Suppression of Th1-mediated autoimmunity by embryonic stem cell-derived dendritic cells.
We herein demonstrate the immune-regulatory effect of embryonic stem cell-derived dendritic cells (ES-DCs) using two models of autoimmune disease, namely non-obese diabetic (NOD) mice and experimental autoimmune encephalomyelitis (EAE). Treatment of pre-diabetic NOD mice with ES-DCs exerted almost complete suppression of diabetes development during the observation period for more than 40 weeks. The prevention of diabetes by ES-DCs was accompanied with significant reduction of insulitis and decreased number of Th1 and Th17 cells in the spleen. Development of EAE was also inhibited by the treatment with ES-DCs, and the therapeutic effect was obtained even if ES-DCs were administrated after the onset of clinical symptoms. Treatment of EAE-induced mice with ES-DCs reduced the infiltration of inflammatory cells into the spinal cord and suppressed the T cell response to the myelin antigen. Importantly, the ES-DC treatment did not affect T cell response to an exogenous antigen. As the mechanisms underlying the reduction of the number of infiltrating Th1 cells, we observed the inhibition of differentiation and proliferation of Th1 cells by ES-DCs. Furthermore, the expression of VLA-4α on Th1 cells was significantly inhibited by ES-DCs. Considering the recent advances in human induced pluripotent stem cell-related technologies, these results suggest a clinical application for pluripotent stem cell-derived dendritic cells as a therapy for T cell-mediated autoimmune diseases.


Effects of ceiling phase gradients on the acoustic environment on roadside balconies.
The screening effect of a roadside balcony deteriorates considerably due to sound reflection from its ceiling. Nonetheless, this drawback can be eliminated by artificially steering the reflected sound away from the building facade, which is achieved by introducing impedance inhomogeneity to the ceiling surface. This paper presents an elaborated investigation on the effect of the phase gradient of a ceiling surface on screening exterior noise, theoretically and numerically. By balancing its sound-steering capability and performance fluctuation level, such a balcony ceiling may have the potential to be widely used on roadside buildings.


Relationship Between Parent Vowel Hyperarticulation in Infant-Directed Speech and Infant Phonetic Complexity on the Level of Conversational Turns.
When speaking to infants, parents typically use infant-directed speech, a speech register that in several aspects differs from that directed to adults. Vowel hyperarticulation, that is, extreme articulation of vowels, is one characteristic sometimes found in infant-directed speech, and it has been suggested that there exists a relationship between how much vowel hyperarticulation parents use when speaking to their infant and infant language development. In this study, the relationship between parent vowel hyperarticulation and phonetic complexity of infant vocalizations is investigated. Previous research has shown that on the level of subject means, a positive correlational relationship exists. However, the previous findings do not provide information about the directionality of that relationship. In this study the relationship is investigated on a conversational turn level, which makes it possible to draw conclusions on whether the behavior of the infant is impacting the parent, the behavior of the parent is impacting the infant, or both. Parent vowel hyperarticulation was quantified using the vhh-index, a measure that allows vowel hyperarticulation to be estimated for individual vowel tokens. Phonetic complexity of infant vocalizations was calculated using the Word Complexity Measure for Swedish. Findings were unexpected in that a negative relationship was found between parent vowel hyperarticulation and phonetic complexity of the immediately following infant vocalization. Directionality was suggested by the fact that no such relationship was found between infant phonetic complexity and vowel hyperarticulation of the immediately following parent utterance. A potential explanation for these results is that high degrees of vowel hyperarticulation either provide, or co-occur with, large amounts of phonetic and/or linguistic information, which may occupy processing resources to an extent that affects production of the next vocalization.


Blood conservation in extracorporeal membrane oxygenation for acute respiratory distress syndrome.
Extracorporeal membrane oxygenation support (ECMO) typically requires multiple blood transfusions and is associated with frequent bleeding complications. Blood transfusions are known to increase morbidity and mortality in critically ill patients, which may extend to patients receiving ECMO. Aiming to reduce transfusion requirements, we implemented a blood conservation protocol in adults with severe acute respiratory distress syndrome (ARDS) receiving ECMO. This was a retrospective study of adults receiving ECMO for ARDS after initiation of a blood conservation protocol that included a transfusion trigger of hemoglobin of less than 7.0 g/dL, use of low-dose anticoagulation targeting an activated partial thromboplastin time of 40 to 60 seconds, and autotransfusion of circuit blood during decannulation. The primary objective was to evaluate transfusion requirements during ECMO support. Clinical outcomes included survival, neurologic function, renal function, bleeding, and thrombotic complications. The analysis included 38 patients; of these, 24 (63.2%) received a transfusion while receiving ECMO. Median hemoglobin was 8.29 g/dL. A median of 1.0 units (range, 250 to 300 mL) was transfused during ECMO support over a median duration of 9.0 days, equivalent to 0.11 U/d (range, 27.5 to 33.3 mL/d). The median activated partial thromboplastin time was 46.5 seconds. Bleeding occurred in 10 patients (26.3%); severe bleeding occurred in 2 patients (5.3%). Twenty-eight patients (73.7%) survived to hospital discharge. Implementation of a blood conservation protocol in adults receiving ECMO for ARDS resulted in lower transfusion requirements and bleeding complications than previously reported in the literature and was associated with comparable survival and organ recovery.


Transfection with fluorinated lipoplexes based on new fluorinated cationic lipids and in the presence of a bile salt surfactant.
The synthesis of two fluorinated cationic lipids, which are analogues of frequently used synthetic gene carrier agents (including the cationic 2,3-dioleoyloxy-N-[2-(spermine-carboxamido)ethyl]-N,N-dimethyl-1-propanaminium (DOSPA) component of the commercially available liposomal Lipofectamine), and the disintegration and DNA accessibility (evaluated by the ethidium bromide (BET) intercalation assay) as well as the in vitro transfection efficacy of cationic lipoplexes formulated with these new lipids in conjunction with conventional or fluorinated helper lipids, in the absence or presence of sodium taurocholate (STC), a powerful anionic bile salt detergent, is reported. A higher stability, with respect to the STC lytic activity and DNA accessibility, of the fluorinated cationic lipoplexes as compared with their respective lipofectamine-based ones was demonstrated. Indeed, while the Lipofectamine lipoplexes were fully disintegrated at a [STC]/[lipid] molar ratio of 2000, only 40-60% of the DNA intercalation sites of the lipoplexes based on the fluorinated analogue of DOSPA were accessible to ethidium bromide. A higher transfection potential in the presence of STC was further found for the lipoplexes formulated with the fluorinated analogue of DOSPA as compared with the Lipofectamine preparation. For a STC concentration of 7.5 mM, lipofection mediated with these fluorinated lipoplexes was significantly higher (nearly 30- to 50-fold, p < 0.05) than with the Lipofectamine ones. These results confirm the remarkable transfection potential of fluorinated lipoplexes.


Melperone: electrophysiologic and antiarrhythmic activity in humans.
Previous studies in animals and in humans have shown that melperone, a neuroleptic butyrophenone, has class III electrophysiologic activity. However, its antiarrhythmic activity has not been assessed in humans. Accordingly, the electrophysiologic and antiarrhythmic effects of melperone were assessed in 23 patients with symptomatic ventricular tachyarrhythmias. Seventeen patients had electrophysiologic testing while receiving melperone. At oral daily dosages greater than or equal to 240 mg, melperone produced significant prolongations of QT intervals (385 +/- 11 vs. 355 +/- 22 ms, p less than 0.05), ventricular effective refractory periods (263 +/- 18 vs. 243 +/- 28 ms, p less than 0.05; 260 +/- 18 vs. 235 +/- 27 ms, p less than 0.01; and 243 +/- 23 vs. 222 +/- 28 ms, p less than 0.01; at 600-, 500-, and 400-ms pacing cycle lengths, respectively) and ventricular tachycardia (VT) cycle lengths (286 +/- 46 vs. 239 +/- 70 ms, p less than 0.05). Inducible VT was suppressed entirely in one patient. In three other patients, inducible sustained VT became nonsustained. No significant negative inotropic effects were observed. The majority of patients (70%) experienced some adverse effect, the commonest of which was neurologic. In conclusion, melperone had significant class III electrophysiologic and antiarrhythmic activity in humans. Its clinical use may be limited by the high incidence of adverse effects.


Influence of sex on early growth of pig conceptuses.
Nineteen gilts were used in an experiment to examine the relationship between rate of development and embryonic sex on day 10 of pregnancy. All gilts were mated to the same boar approximately 24 h after detection of second oestrus. They were individually housed and fed similar diets until slaughter on day 10 of gestation (day 0 = day of insemination) for subsequent recovery of the conceptus. All conceptuses were photographed and their surface areas (mm2) measured by tracing outlines on a digitized tablet interfaced with a computer program. Within each litter, individuals were categorized as small, medium or large by three equal divisions of the size range between the smallest and largest member. Conceptuses were individually cultured in Medium 199 with 1% colcemid and stained with 4% Giemsa. Metaphase spreads were located and sex was determined by presence or absence of the Y chromosome in at least two spreads from each specimen. A total of 214 conceptuses were recovered but only 125 (58%) were successfully karyotyped. The overall sex ratio was not significantly different from 1:1 (57 males and 68 females; P > 0.25). Sex was determined in 51 of 88 small embryos, 22 of 44 medium embryos and 52 of 82 large embryos and males represented 9 (17.6%), 10 (45.5%) and 38 (73%), respectively. Logistic analysis indicated significantly more females in the small and significantly more males in the large groups (P < 0.001). Results demonstrate that most male conceptuses grow faster than females before commencement of attachment to the uterine lining.


Structural and Magnetic Properties of BaFeO2.667 Synthesized by Oxidizing BaFeO2.5 Obtained via Nebulized Spray Pyrolysis.
A vacancy-ordered perovskite-type compound Ba3Fe3O8 (BaFeO2.667) was prepared by oxidizing BaFeO2.5 (P21/c) with the latter compound obtained by a spray pyrolysis technique. The structure of Ba3Fe3O8 was found to be isotypic to Ba3Fe3O7F (P21/m) and can be written as Ba3Fe3+2Fe4+1O8. Mössbauer spectroscopy and ab initio calculations were used to confirm mixed iron oxidation states, showing allocation of the tetravalent iron species on the tetrahedral site, and octahedral as well as square pyramidal coordination for the trivalent species within a G-type antiferromagnetic ordering. The uptake and release of oxygen were investigated over a broad temperature range from room temperature to 1100 °C under pure oxygen and ambient atmosphere via a combination of DTA/TG and variable temperature diffraction measurements. The compound exhibited a strong lattice enthalpy driven reduction to monoclinic and cubic BaFeO2.5 at elevated temperatures.


Modernizing the United States' Public Health Infrastructure: A Position Paper From the American College of Physicians.
The United States' public health sector plays a crucial role in preventing illness and promoting health. Public health drove massive gains in life expectancy during the 20th century by supporting vaccination campaigns, promoting motor vehicle safety, and preventing and treating tobacco use. However, public health is underfunded and underappreciated, forcing the field to do more with fewer resources. In this position paper, the American College of Physicians (ACP) updates its 2012 policy recommendations on strengthening the nation's public health infrastructure. ACP calls for effective coordination of public health activities, robust and stable year-to-year funding of public health services, a renewed and well-supported public health workforce, action to address health-related dis- and misinformation, modernized public health data systems, and greater coordination between public health and medical sectors.


Brain barrier systems: a new frontier in metal neurotoxicological research.
The concept of brain barriers or a brain barrier system embraces the blood-brain interface, referred to as the blood-brain barrier, and the blood-cerebrospinal fluid (CSF) interface, referred to as the blood-CSF barrier. These brain barriers protect the CNS against chemical insults, by different complementary mechanisms. Toxic metal molecules can either bypass these mechanisms or be sequestered in and therefore potentially deleterious to brain barriers. Supportive evidence suggests that damage to blood-brain interfaces can lead to chemical-induced neurotoxicities. This review article examines the unique structure, specialization, and function of the brain barrier system, with particular emphasis on its toxicological implications. Typical examples of metal transport and toxicity at the barriers, such as lead (Pb), mercury (Hg), iron (Fe), and manganese (Mn), are discussed in detail with a special focus on the relevance to their toxic neurological consequences. Based on these discussions, the emerging research needs, such as construction of the new concept of blood-brain regional barriers, understanding of chemical effect on aged or immature barriers, and elucidation of the susceptibility of tight junctions to toxicants, are identified and addressed in this newly evolving field of neurotoxicology. They represent both clear challenges and fruitful research domains not only in neurotoxicology, but also in neurophysiology and pharmacology.


'Small changes have a huge impact'.
'In the past when my dad was in hospital, I had been made to feel like an intruder without a valid opinion,' says Geraldine Strohm. 'I was amazed to hear that I could get help with the extortionate parking costs. That small gesture meant so much to me, as all thoughts of personal care went out of the window while I was trying to help keep dad alive.'


Odour discrimination and identification as a biomarker of long-term disability worsening in multiple sclerosis.
Odour discrimination and identification (DI) are markers associated with disability worsening and neuroaxonal damage in multiple sclerosis (MS). The main objective of this research is to investigate whether longitudinal change of DI predicts long-term MS disease course. This is a 6-year prospective longitudinal study on MS patients at the MS Clinic Innsbruck. Clinical, bi-annual visits assessed patients' history and Expanded Disability Status Scale (EDSS) score. DI and cognitive function were assessed at baseline (BL), Year 1 (Y1), Year 2 (Y2) and Year 6 (Y6) by the 'Sniffin' Sticks'/Symbol Digit Modalities Test. Around 92 of 139 patients were available for Y6 follow-up. Mean DI scores significantly decreased over time (BL = 27.8, Y1 = 27.5, Y2 = 26.3 and Y6 = 26.3; p < 0.001) and negatively correlated with patients' age (rs = -0.120, p = 0.032) and disease duration (rs = -0.103, p = 0.041). Multivariable regression analyses revealed that lower absolute DI scores and larger DI score loss over time were associated with higher probability of EDSS worsening (per -1 point: hazard ratio (HR) = 1.40 (1.16-1.68) and 2.34 (1.27-4.21)), progression independent of relapse activity (PIRA) (HR = 1.49 (1.20-1.85) and 2.22 (1.33-3.31)) and cognitive deterioration (HR = 1.75 (1.35-2.27) and 4.29 (1.26-2.84)) at Y6, but not with time to first relapse. Odour DI is an irreversible marker of neuroaxonal damage, associated with PIRA, cognitive deterioration and EDSS worsening.


Acid-Catalyzed Condensations of Ninhydrin with Aromatic Compounds. Preparation of 2,2-Diaryl-1,3-indanediones and 3-(Diarylmethylene)isobenzofuranones1.
Ninhydrin (1) reacts with aromatic compounds in acid solution to give condensation products. In H2SO4, 1 reacts with arenes to give 2,2-diaryl-1,3-indanediones (2a-f). In superacidic triflic acid (CF3SO3H, TfOH), 1 reacts with arenes to give 3-(diarylmethylene)isobenzofuranones (3a-e). Products 3a-e are proposed to have formed by a condensation and rearrangement involving dicationic intermediates. Benzo[f]ninhydrin also reacts with C6H6 in H2SO4 to give a similar condensation product.


Effect of skeletonizing dissection on the internal thoracic artery.
Skeletonization of the internal thoracic artery (ITA) produces greater length for coronary bypass grafting. We studied the effect of skeletonization on the morphology, histology, and tissue viability of the ITA wall. Six mongrel dogs underwent unilateral ITA dissection; the contralateral ITA was the control. Study periods were 3 weeks (n=3) and 12 weeks (n=3). At sacrifice, the entire anterior chest wall was removed and dynamically fixed with formalin. Extensive histologic comparisons were performed on three tissue blocks taken from each ITA, 2, 8, and 24 cm from their origin. Flows at the end of the study were comparable to measurements taken during operation, immediately after skeletonization. Grossly, the ITA wall was not injured by skeletonization and there was no adventitial hematoma or bleeding from the sealed branch ends. Microscopic observations showed intact, normal wall structures. Histologic data showed no major significant difference between controls and skeletonized ITAs. Careful skeletonizing dissection is not detrimental to the integrity of ITAs, which justifies their use for myocardial revascularization.


Characterization and Quantification of Polyquaterniums via Single-Use Polymer Membrane-Based Polyion-Sensitive Electrodes.
Two facile, robust, and universal methods by which various polymeric quaternary ammonium salts (polyquaterniums (PQs)) can be quantified and characterized using simple potentiometric polymeric membrane polyion-sensitive electrodes as detectors are described. The two methods are (a) direct detection with polycation sensitive membrane electrodes based on the sodium salt of dinonylnaphthalenesulfonate (NaDNNS), and (b) indirect detection using polyanion sensors based on tridodecylmethylammonium chloride (TDMAC) and dextran sulfate (DS) as a titrant to complex the various polyquaternary species (four different PQs: PQ-2, PQ-6, PQ-10, and poly(2-methacryloxyethyltrimethylammonium) chloride (PMETAC)). Direct detection yields information regarding the charge density of the polycationic species. For the titration method, a series of polyanion sensors doped with TDMAC are used to follow a potentiometric titration of a PQ species using a syringe pump to deliver the titrant. This indirect detection method is more reliable and yields limits of detection in the ppm range for the four PQs examined. The titration method is further explored for detecting excess levels of PQ-6, a common flocculating agent for municipal water supply systems, within the purified water emitted by the Ann Arbor, MI, drinking water treatment plant.


Swallow-related Brain Activity in Post-total Laryngectomy Patients: A Case Series Study.
Total laryngectomy is a surgical procedure to completely remove the hyoid bone, larynx, and associated muscles as a curative treatment for laryngeal cancer. This leads to insufficient swallowing function with compensative movements of the residual tongue to propel the food bolus to the pharynx and esophagus. However, the neurophysiological mechanisms of compensative swallowing after total laryngectomy remain unclear. Recently, swallowing-related cortical activation such as event-related desynchronization (ERD) during swallowing has been reported in healthy participants and neurological patients with dysphagia. Abnormal ERD elucidates the pathophysiological cortical activities that are related to swallowing. No report has investigated ERD in post-total laryngectomy patients. We investigated ERD during volitional swallowing using electroencephalography in three male patients after total laryngectomy for laryngeal cancer (age and time after surgery: Case 1, 75 years, 10 years; Case 2, 85 years, 19 years; Case 3, 73 years, 19 years). In video fluorographic swallowing studies, we observed compensatory tongue movements such as posterior-inferior retraction of the tongue and contact on the posterior pharyngeal wall in all three cases. Significant ERD was localized in the bilateral medial sensorimotor areas and the left lateral parietal area in Case 1, in the bilateral frontal and left temporal areas in Case 2, and in the left prefrontal and premotor areas in Case 3. These results suggest that cortical activities related to swallowing might reflect cortical reorganization for modified swallowing movements of residual tongue muscles to compensate for reduced swallowing pressure in patients after total laryngectomy.


Production and characterization of monoclonal antibodies against the major cysteine proteinase of Trypanosoma cruzi.
In the present study we describe the production and characterization of a panel of monoclonal antibodies (MoAbs) directed against cruzipain (Crz), the major cysteine proteinase from Trypanosoma cruzi. The five MoAbs, BD6, BF2, CG2, CH8, and DC10 were analysed with respect to affinity and specificity. None of the MoAbs cross-reacted with papain, which has regions of high homology with Crz. Treatment of the antigen with periodate did not affect the binding of the MoAbs, suggesting that they bind to the polypeptide moiety of Crz. CH8 recognized a continuous epitope located at the C-terminal extension of the proteinase that appeared to be highly immunogenic. Although the rest of the MoAbs recognized epitopes located in the catalytic domain, the enzymatic activity of Crz was not impaired by the binding of the MoAbs. Characterization of the antibody-binding sites revealed the presence of at least four separate epitopes.


Coding and decoding of oscillatory Ca2+ signals.
About 30 years after their first observation, Ca2+ oscillations are now recognised as a universal mechanism of signal transduction. These oscillations are driven by periodic cycles of release and uptake of Ca2+ between the cytoplasm and the endoplasmic reticulum. Their frequency often increases with the level of stimulation, which can be decoded by some molecules. However, it is becoming increasingly evident that the widespread core oscillatory mechanism is modulated in many ways, depending on the cell type and on the physiological conditions. Interplay with inositol 1,4,5-trisphosphate metabolism and with other Ca2+ stores as the extracellular medium or mitochondria can much affect the properties of these oscillations. In many cases, these finely tuned characteristics of Ca2+ oscillations impact the physiological response that is triggered by the signal. Moreover, oscillations are intrinsically irregular. This randomness can also be exploited by the cell. In this review, we discuss evidences of these additional manifestations of the versatility of Ca2+ signalling.


Reliability, convergent validity and factor structure of the DASS-21 in a sample of Vietnamese adolescents.
To assess the internal consistency, latent structure and convergent validity of the Depression, Anxiety and Stress Scale-21 (DASS-21) among adolescents in Vietnam. An anonymous, self-completed questionnaire was conducted among 1,745 high school students in Hanoi, Vietnam between October, 2013 and January, 2014. Confirmatory factor analyses were performed to assess the latent structure of the DASS-21. Factorial invariance between girls and boys was examined. Cronbach alphas and correlation coefficients between DASS-21 factor scores and the domain scores of the Duke Health Profile Adolescent Vietnamese validated version (ADHP-V) were calculated to assess DASS-21 internal consistency and convergent validity. A total of 1,606/ 1,745 (92.6%) students returned the questionnaire. Of those, 1,387 students provided complete DASS-21 data. The scale demonstrated adequate internal consistency (Cronbach α: 0.761 to 0.906). A four-factor model showed the best fit to the data. Items loaded significantly on a common general distress factor, the depression, and the anxiety factors, but few on the stress factor (p<0.05). DASS-21 convergent validity was confirmed with moderate correlation coefficients (-0.47 to -0.66) between its factor scores and the ADHP-V mental health related domains. The DASS-21 is reliable and suitable for use to assess symptoms of common mental health problems, especially depression and anxiety among Vietnamese adolescents. However, its ability in detecting stress among these adolescents may be limited. Further research is warrant to explore these results.


Epidemiology of neuroinvasive arboviral disease in the United States, 1999-2007.
From 1999-2007, the most common causes of neuroinvasive arboviral disease in the United States, after West Nile virus (WNV), were California (CAL) serogroup viruses, St. Louis encephalitis virus (SLEV), and eastern equine encephalitis virus (EEEV). The CAL serogroup virus disease was primarily reported from Appalachia and the upper Midwest, SLEV disease from southern states, and EEEV disease from areas along the Atlantic and Gulf coasts. Children accounted for 88% of CAL serogroup virus disease, whereas 75% of SLEV disease occurred among older adults. The EEEV disease had the highest case-fatality rate (42%). The incidence of CAL serogroup virus and EEEV disease remained stable before and after the detection of WNV in the United States in 1999. The SLEV disease declined 3-fold after 1999; however, SLEV disease has occurred in sporadic epidemics that make trends difficult to interpret. The CAL serogroup virus, SLEV, and EEEV disease are persistent public health concerns in the United States warranting ongoing prevention efforts.


Fine-tuning of colloidal polymer crystals by molecular simulation.
Through extensive molecular simulations we determine a phase diagram of attractive, fully flexible polymer chains in two and three dimensions. A rich collection of distinct crystal morphologies appear, which can be finely tuned through the range of attraction. In three dimensions these include the face-centered cubic, hexagonal close packed, simple hexagonal, and body-centered cubic crystals and the Frank-Kasper phase. In two dimensions the dominant structures are the triangular and square crystals. A simple geometric model is proposed, based on the concept of cumulative neighbors of ideal crystals, which can accurately predict most of the observed structures and the corresponding transitions. The attraction range can thus be considered as an adjustable parameter for the design of colloidal polymer crystals with tailored morphologies.


Beware batch culture: Seasonality and niche construction predicted to favor bacterial adaptive diversification.
Metabolic cross-feeding interactions between microbial strains are common in nature, and emerge during evolution experiments in the laboratory, even in homogeneous environments providing a single carbon source. In sympatry, when the environment is well-mixed, the reasons why emerging cross-feeding interactions may sometimes become stable and lead to monophyletic genotypic clusters occupying specific niches, named ecotypes, remain unclear. As an alternative to evolution experiments in the laboratory, we developed Evo2Sim, a multi-scale model of in silico experimental evolution, equipped with the whole tool case of experimental setups, competition assays, phylogenetic analysis, and, most importantly, allowing for evolvable ecological interactions. Digital organisms with an evolvable genome structure encoding an evolvable metabolic network evolved for tens of thousands of generations in environments mimicking the dynamics of real controlled environments, including chemostat or batch culture providing a single limiting resource. We show here that the evolution of stable cross-feeding interactions requires seasonal batch conditions. In this case, adaptive diversification events result in two stably co-existing ecotypes, with one feeding on the primary resource and the other on by-products. We show that the regularity of serial transfers is essential for the maintenance of the polymorphism, as it allows for at least two stable seasons and thus two temporal niches. A first season is externally generated by the transfer into fresh medium, while a second one is internally generated by niche construction as the provided nutrient is replaced by secreted by-products derived from bacterial growth. In chemostat conditions, even if cross-feeding interactions emerge, they are not stable on the long-term because fitter mutants eventually invade the whole population. We also show that the long-term evolution of the two stable ecotypes leads to character displacement, at the level of the metabolic network but also of the genome structure. This difference of genome structure between both ecotypes impacts the stability of the cross-feeding interaction, when the population is propagated in chemostat conditions. This study shows the crucial role played by seasonality in temporal niche partitioning and in promoting cross-feeding subgroups into stable ecotypes, a premise to sympatric speciation.


The role of succinate and ROS in reperfusion injury - A critical appraisal.
We critically assess the proposal that succinate-fuelled reverse electron flow (REF) drives mitochondrial matrix superoxide production from Complex I early in reperfusion, thus acting as a key mediator of ischemia/reperfusion (IR) injury. Real-time surface fluorescence measurements of NAD(P)H and flavoprotein redox state suggest that conditions are unfavourable for REF during early reperfusion. Furthermore, rapid loss of succinate accumulated during ischemia can be explained by its efflux rather than oxidation. Moreover, succinate accumulation during ischemia is not attenuated by ischemic preconditioning (IP) despite powerful cardioprotection. In addition, measurement of intracellular reactive oxygen species (ROS) during reperfusion using surface fluorescence and mitochondrial aconitase activity detected major increases in ROS only after mitochondrial permeability transition pore (mPTP) opening was first detected. We conclude that mPTP opening is probably triggered initially by factors other than ROS, including increased mitochondrial [Ca2+]. However, IP only attenuates [Ca2+] increases later in reperfusion, again after initial mPTP opening, implying that IP regulates mPTP opening through additional mechanisms. One such is mitochondria-bound hexokinase 2 (HK2) which dissociates from mitochondria during ischemia in control hearts but not those subject to IP. Indeed, there is a strong correlation between the extent of HK2 loss from mitochondria during ischemia and infarct size on subsequent reperfusion. Mechanisms linking HK2 dissociation to mPTP sensitisation remain to be fully established but several related processes have been implicated including VDAC1 oligomerisation, the stability of contact sites between the inner and outer membranes, cristae morphology, Bcl-2 family members and mitochondrial fission proteins such as Drp1.


Direct surface analysis mass spectrometry uncovers the vertical distribution of cuticle-associated metabolites in plants.
The plant cuticle covers the plant's entire aerial surface and acts as the outermost protective layer. Despite being crucial for the survival of plants, surprisingly little is known about its biosynthesis. Conventional analytical techniques are limited to the isolation and depolymerization of the polyester cutin, which forms the cuticular scaffold. Although this approach allows the elucidation of incorporated cutin monomers, it neglects unincorporated metabolites participating in cutin polymerization. The feasibility of a novel approach is tested for in situ analysis of unpolymerized cuticular metabolites to enhance the understanding of cuticle biology. Intact cotyledons of Brassica napus and Arabidopsis thaliana seedlings are immersed in organic solvents for 60 seconds. Extracts are analyzed using high-resolution direct infusion mass spectrometry. A variety of different diffusion routes of plant metabolites across the cuticle are discussed. The results reveal different feasibilities depending on the research question and cuticle permeabilities in combination with the analyte's polarity. Especially hydrophilic analytes are expected to be co-located in the cell wall beneath the cuticle causing systematic interferences when comparing plants with different cuticle permeabilities. These interferences limit data interpretation to qualitative rather than quantitative comparison. In contrast, quantitative data evaluation is facilitated when analyzing cuticle-specific metabolites or plants with similar cuticle permeabilities.


Animal fatty acid synthase: functional mapping and cloning and expression of the domain I constituent activities.
Animal fatty acid synthase (FAS; EC 220.127.116.11) is a homodimer of a multifunctional subunit protein and catalyzes the synthesis of palmitate from acetyl-CoA, malonyl-CoA, and NADPH. The subunit (Mr approximately 270,000) carries seven distinct component activities and a site for the prosthetic group 4'-phosphopantetheine (acyl carrier protein). Based on proteolytic mapping, the organization of the activity domains along the subunit polypeptide from the N terminus is as follows: beta-ketoacyl synthase, acetyl and malonyl transacylases, beta-hydroxyacyl dehydratase, enoyl reductase, beta-ketoacyl reductase, acyl carrier protein, and thioesterase. By comparing the amino acid sequences of the chicken, rat, and human synthases, we found that kallikrein cleavage sites occur in the least conserved regions of the FAS polypeptide subunit. Determining the amino acid sequences of the N-terminal end of the major kallikrein cleavage peptides helped delineate the most likely boundaries of the component activities in the cDNA-derived amino acid sequence. To confirm this organization, we cloned the chicken FAS cDNA coding for domain I and expressed it in Escherichia coli as a maltose-binding fusion protein. The isolated recombinant protein contained the activities of the acetyl and malonyl transacylases and the beta-hydroxyacyl dehydratase. Based on the boundaries of the acetyl and malonyl transacylases and the beta-hydroxyacyl dehydratase, we also cloned the appropriate cDNA fragments encoding the domains that contain the transacylases and the dehydratase in pET vectors and expressed them in E. coli as thioredoxin-6xHis fusion proteins. The purified recombinant proteins contained, respectively, the activities of the acetyl and malonyl transacylases and the dehydratase. These results not only confirmed the order of the component activities in domain I, but also paved the way for successful expression and characterization of the remaining activities.


Carcinoma of the prostate in Israel: some epidemiological and therapeutic considerations.
Analysis of the different rate of prostatic cancer in Israel among Jews from various countries of origin reveals some very interesting and marked varieties in incidence, which are studied more closely now. Aggressive, combined treatment for the invasive cases of prostatic cancer has been used since 1975. This was based on orchiectomy, DES, and chemotherapy for the stage D2 disease, and on radiotherapy and hormonal therapy for the stage C, and possibly also the stage D1 disease. Results so far have been very encouraging indeed, and with considerably better results than obtained with the individual, more conventional forms of therapy. Five-year survival in the stage D2 disease has been 63.5%, and 87.6% in the stage C (+D1?) disease. It appears that this approach is more justified, certainly in the advanced stages of this disease.


Balance disorders in the elderly.
Good balance is an imperative skill for daily life that requires the complex integration of sensory information regarding the position of the body relative to the surroundings and the ability to generate appropriate motor responses to control body movement. Balance calls upon contributions from vision, vestibular sense, proprioception, muscle strength and reaction time. With increased age, there is a progressive loss of functioning of these systems which can contribute to balance deficits. Balance disorders represent a growing public health concern due to the association with falls and fall-related injuries, particularly in regions of the world in which high proportions of the population are elderly. Falls present one of the most serious and costly problems associated with older adulthood. Falls can mark the beginning of a decline in function and independence and are the leading cause of injury-related hospitalisation in older people. One in three people over the age of 65 years who are living in the community experience at least one fall each year and 10-15% of these falls are associated with serious injury. In economic terms, the direct and indirect costs associated with falls are large and will grow as the proportion of older people increases. Consequently, understanding age-related changes in the physiological systems imperative to balance is of utmost importance to prevent falls in older people and reduce the injury-related burden on individuals and society.


New statistical mechanical model for calculating Kirkwood factors in self-associating liquid systems and its application to alkanol+cyclohexane mixtures.
A new statistical mechanical model for calculating Kirkwood factors in self-associating molecular liquids and their mixtures with nonassociating components has been developed in a consistent way which is based on an extended version of the Flory-Huggins model taking into account chemical association equilibria. The majority of molecular parameters involved into the theory has been fixed by independent quantum mechanical ab initio calculations of associated molecular clusters. The model is also able to predict other thermodynamic mixture properties such as the enthalpy of mixing and also the infrared absorbance of monomer alcohol species as function of concentration. Experimental results of nine alcohol+cyclohexane mixtures taken from the literature have been used to test the new model. The Kirkwood correlation factor gK, the molar enthalpy of mixing HmE, and the monomer IR absorbance can be described simultaneously in excellent agreement with experimental data covering the whole range of mole fraction including temperature dependence of gK, HmE, and the IR absorbance. Two parameters have been adjusted freely for each system. A third parameter for the nonspecific intermolecular dispersion interactions has been adjusted within a limited range of possible values given by physical arguments. The model opens a new way of a more reliable understanding of structures and equilibrium properties of hydrogen bonded systems in the condensed liquid state.


[Chemical Species of PM2.5 in the Urban Area of Beijing].
From August 2012 to July 2013, 220 groups of PM2.5 samples were continuously collected at four locations in the urban area of Beijing (Shijingshan, Chegongzhuang, Dongsi, and Tongzhou), and the primary chemical species of PM2.5 were analysed by the chemical mass balance method. It was found that the mass of PM2.5 obtained from chemical mass balance method agreed well with the value from gravimetric measurement, with a good correlation of 0. 95 in spring, autumn, and winter. However, the correlation seasonally changed in summer, with a relatively lower correlation coefficient of 0. 77. The concentrations of OM, EC, SO(4)2-, NO3-, NH4+, Cl-, crustal matter, and trace species were 31. 4, 3. 8, 19. 9, 21. 6, 14. 4, 4. 0, 15. 4, and 2. 9 µg.m-3, which accounted for 25. 1%, 3. 0% , 15. 9%, 17. 2%, 11. 5%, 3. 2%, 12. 3%, and 2. 3% of PM2, , respectively. Besides crustal matter, concentrations of the primary chemical species in PM2.5 from the west to the east gradually increased. The most serious PM pollution occurred between 11 and 14 February 2013, during which concentrations of OM, SO2-, NO3-, NH4+ were 1. 9, 5. 0, 3.2 and 4. 2 times as high as the annual average. SO(4)2- was recognized as the most important species for the pollution in the process. OM was the largest component of urban PM2.5 during both heating and non-heating periods. Comparing to non-heating period, the concentrations of OM, NH4+, NO3-, and SO(4)2- all increased during the heating period, except for the component of crust and EC. The biggest difference between the two periods was the component of Cl- (4. 4 fold), which can be attributed to the burning of coal. For unknown components, the main component was moisture, which accounted for about 6.0% in urban PM2.5. The highest moisture appeared in summer (6. 5%), followed by spring and winter, and the least appeared in fall (3. 7% ).


Obsessive-compulsive and other behavioural changes with bilateral basal ganglia lesions. A neuropsychological, magnetic resonance imaging and positron tomography study.
Eight patients are reported who shared the combination of bilateral basal ganglia lesions and a frontal lobe-like syndrome. The main features were inertia and loss of drive, with preservation of intellectual function. Some patients showed stereotyped activities with compulsive and obsessive behaviour which were sometimes highly elaborate in pattern. Extrapyramidal clinical signs were absent or mild. Brain damage, related to anoxic or toxic encephalopathy, was demonstrated by CT scans and MRI. The lesions appeared to be confined to the lentiform nuclei, particularly affecting the pallidum, although there was generalized brain atrophy in 2 cases. Positron emission tomography (PET) in 7 patients revealed hypometabolism of the prefrontal cortex relative to other parts of the brain. The PET studies suggest dysfunction of the prefrontal cortex as a result of damage to the lentiform nuclei. These clinical, anatomical and functional observations emphasize the role of the circuits linking the prefrontal associative cortex and some specific areas of the neostriatum, including the pallidum. The existence of distinct nonoverlapping circuits in the motor field or in the associative field can explain the fact that basal ganglia lesions may give rise to a clinical picture that is either purely motor, purely behavioural (as in some of our patients), or both. Similarities existed between some symptoms found in our patients and certain features of major psychiatric illnesses such as severe depression, catatonic schizophrenia, and obsessive-compulsive disorder. This raises the hypothesis that some aspects of these psychiatric disorders could be related to structural and physiological disturbances in the systems linking the frontal associative cortex and the basal ganglia.


Navigating Clinical Ethics: Using Real Case Constellations to Guide Learners and Teachers in Medicine.
Case-based learning is a staple of clinical ethics education in medicine. The sources for medical educators generally are lengthy case books or single, often rare, case analyses in the literature. Busy clinicians may not have the time or inclination to sift through case books to find suitable teaching material, and the latter present unusual cases that many physicians may never encounter in their own practice. Relatively few articles present multiple cases involving ethical issues that are likely to appear in everyday practice in an accessible format for teaching. To fill this gap, we developed a series of paradigmatic cases based on the recurrent themes we identified through a systematic analysis of our clinical ethics consultations in a 5-year period and our collective clinical ethics judgment. We constructed four amalgam "bread-and-butter" ethics cases that are not overly service specific and can be used in medical and residency education along with specific questions for discussion. Topics include decision-making capacity, withholding and withdrawing life-sustaining treatment, patient wishes and do not resuscitate orders, and brain death. Our objective was to help a range of residents and other physicians become more confident and facile in identifying and addressing recurrent ethical issues in their practice.


Tongue swelling complicating management of a ventilated patient with acute respiratory distress syndrome secondary to novel influenza A (H1N1).
The recently emerged novel influenza A H1N1 virus continues to spread globally. The use of oseltamivir for treatment and prophylaxis of infection is recommended and its use has climbed steeply although there is little data available on its benefit in critically unwell patients with H1N1 influenza. A rare side-effect of oseltamivir treatment reported in post-marketing surveillance is tongue and lip swelling/angioedema. This case report describes the management of a critically ill ventilated patient with severe acute respiratory distress syndrome who developed clinically significant tongue and lip swelling during treatment with oseltamivir.


Urticaria pigmentosa-like skin disease in a domestic shorthair cat.
A 14-month-old castrated male domestic shorthair cat presented with an 8 month history of severe pruritus, alopecia, papules and excoriations. Initial evaluation and treatment prior to referral included skin scrape, cytology, two strict food trials, dermatophyte culture, and bacterial culture and sensitivity, as well as antibiotic therapy, empiric treatment for mites, steroids and ciclosporin A (Atopica; Elanco). The cat was referred to the Dermatology and Otology Clinic at the University of Illinois Veterinary Teaching Hospital for further diagnostics and treatment. Skin scrapes were unremarkable. Cytology showed rare bacteria and moderate neutrophils. The cat was given an injection of triamcinolone acetonide, which was ineffective. Oclacitinib (Apoquel; Zoetis) was given for 4 weeks with no improvement. A skin biopsy was performed, and histopathology showed large numbers of well-differentiated monomorphic mast cells with fewer eosinophils that diffusely infiltrated the superficial dermis, supportive of urticaria pigmentosa. Oral dexamethasone and cetirizine hydrochloride were initiated, and the cat responded favorably. At the time of writing, the cat continues to do well on cetirizine hydrochloride with only intermittent tapering courses of dexamethasone. To the best of our knowledge, this is the first reported case of urticaria pigmentosa in a domestic shorthair cat. This case also highlights the importance of biopsy after a thorough, systematic work-up in a cat with severe, intractable pruritus to reveal an uncommon disease pattern, as well as the efficacy of oral dexamethasone and cetirizine hydrochloride as a potential management option.


What has bioethics to offer the developing countries.
My paper consists of three parts. In the first part I try to explain the intellectual basis of bioethics in developing countries. In the second part I describe the bioethical dilemmas facing these countries. In the third part I shall discuss the changes that have to be made in bioethics if it is to take root in these countries, and thereby help them to improve the human existence.


Pharmacology of capsaicin-, anandamide-, and N-arachidonoyl-dopamine-evoked cell death in a homogeneous transient receptor potential vanilloid subtype 1 receptor population.
Transient receptor potential vanilloid subtype 1 (TRPV1) receptor is a primary pain-sensing relay at peripheral sensory nerve endings and is also widespread in the brain, where it is implicated in neurodegeneration. Previous studies of TRPV1 neurotoxicity have utilized heterogeneous receptor populations, non-selective ligands, or non-neuronal cell types. Here, we explored the pharmacology of TRPV1-induced cytotoxicity in a homogeneous, neurone-like cellular environment. Cell death was examined in a human neurone-like cell line, stably expressing recombinant human TRPV1. Cytotoxicity was quantified in terms of nuclear morphology and mitochondrial complex II activity. Immunocytochemical markers of apoptotic cell death were also examined. The TRPV1-selective agonist capsaicin, and the endovanilloids anandamide and N-arachidonoyl-dopamine (NADA), induced TRPV1-dependent delayed cell death in a concentration- and time-dependent manner. Capsaicin exposure time was significantly correlated with potency (r(2)=0.91, P=0.01). Release of cytochrome c from mitochondria, activation of caspase-3, and condensed nuclear chromatin were evident 6 h after capsaicin exposure, but cytotoxicity was unaffected by a pan-caspase inhibitor (zVAD-fmk, 50 microM). We conclude that capsaicin, anandamide, and NADA can initiate TRPV1-dependent delayed cell death in neurone-like cells. This is an apoptosis-like process, but independent of caspase activity.


Growing static and dynamic length scales in a glass-forming liquid.
We investigate the characteristic length scales associated with the glass transition phenomenon. By studying an atomic glass-forming liquid in negatively curved space, for which the local order is well identified and the amount of frustration opposing the spatial extension of this order is tunable, we provide insight into the structural origin of the main characteristics of the dynamics leading to glass formation. We find that the structural length and the correlation length characterizing the increasing heterogeneity of the dynamics grow together as temperature decreases. However, the system eventually enters a regime in which the former saturates as a result of frustration whereas dynamic correlations keep building up.


Dimethyl Sulfide-Dimethyl Ether and Ethylene Oxide-Ethylene Sulfide Complexes Investigated by Fourier Transform Microwave Spectroscopy and Ab Initio Calculation.
The ground-state rotational spectra of the dimethyl sulfide-dimethyl ether (DMS-DME) and the ethylene oxide-ethylene sulfide (EO-ES) complexes were observed by Fourier transform microwave spectroscopy, and a-type and c-type transitions were assigned for the normal, (34)S, and three (13)C species of the DMS-DME and a-type and b-type transitions for the normal, (34)S, and two (13)C species of the EO-ES complexes. The transition frequencies measured for both the complexes were analyzed by using an S-reduced asymmetric-top rotational Hamiltonian. The rotational parameters thus derived for the DMS-DME were found to be consistent with a structure of Cs symmetry with the DMS bound to the DME by two C-H(DMS)···O and one S···H-C(DME) hydrogen bonds. Some high-Ka lines were found to be split, and we have interpreted these splittings in terms of internal rotations of the two methyl groups of the DMS and of the "free", i.e., outer group, of the DME. Some forbidden transitions were also observed in cases where Ka = 3 levels were involved, for the DMS-DME complex in the internal-rotation E state. The barrier height, V3, to internal rotation of the CH3 in the DME thus derived is smaller than that of the DME monomer, while the V3 of the CH3 groups in the DMS is nearly the same as that of the DMS monomer. For the EO-ES complex, the observed data were interpreted in terms of an antiparallel structure of Cs symmetry with the EO bound to the ES by two C-H(ES)···O and two S···H-C(EO) hydrogen bonds. An attempt was also made to observe a-type transitions of the DMS dimer without success. We have applied a natural bond orbital analysis to the DMS-DME and EO-ES to calculate the stabilization energy CT (= ΔEσσ*), which was correlated closely with the binding energy as found for other related complexes.


Targeting gut microbiota-derived kynurenine to predict and protect the remodeling of the pressure-overloaded young heart.
Pressure-overloaded left ventricular remodeling in young population is progressive and readily degenerate into heart failure. The aims of this study were to identify a plasma metabolite that predicts and is mechanistically linked to the disease. Untargeted metabolomics determined elevated plasma kynurenine (Kyn) in both the patient cohorts and the mice model, which was correlated with remodeling parameters. In vitro and in vivo evidence, combined with single-nucleus RNA sequencing (snRNA-seq), demonstrated that Kyn affected both cardiomyocytes and cardiac fibroblasts by activating aryl hydrocarbon receptors (AHR) to up-regulate hypertrophy- and fibrosis-related genes. Shotgun metagenomics and fecal microbiota transplantation revealed the existence of the altered gut microbiota-Kyn relationship. Supplementation of selected microbes reconstructed the gut microbiota, reduced plasma Kyn, and alleviated ventricular remodeling. Our data collectively discovered a gut microbiota-derived metabolite to activate AHR and its gene targets in remodeling young heart, a process that could be prevented by specific gut microbiota modulation.


Overexpression of p21-activated kinase 1 promotes endometrial cancer progression.
Endometrial cancer (EC) is the most common gynecologic malignancy, but the molecular events involved in the development and progression of EC remain unclear. P21-activated kinase 1 (Pak1) plays important roles in cell motility and survival. This study investigated the clinical significance of Pak1 expression and its functional roles in EC. The expression of Pak1 in clinical samples and EC cell lines was evaluated. The effects of Pak1 on EC cell functions were determined by either overexpressing it via plasmid transfection or depleting its expression using short hairpin RNA (shRNA) in human EC cell lines. Pak1 was overexpressed in clinical samples of EC compared with normal endometrium. High Pak1 expression in EC was positively correlated with lymph node metastasis, advanced disease stage and poor histological differentiation. Pak1 over-expression was also observed in multiple human EC cell lines. In EC cell lines, Pak1 overexpression promoted cell proliferation, migration, invasion and anchorage-independent growth in vitro. Conversely, shRNA-mediated stable knockdown of Pak1 reduced cell proliferation, migration, invasion and anchorage-independent growth. In addition, ectopic Pak1 overexpression protected EC cells from apoptosis, along with decreased caspase-3 activation. These results suggest that Pak1 plays important roles at multiple stages of EC progression.


MR imaging evaluation of regional, remote, and global effects of percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy.
To evaluate regional, remote, and global effects of percutaneous transluminal septal myocardial ablation (PTSMA) in hypertrophic obstructive cardiomyopathy (HOCM) using magnetic resonance (MR) imaging. Twenty-one patients with HOCM underwent cine and delayed contrast-enhanced MR imaging. The regional effects of ablated myocardium as well as remote and global effects of PTSMA were assessed. The ablated interventricular septal myocardium was hyperenhanced and thinned after successful PTSMA. Decreases in posterior wall thickness and myocardial mass were observed more than 12 weeks after PTSMA. Decreases in posterior wall thickness, myocardial mass, and left atrial diameter were observed in patients without myocardial hyperenhancement before PTSMA. Neither reduction nor increase in hyperenhancing myocardium, except for the ablated myocardium, was observed after PTSMA. Cardiac MR imaging showed regional, remote, and global effects of PTSMA on the myocardium in HOCM and might indicate patients with a good global response to PTSMA.


Having a Conscious Patient During Cardiopulmonary Resuscitation: Is It Not Time to Consider Sedation Protocol?: A Case Report.
A middle-aged man with acute inferior wall myocardial infarction was admitted in cardiac arrest and in an unresponsive state to the hospital. Cardiopulmonary resuscitation (CPR) was initiated. Patient showed signs of consciousness throughout the CPR. The impact of awareness during CPR on the neuropsychological status of a patient with a favorable neurological outcome is yet to be studied on a large scale. Sedation protocol without compromising hemodynamic status may prove a fair choice in such cases.


Decompression of malignant biliary obstruction by duodenoscopic intubation of bile duct.
Interest is increasing in non-operative methods of relieving malignant obstruction of the bile duct, and drainage tubes and prostheses may be placed in the bile duct via the percutaneous transhepatic route. Two cases are described, however, in which a duodenoscope was used and the approach was via the papilla of Vater. This method allows temporary or permanent drainage tubes to be placed through malignant strictures. This endoscopic approach is less invasive and should be safer than that by the transhepatic route; furthermore, removing and replacing a blocked endoprosthesis should be easier. Further study is needed, as the procedure is technically more difficult and its role in managing biliary strictures has yet to be defined.


Frontline: Characterization of BT3 molecules belonging to the B7 family expressed on immune cells.
New members of the B7 family have been recently described as regulators of T cell activation and function. Butyrophilin (BT) has also been related to the B7 family by sequence similarity analyses. We present a new subfamily called BT3, which belongs to the B7/BT family. The BT3 subfamily comprises three members (BT3.1,.2 and.3) that exhibit 95% identity and form a monophylogenetic group along with the BT-related members. High expression levels of BT3 transcripts were detected in lymphoid tissues (mainly spleen, lymph node and PBL). Using anti-BT3 mAb we could demonstrate BT3 expression on immune cells including T, B and NK cells, monocytes and dendritic cells as well as hematopoietic precursors and some tumor cell lines. As described earlier for PDL-1 and ICOS-L, BT3 molecules are expressed on endothelial cells and up-regulated upon activation by IFN-gamma or TNF-alpha. The BT3.1 counter-receptor (BT3.1-R) was analyzed by means of binding experiments using BT3.1-Ig soluble protein. The BT3.1-R is not CD28, CTLA-4, ICOS, PD-1 or BTLA and seems restricted to some T cell and hematopoietic cell lines. Altogether, these data describe new members of the B7/BT family that may play a role in regulation of the immune response.


Palliative and end-of-life care in the masters of social work curriculum.
ABSTRACTObjective:There is a shortage of social workers who have palliative care expertise. The aging U.S. population and advances in extending life for seriously ill persons require social workers in a wide range of health care and other settings with specialized palliative care expertise, as well as those with basic competence in palliative care. The objective of the present study was to document course content on palliative care in MSW programs in the United States and Canada. A cross-sectional design with an online questionnaire was used. All 248 accredited MSW programs in the United States and 32 programs in Canada were invited to participate. The measures included the characteristics of the courses on palliative care. Of the 105 participating programs, only 10 had courses dedicated to palliative care, 9 of which were part of a specialization/certificate program. Few programs had plans to develop a dedicated course. There were 106 courses in 63 MSW programs with some content on palliative care. The majority of these had <25%, and few had at least 50%, of palliative care content. Curricula are needed for preparing MSW graduates for specialty hospice and palliative care practice and non-specialty practice. While there are practice competencies for specialty practitioners, consensus on a core curriculum for all MSW students would be beneficial. Consensus on basic palliative care knowledge and skills for non-specialty social workers in health care and other settings and subsequent curriculum development are also needed. Innovative ways in which to introduce basic and more specialized content on palliative care into the already-crowded MSW curricula will be needed.


Spatial control over near-critical-point operation ensures fidelity of ParABS-mediated DNA partition.
In bacteria, most low-copy-number plasmid and chromosomally encoded partition systems belong to the tripartite ParABS partition machinery. Despite the importance in genetic inheritance, the mechanisms of ParABS-mediated genome partition are not well understood. Combining theory and experiment, we provided evidence that the ParABS system-DNA partitioning in vivo via the ParA-gradient-based Brownian ratcheting-operates near a transition point in parameter space (i.e., a critical point), across which the system displays qualitatively different motile behaviors. This near-critical-point operation adapts the segregation distance of replicated plasmids to the half length of the elongating nucleoid, ensuring both cell halves to inherit one copy of the plasmids. Further, we demonstrated that the plasmid localizes the cytoplasmic ParA to buffer the partition fidelity against the large cell-to-cell fluctuations in ParA level. The spatial control over the near-critical-point operation not only ensures both sensitive adaptation and robust execution of partitioning but also sheds light on the fundamental question in cell biology: how do cells faithfully measure cellular-scale distance by only using molecular-scale interactions?


Psychosocial and health correlates of types of traumatic event exposures among U.S. military personnel.
The prevalence of lifetime exposure to violence, natural disaster, or major accidents involving injuries or fatalities was examined in the largest population-based epidemiologic survey of U.S. military personnel to date. The psychosocial and health effects of types of exposure experience (witness only, victim/survivor, relief worker), gender differences, and social support were also evaluated. Over 15,000 active duty U.S. military personnel from stratified random samples of active duty U.S. personnel from all services responded to either mail questionnaires and/or worksite surveys. The lifetime exposure to one or more traumatic events was 65%; the most prevalent trauma for men was witnessing a major accident, and for women, witnessing a natural disaster. Victims of any traumatic event were at twice the risk of having two or more physical and mental health problems than nonexposed controls. Health outcomes of trauma exposure vary by type of traumatic event: type of exposure experience, rank, and gender.


Nervous control of alkaline secretion in the duodenum as studied by the use of cholera toxin in the anaesthetized rat.
There is experimental evidence for an axon reflex control of alkaline secretion in the rat duodenum. We have investigated if there is also an intramural reflex control of alkaline secretion similar to that demonstrated with regard to the control of the fluid transport in the rat jejunum. Alkaline secretion in the duodenum of an anesthetized rat was continuously monitored using an in situ titration technique. The segment was extrinsically denervated. Exposing the duodenal segment to 80 microg cholera toxin markedly increased alkaline secretion. This response was abolished by hexamethonium (28 micromol (10 mg) kg(-1) body wt), a nicotinic receptor blocker, lidocaine (0.5 mL of a 1% solution on the serosal surface), a local anaesthetic, and nifedipine (5.75 micromol (2 mg) kg(-1) body wt i.v.), a calcium channel blocker. The response to cholera toxin was partially abolished by granisetron (0.11 micromol (40 microg) kg(-1) body wt i.v.), a 5-HT3 receptor blocker. Atropine (1.7 micromol (0.5 mg) kg(-1) body wt i.v.), a muscarinic receptor blocker, had no effect. We therefore conclude that the alkaline secretion in the rat jejunum evoked by cholera toxin exhibits the same pharmacological properties as the fluid secretion caused by the toxin in the jejunum. This suggests that the alkaline secretion in the rat duodenum is controlled not only by an axon reflex but also by an intramural secretory reflex similar to that controlling fluid transport in the rat jejunum.


["Sexual atrophy" in psychiatric patients--an essay review].
Sexuality of psychiatric inpatients is scarcely noticed and so rather negated. The therapeutic discourse remains scanty and contradictory. This article tries a survey of the literature as well as of the topics in the field of lust, sexuality, of the destinies of drives, and instinct disturbances of mental ill inpatients.


The epigenetics of prostate cancer diagnosis and prognosis: update on clinical applications.
There is a major deficit in our ability to detect and predict the clinical behavior of prostate cancer (PCa). Epigenetic changes are associated with PCa development and progression. This review will focus on recent results in the clinical application of diagnostic and prognostic epigenetic markers. The development of high throughput technology has seen an enormous increase in the discovery of new markers that encompass epigenetic changes including those in DNA methylation and histone modifications. Application of these findings to urine and other biofluids, but also cancer and noncancerous prostate tissue, has resulted in new biomarkers. There has been a recent commercial development of a DNA methylation-based assay for identifying PCa risk from normal biopsy tissue. Other biomarkers are currently in the validation phase and encompass combinations of multiple genes. Epigenetic changes improve the specificity and sensitivity of PCa diagnosis and have the potential to help determine clinical prognosis. Additional studies will not only provide new and better biomarker candidates, but also have the potential to inform new therapeutic strategies given the reversibility of these processes.


Clinical needs and opportunities in assessing body composition.
Protein-energy malnutrition (PEM) and obesity are hazardous to health with high morbidity and mortality rates. The assessment of body composition is essential to prevent, diagnose and determine the severity of these disorders as well as their response to therapy. Body weight is the sum of fat and fat-free mass (FFM) whereas its chemical model consists of triglyceride, protein, water, and minerals. Thus one must recognize the appropriate method to assess each compartment of body composition. In clinical practice, the method must be simple, accurate, noninvasive and inexpensive. Body mass index (BMI) is a practical anthropometric parameter to assess protein-energy status in adults because it can easily be calculated from weight in kg divided by (height in meter), and correlates with fatness and mortality. Total body fat can be estimated by measuring the amount of subcutaneous fat by measuring the thickness of the subcutaneous fat layer at different sites of the body by a skinfold caliper or near-infrared interactance. A high waist-over-hip circumference ratio (WHR) can be used to diagnose abdominal obesity. Upper arm muscle circumference can be employed to measure muscle mass. However, whenever these methods are used to assess body composition their limitations should be recognized.


Prediction of lifetime risk for cardiovascular disease, by risk factors level: the ATTICA epidemiological cohort study (2002-2022).
We aimed to predict lifetime risk for cardiovascular disease (CVD). The sample consisted of 1988 participants with complete CVD data during the 20-year follow-up (50% men, 45 ± 14 years) of the ATTICA study. Lifetime risk for CVD was predicted at specific index ages (40, 50, and 60 years), based on the life-table method, with death free-of-CVD treated as a competing event. 718 participants experienced a fatal or nonfatal CVD event, corresponding to a crude CVD incidence of 36.1% (men: 40.2%, women: 32.1%, P-value < .001). Overall, women and men had similar lifetime CVD risk (P-value = .245); at index age of 40, the lifetime risk for CVD was 68% for men and 63% for women, with a progressive decline to 56% and 50% at the index age of 50, and to 55% for both men and women, at the index age of 60 years, respectively. These results on lifetime risk for CVD can guide the allocation of resources to improve public health and preventive services, especially in ages below 50 years, in both men and women.


Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut.
Epithelial-to-mesenchymal transition-like (EMT-like) is a critical process allowing initiation of metastases during tumour progression. Here, to investigate its role in intestinal cancer, we combine computational network-based and experimental approaches to create a mouse model with high metastatic potential. Construction and analysis of this network map depicting molecular mechanisms of EMT regulation based on the literature suggests that Notch activation and p53 deletion have a synergistic effect in activating EMT-like processes. To confirm this prediction, we generate transgenic mice by conditionally activating the Notch1 receptor and deleting p53 in the digestive epithelium (NICD/p53(-/-)). These mice develop metastatic tumours with high penetrance. Using GFP lineage tracing, we identify single malignant cells with mesenchymal features in primary and metastatic tumours in vivo. The development of such a model that recapitulates the cellular features observed in invasive human colorectal tumours is appealing for innovative drug discovery.


Relationship between cartilage oligomeric matrix protein (COMP) and rheumatoid arthritis severity.
Serum cartilage oligomeric matrix protein (COMP) is a non-collagen glycoprotein produced by the cartilage, synovium, tendon, and meniscus. Recent studies showed that COMP is a reliable factor for monitoring cartilage damage. To determine the relationship between serum COMP concentration and the severity of rheumatoid arthritis (RA). This cross-sectional study lasted from 2013 to 2015 at the Rheumatology Clinic of Ghaem Hospital, Mashhad, Iran. The study population consisted of eligible patients who presented to our clinic during the study period. Four groups (150 subjects) were included as early RA (50 patients), late RA (50 patients), grades II and III OA (osteoarthritis) (25 cases, 17 grade II and 8 grade III joint destruction), and healthy controls (25 individuals). These were included consecutively. Serum COMP level was assessed by sandwich ELISA technique. In addition, ESR, hs-CRP, serum RF, and anti-CCP were assayed. X-rays of the knees (in OA) and hands (in RA) were examined for the degree of joint damage/erosion using the Short Erosion Scale (SES) in RA and Kellgren-Lawrence grading in OA. Analysis of variance (ANOVA) to compare mean COMP level among the groups and ROC (Receiver Operating Characteristic) analysis to determine the diagnostic accuracy of COMP in diagnosis of late RA were used by SPSS software (ver. 20.0). Mean (±SD) serum COMP levels were 18 (±10.6) U/L in early RA, 19.3 (±9.6) U/L in late RA, 10.9 (±4.5) U/L in OA, and 4.2 (±3.8) in controls; p<0.001. Serum COMP level was higher in RA and OA groups when compared to control group. Mean (±SD) SES score was 13.5 (±7.5) in early RA and 16.4 (±9.7) in late RA (p=0.093). There was a significant positive correlation between COMP level and disease severity in early RA (r=0.677, p<0.001) as well as in late RA (r=0.753, p<0.001). Serum COMP level at a concentration of 15.25 U/L had a sensitivity of 68% and specificity of 70% to discriminate late RA from early RA (area under curve= 69% (95% CI: 58% to 79%; p=0.001). COMP had positive significant correlation with early and late RA severity. This serum biomarker can be a useful and easy tool for monitoring of RA patients either at early or late stages of the disease.


Assessment of skeletal muscle mass in men with spinal cord injury using dual-energy X-ray absorptiometry and magnetic resonance imaging.
The purpose of this study was to determine whether the proportion of skeletal muscle in the fat-free soft tissue mass (FFST) is the same in men with spinal cord injury (SCI) and able-bodied controls. Skeletal muscle mass and FFST of the midthigh were determined by using magnetic resonance imaging and dual-energy X-ray absorptiometry, respectively, in men with long-term (>2 yr) complete SCI (n = 8) and able-bodied controls of similar age, height, and weight (n = 8). Muscle mass (1.36 +/- 0.77 vs. 2.44 +/- 0.47 kg) and FFST (1.70 +/- 0.94 vs. 2.73 +/- 0.80 kg) were lower in the SCI group than in the controls (P < 0.05), but the lower ratio of muscle to FFST in the SCI group (0.80 +/- 0.09 vs. 0.91 +/- 0.10, P < 0.05) suggested that they had a lower proportion of muscle in the FFST than in controls. This notion was supported by analysis of covariance, in that the mean muscle adjusted to the mean FFST of the groups combined was lower in the SCI group. Despite the lower proportion of muscle in the FFST of the SCI group, the relation between muscle and FFST was strong in the SCI group (r = 0.99) and controls (r = 0.96). The findings suggest a disproportionate loss of muscle in the paralyzed thighs after SCI relative to other nonfat constituents, which may be accurately estimated in men with long-term SCI by dual-energy X-ray absorptiometry if the lower proportion of muscle in the FFST (approximately 15%) is taken into account.


Physiological and clinical consequences of positive end-expiratory pressure.
The aims of positive end-expiratory pressure (PEEP) are: 1) in acute lung failure, to increase lung volume and to improve oxygenation; 2) in acute exacerbation of chronic obstructive pulmonary disease (COPD), to unload inspiratory muscles. Excessive levels of PEEP may increase the risk of barotrauma. Application of low levels of PEEP may replace intrinsic PEEP in acute exacerbation of COPD, without increasing lung volume; however, the haemodynamic consequences of PEEP must be taken into account.


Intralesional ultrasound-guided combined treatment with triamcinolone plus lincomycin in hidradenitis suppurativa: A pilot study.
Hidradenitis suppurativa (HS) is a chronic, inflammatory, disease of the hair follicle. Intralesional corticosteroid treatment in HS patients has been reported, and while several data described this route of administration as an efficient delivery system, its efficacy is still debated. The aim of this study was to explore the clinical efficacy and the effect on quality of life (QoL) of an innovative intralesional treatment in HS patients. This was an interventional prospective study. The treatment consisted of two intralesional ultrasound-guided injections of triamcinolone plus lincomycin, at baseline and after 2 weeks. Lesions and QoL were evaluated at baseline and at 4 weeks following intralesional therapy. All clinical variables of 36 HS patients significantly improved after 4 weeks. Mean values of the visual analog scale (VAS) pain decreased from 4.6 to 1.5, P = .027. The Bodily Pain (BP) scale of the Short-Form Health Survey (SF-36) significantly improved from 36.2 at baseline to 53.9 at 4-week follow-up (P < .001). On a scale from 0 to 10, over 90% of the patients gave a satisfaction score of 8 or more. This combination of corticosteroids and antibiotics delivered intralesionally seems to be effective, as it improved both patient- and physician-reported outcomes.


Stability of comorbid psychiatric diagnosis among youths in treatment and aftercare for alcohol use disorders.
To examine the stability of comorbid psychiatric diagnoses among a sample of 50 adolescents in cognitive-behaviorally-based treatment for alcohol and other substance use disorders (AOSUD). A standardized psychiatric interview was administered at baseline and 12 month later to obtain current comorbid psychiatric disorders. Chi square and Wilconxon sign tests coefficients were used to examine changes in threshold status by type of disorder. Pearson's coefficients were used to identify correlates with improvements in threshold status, include the need for alcohol treatment and alcohol consumption at follow-up. Diagnostic status changes considerably over time. Prevalence rates for comorbid disorders overall declined. Only declines in mood and externalizing disorders achieved statistical significance. Improvements were positively correlated with mental health service utilization and negatively correlated with the need for alcohol treatment and consumption at 12 months. Further investigation on the stability and change in diagnostic status of AOSUD.


A rapid and sensitive liquid chromatography-tandem mass spectrometric method for the determination of timosaponin B-II in blood plasma and a study of the pharmacokinetics of saponin in the rat.
A rapid, sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of Timosaponin B-II (TB-II), a pharmacologically active constituent isolated from Anemarrhena asphodeloides. This method was used to examine the pharmacokinetics and bioavailability of TB-II in rats using ginsenoside Re as an internal standard. After simple protein precipitation of the plasma samples with acetonitrile, the analytes were separated on an ODS column (150 mm x 2.1 mm i.d., 5 microm) with the mobile phase of acetonitrile-water (35:65, v/v) containing 0.05% formic acid and detected by electrospray ionization mass spectrometry in the negative multiple reaction monitoring (MRM) mode with a chromatographic run time of 3.0 min. The calibration curves were linear over the range of 5-15,000 ng/ml and the lower limit of quantification (LLOQ) was 5 ng/ml in rat plasma. In this range, relative standard deviations (R.S.D.) were <7.4% for intra-day precision and <9.0% for inter-day precision. The accuracy was within the range of 97.7-107.3%. The method was successfully applied to assess the pharmacokinetics and oral bioavailability of TB-II after intravenous and oral administration in rats, with the oral bioavailability being only 1.1%.


The functioning of different beetle (Coleoptera) sampling methods across altitudinal gradients in Peninsular Malaysia.
Biodiversity research relies largely on knowledge about species responses to environmental gradients, assessed using some commonly applied sampling method. However, the consistency of detected responses using different sampling methods, and thus the generality of findings, has seldom been assessed in tropical ecosystems. Hence, we studied the response consistency and indicator functioning of beetle assemblages in altitudinal gradients from two mountains in Malaysia, using Malaise, light, and pitfall traps. The data were analyzed using generalized linear mixed-effects models (GLMM), non-metric multidimensional scaling (NMDS), multivariate regression trees (MRT), and indicator species analysis (IndVal). We collected 198 morpho-species of beetles representing 32 families, with a total number of 3,052 individual beetles. The richness measures generally declined with increasing altitude. The mountains differed little in terms of light and Malaise trap data but differed remarkably in pitfall-trap data. Only light traps (but not the other trap types) distinguished high from middle or low altitudes in terms of beetle richness and assemblage composition. The lower altitudes hosted about twice as many indicators as middle or high altitudes, and many species were trap-type specific in our data. These results suggest that the three sampling methods reflected the altitudinal gradient in different ways and the detection of community variation in the environment thus depends on the chosen sampling method. However, also the analytical approach appeared important, further underlining the need to use multiple methods in environmental assessments.


Three-dimensional architecture of the ligamentum teres in the human hip joint.
We aimed to investigate the three-dimensional structure of the collagenous fibers of the ligamentum teres (LT) of the human hip and clarify the LT micro-anatomy at the attachment of the femoral head. Femoral heads and LT were collected during hip arthroplasty. Specimens were cut into 5-10-mm squares, prepared, developed, and observed under a light microscope. Next, specimens were prepared and examined under a scanning electron microscope (SEM). Under optical microscope, LT adhered to the artificial cartilage at the attachment of the femoral head. Under SEM, LT comprised parallelly arranged collagenous fibers and the fine collagenous fibrils were twisted. While the central collagenous fibers of the LT at the attachment of the femoral head penetrated the articular cartilage tissue and reached the ring-shaped bone, fibers at the margin traversed and adhered to the cartilage surface. Articular cartilage and subchondral bone are present at the LT attachment to the femoral head. Although collagenous fibers of the LT show parallel arrangement at the main trunk, they are dispersed at the cartilage surface and not all reach the thin subchondral bone of the femoral head. This could possibly weaken ligament strength at the attachment of the femoral head. IV.


Clinical studies of buspirone.
This literature review addresses two related questions: Is buspirone as clinically effective an antianxiety agent as the benzodiazepines? And does buspirone offer any safety advantages? Data from over 1,000 anxious outpatients reveal that an average dose of 20 mg of buspirone/day appears to be as effective an antianxiety agent as comparable doses of diazepam or clorazepate in both acute and more chronic administration studies. Buspirone appears to cause less clinically significant impairment in cognition or motor performance, is less likely to potentiate the effects of brain depressants like alcohol, has little if any abuse liability, and produces no clinically identifiable physical abstinence syndrome when discontinued after long-term administration. While the final answer on the clinical usefulness and side effect profile of this interesting drug awaits the results of its use in divergent clinical settings, this new antianxiety agent appears to be equally effective in treating anxiety but is safer than the benzodiazepines.


Properties of a reversible soluble-insoluble cellulase and its application to repeated hydrolysis of crystalline cellulose.
Cellulase was covalently immobilized on an enteric coating polymer, Eudragit L, that is reversibly soluble and insoluble depending on the pH of the medium. The hydrolysis of solid cellulose with the immobilized enzyme can take advantage of the soluble property of the immobilized enzyme itself at the most reactive pH value; on the other hand, recovery of the enzyme can take advantage of the insoluble property of the enzyme at other pH values. It was experimentally confirmed that 100% of immobilized enzyme activity in solution can be recovered by precipitation and by dissolving it again by alternative change of pH. After a period of hydrolysis, immobilized enzyme and unreacted cellulose were precipitated together to remove the product-the soluble sugar solution-by changing pH. Following this, a new buffer solution was added to the precipitate to dissolve it and resume the reaction. This was repeated several times. The hydrolysis rate of this process increased significantly compared with that of a batch process. Utilization of the reversible soluble-insoluble carrier for immobilizing enzyme is promising, not only for cellulose-cellulase systems, but also for other heterogeneous reaction systems.


Age-related change of Iba-1 immunoreactivity in the adult and aged gerbil spinal cord.
In the present study, we examined change of ionized calcium-binding adapter molecule 1 (Iba-1) in the adult and aged gerbil spinal cords. Significant change of morphological feature and neuronal cell loss were not observed in both adult and aged spinal cords of gerbil after NeuN immunohistochemistry and Fluoro-Jade B histofluoresce staining. Iba-1-immunoreactive microglia broadly distributed in the spinal cord. Most of Iba-1-immunoreactive microglia showed ramified forms in the adult gerbil cervical and lumbar spinal cords. However, morphological changes of Iba-1-immunoreactive microglia were observed in the cervical and lumbar regions of the aged gerbil spinal cord. These microglia were showed a hypertrophied body with shortened swollen processes which was characteristic of activated microglia. In addition, Iba-1 protein level significantly higher in aged cervical and lumbar spinal cords than those in the adult gerbil. The present study showed an increase of activated forms of Iba-1-immunoreactive microglia and its protein level without marked changes in morphological features and neuronal loss in the aged spinal cord compared to those in the adult gerbil spinal cord. This result suggests that the increase of Iba-1 expression in the aged spinal cord may be closely associated with age-related changes in aged gerbil spinal cord.


Glycoside hydrolase production by Aspergillus terreus CM20 using mixture design approach for enhanced enzymatic saccharification of alkali pretreated paddy straw.
A successful lignocellulosic ethanol production process needs to address the technological impediments such as cost-competitiveness and sustainability of the process. Effective biomass utilization requires a repertoire of enzymes including various accessory enzymes. Developing an enzyme preparation with defined hydrolytic activities can circumvent the need for supplementing cellulases with accessory enzymes for enhanced hydrolysis. With this objective, mixture design approach was used in the present study to enhance glycoside hydrolase production of a fungal isolate, Aspergillus terreus CM20, by determining the proportion of different lignocellulosic components as enzyme inducers in the culture medium. A mixture of paddy straw and wheat straw (1.42:1.58) resulted in improved cellulolytic activities. The precipitated crude enzyme showed higher CMCase (365.03 18 IU g-1), FPase (161.48 IU g-1), avicelase (15.46 IU g-1), β-glucosidase (920.92 IU g-1) and xylanase (9627.79 IU g-1) activities. The potential of the crude enzyme for saccharification of alkali pretreated paddy straw was also tested. Under optimum conditions, saccharification released 25.0 g L-1 of fermentable sugars. This indicates the superiority of the crude enzyme produced with respect to its hydrolytic enzyme components.


Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo.
We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization. Sorafenib/pazopanib combined with sildenafil in a [GRP78+HSP27] -dependent fashion to: (i) profoundly activate an eIF2α/Beclin1 pathway; (ii) profoundly inactivate mTOR and increase ATG13 phosphorylation, collectively resulting in the formation of toxic autophagosomes. In a fresh PDX isolate of NSCLC combined knock down of [ERBB1+ERBB3] or use of the ERBB1/2/4 inhibitor afatinib altered cell morphology, enhanced ATG13 phosphorylation, inactivated NFκB, and further enhanced [sorafenib/pazopanib + sildenafil] lethality. Identical data to that with afatinib were obtained knocking down PI3K p110α/β or using buparlisib, copanlisib or the specific p110α inhibitor BYL719. Afatinib adapted NSCLC clones were resistant to buparlisib or copanlisib but were more sensitive than control clones to [sorafenib + sildenafil] or [pazopanib + sildenafil]. Lapatinib significantly enhanced the anti-tumor effect of [regorafenib + sildenafil] in vivo; afatinib and BYL719 enhanced the anti-tumor effects of [sorafenib + sildenafil] and [pazopanib] in vivo, respectively.


A two-year study of enteric infections associated with diarrhoeal diseases in children in urban Somalia.
A hospital-based systematic sample of 1667 children with severe diarrhoeal disease was studied in Mogadishu, Somalia, throughout 1983 and 1984. One or more enteric pathogens were found in 61% of the patients. Rotavirus (25%), enterotoxigenic Escherichia coli (11%), Shigella spp. (9%), Aeromonas hydrophila (9%), Giardia lamblia trophozoites (8%), Campylobacter jejuni (8%), and Vibrio cholerae non-O1 (6%) were the most frequently identified pathogens. Age-specific detection rates of enteric pathogens and helminths, seasonal patterns, and relationship of some specific infections with feeding status and main clinical features have been defined for all the sample examined.


[The antiproteinuric action of angiotensin-converting enzyme inhibitors in chronic glomerulonephritis and diabetic nephropathy].
Antiproteinuria effects of angiotensin-converting enzyme (ACE) inhibitors was studied in 23 patients with chronic nephritis (CN) and 32 patients with diabetic nephropathy (DN). CN patients received Capoten, DN patients were given enalapril. The drugs were also examined for the action on systemic arterial pressure, renal function and intrarenal hemodynamics. Significantly decreased urinary excretion of protein occurred in DN patients on the treatment month 1, in CN subjects on month 3. In both groups ACE inhibitors produced marked hypotensive effect, did not affect renal function, noticeably improved intraglomerular hemodynamics. Hypotensive and antiproteinuria activity of the drugs were unrelated. The mechanism of antiproteinuria action of ACE inhibitors works via normalization of intrarenal hemodynamics. Systemic arterial hypertension seems to be an additional factor aggravating disturbances of intrarenal circulation and provoking proteinuria.


Detection of salivary protein biomarkers of saliva secretion disorder in a primary Sjögren syndrome murine model.
Saliva secretion disorder is one of the most common symptoms in primary Sjögren syndrome (pSS). Salivary biomarkers related to saliva secretion disorder were identified in a pSS murine model, NOD/ShiLtJ mouse, using differential proteomic analysis. Candidate biomarkers were screened with Kyoto Encyclopedia of Genes and Genomes pathway analysis and validated in saliva and salivary glands by western blotting and immunohistochemistry (IHC). Biological functions were detected using ingenuity pathway analysis (IPA). We identified 1101 salivary proteins from NOD/ShiLtJ mice and BALB/c mice (control). Catenin alpha-3 (CTNNA3), tyrosine-protein phosphatase non-receptor type 6 (PTPN6), Ras-related C3 botulinum toxin substrate (RAC2), and intermediate conductance calcium-activated potassium channel protein 4 (KCNN4) were screened as candidate biomarkers from 225 significantly dysregulated salivary proteins. These proteins participated in adherens junction or saliva secretion pathway and may be related to saliva secretion disorder. Proteomic analysis revealed that CTNNA3, PTPN6, and RAC2 were dysregulated in saliva and salivary glands and showed satisfactory sensitivity and specificity in receiver-operating characteristic curve; KCNN4 showed no statistical difference. IHC and IPA indicated that CTNNA3 may regulate acinar cell morphology, while PTPN6 and RAC2 promoted lymphocyte adhesion in salivary glands. Thus, CTNNA3, PTPN6, and RAC2 may be related to saliva secretion disorder in pSS.


Totally laparoscopic verse laparoscopic assisted distal gastrostomy for gastric cancer: an update meta-analysis.
Totally laparoscopic distal gastrostomy (TLDG) and laparoscopic- assisted distal gastrostomy (LADG) are the minimally invasive surgical technology for gastric cancer. This study aimed to compare the surgical outcomes of these two methods. Relevant studies were selected through electronic searches of EMBASE, PubMed and Web of Science. In total, 21 non-randomized controlled studies containing 2475 patients in the totally laparoscopic distal gastrostomy and 1889 patients in the laparoscopic-assisted distal gastrostomy were included in this study. And operative time, operative blood loss, retrieved lymph nodes, time to liquid diet (days), postoperative hospital stay and overall complications were pooled and compared using meta-analysis. There were no significant differences between operative time (WMD = 0.38, 95% CI -10.43 -11.18, P = 0.95) and overall complications (RR = 1.09, 95% CI 0.91-1.30, P = 0.36). But totally laparoscopic distal gastrostomy had more advantages in aspects of intraoperative blood loss (WMD = 24.4, 95% CI 12.45-36.36, P < 0.0001), time to liquid diet (days) (WMD = 0.21, 95% CI 0.03-0.40, P = 0.03) and postoperative hospital stay (WMD = 0.72, 95% CI 0.31-1.13, P = 0.0006). Moreover, totally laparoscopic distal gastrostomy had more retrieved lymph nodes (WMD = -1.24, 95% CI-1.90 to-0.58, P = 0.0002). This meta-analysis indicates that totally laparoscopic distal gastrostomy may be a safe, feasible, and favorable surgical technology in terms of less blood loss, faster liquid diet, shorter postoperative hospital stay and more lymph nodes retrieved.


Fluorescence labeling of human rhinovirus capsid and analysis by capillary electrophoresis.
The capsid of human rhinovirus serotype 2, consisting of four viral proteins, was fluorescence-labeled with fluorescein isothiocyanate and analyzed by capillary electrophoresis using UV and laser-induced fluorescence detection. Heat denaturation, proteolytic digestion, and receptor binding were applied for confirmation of the identity of the peak with the labeled virus. Incomplete derivatization with the fluorophore preserved the affinity of the virus for its receptor, indicating that its cell entry pathway is unperturbed by this chemical modification; indeed, an infectivity assay confirms that the labeled virus samples are infectious. The results show that fluorescence labeling of the viral capsid might lead to a valuable probe for studying infection processes in the living cell.


Determination of chemical warfare agent degradation products at low-part-per-billion levels in aqueous samples and sub-part-per-million levels in soils using capillary electrophoresis.
A significant enhancement in the method detection limits is observed in the analysis of chemical warfare agent (CWA) degradation products in environmental samples by capillary electrophoresis (CE) using electrokinetic injection. The CE method uses indirect UV detection of the nonderivitized acidic analyte and a cationic surfactant, didodecyldimethylammonium hydroxide, for reversal of the electroosmotic flow. Analytes studied include the dibasic acid methylphosphonic acid (MPA) and its monoacid/monoalkyl esters, RMPA, where R = ethyl, isopropyl, and pinacolyl (2-(3,3-dimethylbutyl)). The CE method uses an attractive buffer system which is highly stable and inexpensive, and, in addition to reversing the electroosmotic flow, provides excellent separation efficiencies within a 3-min run. This CE method is also free from interference caused by carbonate, humic acids, and fluoride. Compared to pressure injection, electrokinetic injection with this CE buffer system provided substantially lower detection limits, up to 100-fold lower for samples in reagent water. However, to best realize the benefits of the electrokinetic injection enhancement for environmental samples, a prior cleanup of the sample using standard ion-exchange cartridges is necessary. This cleanup step uses sequential cartridges to remove sulfate (barium cartridge), chloride (silver cartridge), and cations (H+ cartridge). Using this approach, detection limits for these four acids were as low as 1-2 micrograms/L for water samples and 25-50 micrograms/L for aqueous leachates of soil samples (10 mL of leachate/1.5 g of soil). The utility of this method for separation of CWA degradation products by CE is discussed in terms of pressure injection versus electokinetic injection. The effects of voltage and time of injection on the separation were investigated. Results from three types of soils and four types of water (groundwater, artificial seawater, tap water, bay water) indicated that the method has potential for environmental monitoring. Quantitative CE analysis with electrokinetic injection enhancement of detection limits of these types of environmental samples requires the use of an appropriate internal standard approach. The data presented here indicate that an internal standard-based approach could be expected to give analysis results in the sub-part-per-million concentration range of 90-110% of the true value.