Conversely, the PANSS negative scale score was significantly higher in negative-cognitive group throughout follow-up, and CGI-S score was reversed at 12 months. The findings indicate that the factor structure derived herein for the CRDPSS could be helpful for predicting the clinical course of recent-onset psychosis patients.


Health-related quality of life and posttraumatic stress disorder among survivors of an outbreak of Legionnaires disease.
A follow-up study of 122 survivors of an outbreak of legionnaires disease (LD) in The Netherlands was conducted to determine persistence of symptoms, health-related quality of life (HRQL), and presence of posttraumatic stress disorder (PTSD). Seventeen months after diagnosis of LD, survivors completed a questionnaire assessing symptoms and HRQL and a questionnaire assessing PTSD. The most prevalent new symptoms were fatigue (in 75% of patients), neurologic symptoms (in 66%), and neuromuscular symptoms (in 63%). HRQL was impaired in 7 of the 8 dimensions assessed by the HRQL questionnaire, and 15% of patients experienced PTSD. Symptoms and impaired HRQL persisted for >1.5 years. As a result of the design of this study, it could not be inferred whether Legionella pneumophila infection, severe pneumonia in general, or the outbreak situation was responsible for impaired well-being. However, awareness of this problem by health care providers may improve the aftercare of patients.


[Tumor markers in human breast cancer].
We described tumor markers which are considered to be useful for the detection of recurrence, index of the efficacy of treatment and assessment for the prognosis of the patients with breast cancer. CEA and CA 15-3 are relatively useful markers among various serological ones. However, although accuracy of the diagnosis with CA 15-3 and CEA is generally thought to be not superior to those of imaging method, CA 15-3 and CEA seems to be clinically useful tools for making diagnosis because of its simplicity and less cost. Estrogen and progesterone receptors shows good responses to endocrine therapy. Response rate was 70 to 80% in both receptor-positive patients. Presence of ER shows higher rate of recurrence and shorter survival of the patients than those with absence of ER. Recent attention has been focused on EGF and proto-oncogene, suggesting relationship of those to prognosis.


Healing of ligaments in synovial fluid. An experimental study in rabbits.
To investigate the importance of nutritive environment in the healing of reconstructed ligaments, the morphology of sutured free patellar ligaments in synovial fluid of the contralateral knee joint, without re-establishment of microcirculation, was studied in rabbits. After two weeks (n = 6) and one (n = 6) and three (n = 5) months, the sutured ligament was removed from the joint and fibroblasts were seen growing into the suture gap. The ligaments were enveloped in a capsule of fibroblasts, which was more developed in those ligaments that were studied three months after operation. The collagen of the piece of ligament was disorganised at all time points, and tensile strength (n = 6) was low compared with non-sutured patellar ligament. Some ligaments disappeared or were partly attached to the synovial membrane and revascularised. The findings indicate that diffusion of nutrients may be important for the survival and healing of reconstructed ligaments, as the ligaments can heal in synovial fluid without re-establishment of the microcirculation.


Acute toxicity tests on raw leachate from a Malaysian dumping site.
Leachate samples collected from the Ampar Tenang open dumping site at Dengkil, Malaysia, were analyzed for acute toxicity. Two in vivo toxicity tests, Acute Oral Toxicity (AOT) and Primary Skin Irritation (PSI), were performed using Sprague Dawley rats and New Zealand Albino rabbits, respectively. The leachate samples were also analyzed chemically for nitrate and phosphate, ammonia-nitrogen, Kjeldahl-nitrogen and Chemical Oxygen Demand (COD). Results from both the AOT and PSI tests showed that the leachate did not contribute to acute toxicity. The AOT test yielded a negative result: no effect was observed in at least half of the rat population. The PSI test on rabbits produced effects only at a leachate concentration of 100%. However, the skin irritation was minor, and the test returned a negative result. The four chemical tests showed high levels of nutrient pollution in the leachate. The nitrate and phosphate concentrations were 2.1 mg/L and 23.6 mg/L, respectively. Further, the ammonia-nitrogen concentration was 1,000 mg NH(3)-N/L the Kjeldahl-nitrogen level was 446 mg NH(3)-N/L, and the Chemical Oxygen Demand was 1,300 mg/L. The in vivo toxicity and chemical analyses showed that the leachate is polluted but not acutely toxic to organisms.


Inter-arm difference in systolic blood pressure: Prevalence and associated factors in an African population.
Inter-arm blood pressure difference (IABPD) can lead to underdiagnosis and poor management of hypertension, when not recognized and are associated with increased cardiovascular mortality and morbidity. However, the prevalence and associated risk factors of IABPD in sub-Saharan Africa are unknown. This study aims to determine the prevalence and associated risk factors of IABPD among Tanve Health Study (TAHES) participants, a cohort about cardiovascular diseases in a rural area in Benin. The cohort was conducted since 2015 among adults aged 25 years and over in Tanve village. Data were collected from February to March, 2020. Brachial blood pressure were recorded at rest on both arm with an electronic device. Systolic IABPD (sIABPD) was defined as the absolute value of the difference in systolic blood pressure between left and right arms ≥ 10 mmHg. A multivariate logistic regression models identified factors associated with sIABPD. A total of 1,505 participants (women 59%) were included. The mean age was 45.08 ±15.65 years. The prevalence of sIABPD ≥ 10 mmHg was 19% (95%CI: 17-21). It was 19% (95%CI: 16-22) in men and 20% (95%CI: 17-22) in women. In final multivariable model, the probability of sIABPD ≥ 10 mmHg increased significantly with age (adjusted OR (aOR) = 1.1; 95%CI: 1.02-1.20 per 10-years), hypertension (aOR = 2.33; 95%CI: 1.77-3.07) and diabetes (aOR = 1.96; 95%CI: 1.09-3.53). Almost quarter of sample have a sIABPD ≥ 10 mmHg, with an increased risk with older age and hypertension and diabetes.


[One center's experience of coronary angioplasty with a 5 French catheter guide by a femoral approach at the same time as coronary angiography].
The object of this study was to assess the feasibility of so-called ad hoc 5 F percutaneous transluminal coronary angioplasty (PTCA). This monocentric register included 200 consecutive procedures (233 lesions) of 5F PTCA by a femoral approach after a bolus of standard heparin (50 to 70 IU/kg). The population included 15.4% of stable angina, 29.4% of unstable angina, 11% acute phase, 13.5% post-revascularisation angina and 30.7% post-infarction cases. A successful procedure was defined as a good angiographic result without ischaemic complications. A failed 5F procedure was defined by the need to fall back on a 6F PTCA. The peripheral vascular complications were recorded. The lesions were stented in 77.4% of cases including 13.4% of direct stenting. There were 200 successful procedures (87%). The failures (N = 26) were mainly explained by the inability to cross chronic obstruction (N = 11). The ischaemic complications included 2 coronary bypasses (2 retrograde dissections of the left anterior descending artery) and 7 enzymatic increases without ECG changes. Fall back to 6F PTCA was required in 4 cases (1.7%) always because of the instability of the 5F catheter guide before the procedure. The quality of coronary contrast was estimated to be good. The vascular complication rate was low with 2% of communicating haematomas (N = 4). Therefore, 5F PTCA is feasible with failure and complication rates comparable to those reported with catheters of larger dimensions. One of its principal advantages is "ad hoc" angioplasty after 5F coronary angiography.


Dural sinus thrombosis with marked enlargement of the venous sinus--case report.
A 36-year-old female presented with dural sinus thrombosis manifesting as marked enlargement of the venous sinus, which could not be differentiated from epidural hematoma on computed tomography during the acute phase. Magnetic resonance imaging showed characteristic serial changes of the thrombus in the healing process. We believe this condition developed from use of oral contraceptives. Systemic anticoagulant therapy was effective without hemorrhagic complication.


Pharmacokinetics of dexloxiglumide after administration of single and repeat oral escalating doses in healthy young males.
To assess the pharmacokinetics, safety and tolerability of dexloxiglumide, a new CCK1 receptor antagonist currently under development for the treatment of the constipation-predominant irritable bowel syndrome. Twelve volunteers were enrolled in the present study and received orally 100, 200 and 400 mg of dexloxiglumide as tablets as a single dose followed by repeated t.i.d. doses for 7 days according to a randomized, double-blind, double-dummy complete crossover design. Plasma and urine were collected before drug administration and up to 72 h after dosing. Dexloxiglumide plasma and urinary concentration, determined using validated HPLC methods with UV detection, were used for the pharmacokinetic analysis by standard noncompartmental methods. In addition, dexloxiglumide safety and tolerability were evaluated throughout the study period by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence and severity of adverse events. After a single oral administration, dexloxiglumide was rapidly bioavailable with mean t(max) ranging from 0.9 - 1.6 h at all doses. The mean peak plasma concentrations (Cmax) were 1.7+/-0.6, 5.4+/-1.7, and 11.9+/-4.7 microg/ml, and the mean area under the plasma concentration-time curves (AUC) were 4.4+/-3.3, 8.6+/-3.6, and 18.3+/-5.9 microg x h/ml at the 3 doses, respectively. Apparent plasma clearance (CL/F) was 30.8+/-13.9, 27.2+/-10.6, and 21.1+/-8.6 l/h at the 3 doses, respectively. The apparent elimination half-life from plasma (t1/2) ranged from 2.6 - 3.3 h at the 3 doses. The excretion of unchanged dexloxiglumide in 0 - 72 h urine accounted for approximately 1% of the administered dose and this was true for all doses. Dexloxiglumide renal clearance (CLR) averaged 0.4+/-0.4, 0.4+/-0.2, and 0.3+/-0.3 l/h for the 3 doses, respectively. After the last dose of the repeated dosing period dexloxiglumide Cmax occurred at 1.1 - 1.6 h after drug administration and averaged 2.4+/-1.3, 7.1+/-2.9, and 15.3+/-2.7 microg/ml for the 3 doses, respectively. The AUC values averaged 5.9+/-3.0, 16.0+/-8.8, and 50.8+/-38.1 microg x h/ml, respectively. The area under the plasma concentration-time curve calculated at steady state within a dosing interval (AUCss) averaged 4.6+/-1.6, 11.3+/-3.6, and 28.4+/-8.2 microg x h/ml, whereas CL/F averaged 20.3+/-8.3, 16.3+/-9.0, and 10.3+/-5.0 l/h at the 3 doses, respectively. Dexloxiglumide t1/2 could not be accurately calculated due to the high inter-subject variability and to sustained dexloxiglumide plasma concentrations that precluded the identification ofthe terminal phase of the plasma concentration-time profiles. However, it appeared that dexloxiglumide t1/2 was considerably prolonged at the dose of 400 mg. CLR averaged 0.4+/-0.4, 0.3+/-0.3, and 0.3+/-0.1 l/h for the 3 doses, respectively. After a single dose, the plasma pharmacokinetics of dexloxiglumide were dose-independent in the dose range 100 - 400 mg. After repeated dose the pharmacokinetics of dexloxiglumide were virtually dose-independent in the dose range 100 - 200 mg. A slight deviation from linear pharmacokinetics was found with a dose of 400 mg. Dexloxiglumide plasma pharmacokinetics were also time-independent in the dose range 100 - 200 mg with a deviation from expectation based on the superimposition principle with a dose of 400 mg. Dexloxiglumide urinary excretion and renal clearance were both dose- and time-independent in the dose range 100 - 400 mg. The safety and tolerability of dexloxiglumide administered to healthy young males was good up to the maximum investigated dose of 400 mg both after single and after repeated doses. The safety and pharmacokinetic profile of dexloxiglumide when the drug is administered as single and repeated doses in the dose range 100 - 400 mg provides the rationale for the choice of the treatment schedule (200 mg t.i.d.) for the efficacy trials in patients with (constipation-predominant) irritable bowel syndrome.


Investigating Bilateral Cochlear Implant Users' Localization of Amplitude- and Time-Panned Stimuli Produced Over a Limited Loudspeaker Arrangement.
The objective of this study was to investigate the localization ability of bilateral cochlear implant (BiCI) users for virtual sound sources produced over a limited loudspeaker arrangement. Ten BiCI users and 10 normal-hearing subjects participated in listening tests in which amplitude- and time-panned virtual sound sources were produced over a limited loudspeaker setup with varying azimuth angles. Three stimuli were utilized: speech, bandpassed pink noise between 20 Hz and 1 kHz, and bandpassed pink noise between 1 kHz and 8 kHz. The data were collected via a two-alternative forced-choice procedure and used to calculate the minimum audible angle (MAA) of each subject, which was subsequently compared to the results of previous studies in which real sound sources were employed. The median MAAs of the amplitude-panned speech, low-frequency pink noise, and high-frequency pink noise stimuli for the BiCI group were calculated to be 20°, 38°, and 12°, respectively. For the time-panned stimuli, the MAAs of the BiCI group for all three stimuli were calculated to be close to the upper limit of the listening test. The computed MAAs of the BiCI group for amplitude-panned speech were marginally larger than BiCI users' previously reported MAAs for real sound sources, whereas their computed MAAs for the time-panned stimuli were significantly larger. Subsequent statistical analysis indicated a statistically significant difference in the performances of the BiCI group in localizing the amplitude-panned sources and the time-panned sources. It follows that time-panning over limited loudspeaker arrangements may not be a useful clinical tool, whereas amplitude-panning utilizing such a setup may be further explored as such. Additionally, a comparison with the patient demographics indicated correlations between the results and the patients' age at time of diagnoses and the time passed between date of diagnosis and their implant surgeries.


Corticotropin releasing factor receptor type 1: molecular cloning and investigation of alternative splicing in the hamster skin.
The coding region of the hamster corticotropin releasing factor receptor type 1 was sequenced. Hamster gene appeared to be similar to mouse, rat, and human sequences with 95%, 94%, and 91% homology, respectively. Protein substitutions were generally found in the corticotropin releasing factor-binding domain. Thus, this domain can be more prone to mutations leading to changes in amino acid sequence. Hamster pituitary, eye, spleen, heart, skin, and four melanoma lines differentially expressed nine corticotropin releasing factor-R1 isoforms. These included the corticotropin releasing factor-R1alpha and corticotropin releasing factor-R1d homologs of human isoforms as well as e, f, h, j, k, m, and n isoforms. Corticotropin releasing factor-R1e mRNA had deletion of exons 3 and 4, CRF-R1j of exon 5, CRF-R1f of exon 11, CRF-R1k of exon 10, CRF-R1m of exons 11 and 12, and CRF-R1n of exons 10, 11, and 12. Corticotropin releasing factor-R1h had an insertion of a cryptic exon between exons 4 and 5. Reading frames of isoforms e, f, j, k, m, and h contained frameshifts, expected to produce truncated proteins. Corticotropin releasing factor-R1n isoform preserved the reading frame, but the transmembrane domains 6, 7, and one-third of the fifth were deleted. The AbC1 hamster melanoma cell line changed the pattern of alternative splicing after irradiation with ultraviolet light or induction of melanogenesis; this suggests that corticotropin releasing factor receptor alternative splicing may be regulated by common stressors, through modifications of activity and/or availability of splicing factors.