A double-blind study of the effect of trimipramine in patients with the irritable bowel syndrome.
The study was performed in 428 patients, of whom 216 were women. The median age was 36.5 (16-75) years and the median weight 67 (42-118) kg. The complaints were registered on a 10-cm-long linear analogue scale by the patients and the physicians. The patients were given coded identical-appearing tablets of placebo and different doses of trimipramine (Surmontil, Rhône-Poulenc) and randomized into groups A-E. During the 6 weeks of treatment the grades of complaints were reduced to about the half of pretreatment levels. The groups treated with trimipramine (groups A-D) felt significantly more improved than the group receiving placebo (group E). The side effect of tiredness was somewhat more pronounced 1-2 weeks after start with 50 mg trimipramine in the evening than in the groups receiving placebo and lower dose schedules of trimipramine.


Searching for Sympatric Speciation in the Genomic Era.
Sympatric speciation illustrates how natural and sexual selection may create new species in isolation without geographic barriers. However, recent genomic reanalyses of classic examples of sympatric speciation reveal complex histories of secondary gene flow from outgroups into the radiation. In contrast, the rich theoretical literature on this process distinguishes among a diverse range of models based on simple genetic histories and different types of reproductive isolating barriers. Thus, there is a need to revisit how to connect theoretical models of sympatric speciation and their predictions to empirical case studies in the face of widespread gene flow. Here, theoretical differences among different types of sympatric speciation and speciation-with-gene-flow models are reviewed and summarized, and genomic analyses are proposed for distinguishing which models apply to case studies based on the timing and function of adaptive introgression. Investigating whether secondary gene flow contributed to reproductive isolation is necessary to test whether predictions of theory are ultimately borne out in nature.


Beating the walker limit with massless domain walls in cylindrical nanowires.
We present a micromagnetic study on the current-induced domain-wall motion in cylindrical Permalloy nanowires with diameters below 50 nm. The transverse domain walls forming in such thin, round wires are found to differ significantly from those known from flat nanostrips. In particular, we show that these domain walls are zero-mass micromagnetic objects. As a consequence, they display outstanding dynamic properties, most importantly the absence of a breakdown velocity generally known as the Walker limit. Our simulation data are confirmed by an analytic model which provides a detailed physical understanding. We further predict that a particular effect of the current-induced dynamics of these domain walls could be exploited to measure the nonadiabatic spin-transfer torque coefficient.


A Theory of the Origin of the State: Traditional theories of state origins are considered and rejected in favor of a new ecological hypothesis.
In summary, then, the circumscription theory in its elaborated form goes far toward accounting for the origin of the state. It explains why states arose where they did, and why they failed to arise elsewhere. It shows the state to be a predictable response to certain specific cultural, demographic, and ecological conditions. Thus, it helps to elucidate what was undoubtedly the most important single step ever taken in the political evolution of mankind.


Pharmacy and consumer-directed accounts.
Employers must make informed design andimplementation choices in order for consumer-directed accounts to optimize the performance of pharmacy benefit strategies. Strategies must contemplate the prevalence of consumer-directed accounts, emerging technologies that support them and the potential impact on employee choices. Employers that align these factors may deliver pharmacy benefits at a lower cost and have an advantage over competitors. In pursuing this end, employers also may play a significant role in making health care affordable to as many Americans as possible.


Protecting a rare commodity.
On 18 May the European Oncology Nursing Society (EONS) celebrated the first European Cancer Nursing Day. We did this to raise the profile of cancer nursing as a pan-European specialism with shared aims: to provide excellent care for cancer patients, and to publicise the wide variation in roles, educational requirements and terms and conditions.


BAFfling pathologies: Alterations of BAF complexes in cancer.
To activate or repress specific genes, chromatin is constantly modified by chromatin-remodeling complexes. Among these complexes, the SWItch/Sucrose Non-Fermenting (SWI/SNF) complex, also referred to as BRG1-Associated Factor (BAF) complex, moves the nucleosome along chromatin using energy provided by ATP hydrolysis. In mammalian organisms, the SWI/SNF complex is composed of 10-15 subunits, depending on cell type, and a defect in one of these subunits can have dramatic consequences. In this review we will focus on the alterations identified in the SWI/SNF (BAF) complex subunits that lead to cancerous pathologies. While SMARCB1 was the first mutated subunit to be reported in a majority of malignant rhabdoid tumors, the advent of next-generation sequencing allowed the discovery of mutations in various SWI/SNF subunits within a broad spectrum of cancers. In most cases, the mutation leads to a loss of expression or to a truncated subunit unable to perform its function. Even though it is now commonly acknowledged that approximately 20% of all cancers present a mutation in a SWI/SNF subunit, some cancers are associated to a specific alteration of a SWI/SNF subunit, which acts either as tumor suppressor genes or as oncogenes, and therefore constitute diagnostic or prognostic biomarkers. Consistently, therapeutic strategies targeting SWI/SNF subunits or the genes affected downstream have been revealed to treat cancers.


Less-than-subtotal parathyroidectomy increases the risk of persistent/recurrent hyperparathyroidism after parathyroidectomy in tertiary hyperparathyroidism after renal transplantation.
The optimal surgical approach for tertiary hyperparathyroidism (HPT) after kidney transplantation is unknown. Existing studies are limited by small sample size, lack of adjustment for kidney function, and no long-term follow-up. We retrospectively analyzed 74 patients with tertiary HPT who underwent parathyroidectomy at two centers since 1978. Persistent HPT was defined as parathyroid hormone (PTH) concentrations in excess of the K/DOQI target range for the corresponding estimated creatinine clearance (eCrCl). Seventy-four patients had 83 operations (72 subtotal and 11 less-than-subtotal parathyroidectomies). Mean follow-up time was 5.4 +/- 4.7 years. Calcium concentrations decreased significantly after parathyroidectomy (2.83 vs 2.28 mmol/L, P < 0.001), as did eCrCl (54.5 vs 44.9 mL/min, P < 0.001) and PTH (382 vs 132 pg/mL, P < 0.001). In the multivariable regression analysis, only the type of operation and postoperative eCrCl were significantly correlated with PTH at follow-up. A limited parathyroidectomy was associated with a fivefold increase in risk of persistent or recurrent hyperparathyroidism. The use of limited parathyroidectomy for tertiary HPT after kidney transplantation has a higher risk of persistent/recurrent HPT. Subtotal parathyroidectomy is recommended for patients with tertiary HPT.


Impact of intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction on left ventricular perfusion and function: a 6-month follow-up gated 99mTc-MIBI single-photon emission computed tomography study.
We investigated the impact of intracoronary injection of autologous mononuclear bone marrow cells (BMC) in patients with acute ST elevation myocardial infarction (STEMI) on left ventricular volumes, global and regional systolic function and myocardial perfusion. The study included 39 patients with first anterior STEMI treated successfully with primary percutaneous coronary intervention. They were randomly assigned to the treatment group or the control group in a 2:1 ratio. The patients underwent baseline gated single-photon emission computed tomography (G-SPECT) 3-10 days after STEMI with quantitative and qualitative analysis of left ventricular perfusion and systolic function. On the following day, patients from the BMC treatment group were subjected to bone marrow aspiration, mononuclear BMC isolation and intracoronary injection. No placebo procedure was performed in the control group. G-SPECT was repeated 6 months after STEMI. Baseline and follow-up G-SPECT studies were available for 36 patients. At 6 months in the BMC group we observed a significantly enhanced improvement in the mean extent of the perfusion defect, the left ventricular perfusion score index, the infarct area perfusion score and the infarct area wall motion score index compared to the control group (p = 0.01-0.04). However, the changes in left ventricular volume, ejection fraction and the left ventricular wall motion score index as well as the relative changes in the infarct area wall motion score index did not differ significantly between the groups. Intracoronary injection of autologous mononuclear BMC in patients with STEMI improves myocardial perfusion at 6 months. The benefit in infarct area systolic function is less pronounced and there is no apparent improvement of global left ventricular systolic function.


[Efficacy of vitreorretinal surgery to improve best corrected visual acuity in diabetics with retinopathy].
complications of proliferative diabetic retinopathy require surgical treatment. In 2007 Flaxel reported visual improvement after vitreoretinal surgery in 37% of Latino diabetics; in our country it is estimated that a higher proportion of patients improves, but this has not been documented. to identify the efficacy of vitreoretinal surgery for improving best corrected visual acuity, in diabetic patients treated at a hospital in Mexico City. an observational, longitudinal, retrospective, descriptive study was conducted in diabetics who underwent vitreoretinal surgery (2007-2010) with one year follow-up. Visual acuity was measured before surgery and one year after, and it was registered when the retinopexy orphacoemulsification was performed, or silicone tamponade wasused. The proportions and 95% confidence intervals (CI) of patients whose visual acuity improved, did not change or worsened, were compared with those reported by Flaxel in Latino patients (χ(2), relative risk [RR]). 63 patients, mean age 58.5 ± 11.6 years, 26 with retinal detachment (41.3%), phacoemulsification was performed in 50 (79.4%), and silicone was used in 27 (42.9%). BCVA worsened in 12 patients (19%), did not change in 5 (8%) and improved in 46 (73%, 95% CI 62-84); the latter proportion exceeded that reported by Flaxel (p = 0.0005, RR 1.97, 95% CI 1.25-3.1). although the difference was not clinically significant, the efficacy of vitreoretinal surgery to improve visual acuity in the sample was consistently higher than that reported by Flaxel in Latinos, and did not vary from other studies. These results do not support an association between an ethnic group and a lower surgical efficacy.


Selection factors for local anesthetic agents.
The decision to inject local anesthetic agents to achieve profound anesthesia is dependent upon many factors, particularly the depth and duration of anesthesia required, and the possible need for hemostasis. To maximize the safety of local anesthetic injections, it is necessary to weigh the risks against the benefits for each patient, for each anesthetic agent, for use of a vasoconstrictor, and for the delivery technique for the selected agent.


Quantum hydrodynamics of strongly coupled electron fluids.
We have extended the classical hydrodynamics formalism to include nonlocal quantum behavior via the phenomenological Bohm potential. We have then solved the quantum hydrodynamics equations to derive an expression for the dynamical structure factor, which describes the density-density correlations in the system. This formalism can be applied to high density strongly coupled electron fluids in the long wavelength domain. We show that at densities above 7×10(25) cm(-3) there are significant differences in the dispersion relation. Future experiments at large laser facilities could provide an experimental test of the theory.


Complications in the use of bilateral inferiorly based nasolabial flaps for advanced oral submucous fibrosis.
Surgical management of advanced oral submucous fibrosis (OSMF) using bilateral inferiorly based nasolabial flaps is becoming increasingly popular. However no comprehensive analysis of delayed complications using this technique is available in the literature. The authors have conducted a retrospective study to examine the delayed complications of bilateral inferiorly based nasolabial flaps used in advanced oral submucous fibrosis at their institute along with a detailed review of literature on the subject. Thirty-two patients from January 2004 to December 2015 with OSMF and an interincisal distance less than 15 mm were included. All patients were treated with bilateral inferiorly based nasolabial flaps for correction of the restricted mouth opening. All patients had postoperative physiotherapy and were followed up for a minimum period of 6 months. All complaints of patients during the follow up phase were included in this study. In this series, complications such as partial necrosis, intra-oral hair growth, unacceptable extra-oral scar, wound dehiscence, orocutaneous fistula, and pincushioning effect were observed. Numerous complications can occur with the use of nasolabial flaps for the management of advanced oral submucous fibrosis. Although most complications are of inconsequential nature the surgeon must observe due diligence when using this flap.


SET kinetics of electrochemical metallization cells: influence of counter-electrodes in SiO2/Ag based systems.
The counter-electrode material in resistively switching electrochemical metallization cells (ECMs) is a crucial factor influencing the nucleation of conductive filaments, the equilibrium electrode potentials, and kinetics in the devices, and hence the overall switching characteristics. Here, we demonstrate the influence of the counter-electrode (CE) material on the SET events and the importance of appropriate choice and combination of materials. The counter-electrode material influences the counter-electrode processes at the CE/insulator interface and consequently determines the metal ion concentration in the cells. We measured the switching kinetics for SiO2/Ag based ECM cells using different counter-electrode materials with different electrocatalytic activities towards water reduction, namely platinum, ruthenium, and iridium oxide, as well as titanium nitride and tantalum. The experimental results are fitted using a physical simulation model and are analysed for the limiting factors for fast SET kinetics.


Urinary Extracellular Vesicles of Podocyte Origin and Renal Injury in Preeclampsia.
Renal histologic expression of the podocyte-specific protein, nephrin, but not podocin, is reduced in preeclamptic compared with normotensive pregnancies. We hypothesized that renal expression of podocyte-specific proteins would be reflected in urinary extracellular vesicles (EVs) of podocyte origin and accompanied by increased urinary soluble nephrin levels (nephrinuria) in preeclampsia. We further postulated that podocyte injury and attendant formation of EVs are related mechanistically to cellfree fetal hemoglobin (HbF) in maternal plasma. Our study population included preeclamptic (n=49) and normotensive (n=42) pregnant women recruited at delivery. Plasma measurements included HbF concentrations and concentrations of the endogenous chelators haptoglobin, hemopexin, and α1- microglobulin. We assessed concentrations of urinary EVs containing immunologically detectable podocyte-specific proteins by digital flow cytometry and measured nephrinuria by ELISA. The mechanistic role of HbF in podocyte injury was studied in pregnant rabbits. Compared with urine from women with normotensive pregnancies, urine from women with preeclamptic pregnancies contained a high ratio of podocin-positive to nephrin-positive urinary EVs (podocin+ EVs-to-nephrin+ EVs ratio) and increased nephrinuria, both of which correlated with proteinuria. Plasma levels of hemopexin, which were decreased in women with preeclampsia, negatively correlated with proteinuria, urinary podocin+ EVs-to-nephrin+ EVs ratio, and nephrinuria. Administration of HbF to pregnant rabbits increased the number of urinary EVs of podocyte origin. These findings provide evidence that urinary EVs are reflective of preeclampsia-related altered podocyte protein expression. Furthermore, renal injury in preeclampsia associated with an elevated urinary podocin+ EVs-to-nephrin+ EVs ratio and may be mediated by prolonged exposure to cellfree HbF.


Impact of time factor and patient characteristics on the efficacy of PCI vs CABG for left main coronary disease: A meta-analysis.
The impact of time factor and patient characteristics on the efficacy of percutaneous coronary intervention (PCI) with drug-eluting stents vs. coronary-artery bypass grafting (CABG) for left main coronary disease is unclear. We searched PubMed and Embase for related trials. Two outcomes of interest were major adverse cardiac or cerebrovascular events (MACCE, defined as a composite of all-cause mortality, myocardial infarction, stroke, or unplanned revascularization) and a composite of all-cause mortality, myocardial infarction, or stroke. We conducted random-effects meta-analysis stratified by follow-up duration and 7 factors of interest related to patient characteristics. Random-effects meta-regression was performed to calculate P values for trend and those for subgroup differences. We included 11 articles from 5 trials. Compared with CABG, PCI increased MACCE at the end of 3-year (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.04-1.40, I2 = 0) and 5-year (HR 1.33, 95% CI 1.20-1.48, I2 = 0) follow-up, but did not increase all-cause mortality, myocardial infarction, or stroke. The logarithm of HR of PCI vs CABG for MACCE increased as follow-up duration increased (β = 0.057, P = .025). PCI vs CABG consistently increased 5-year MACCE across various subgroups defined by 7 factors of interest (Psubgroup ranged from .156 to .830). The long-term benefit of CABG vs PCI on MACCE in patients with left main coronary disease is consistent across patients with different clinical characteristics. The relative benefit of CABG on MACCE is driven by that of CABG on unplanned revascularization, and becomes greater as time goes on.


Phase transitions and dielectric properties of a hexagonal ABX3 perovskite-type organic-inorganic hybrid compound: [C3H4NS][CdBr3].
A new organic-inorganic hexagonal perovskite-type compound with the formula ABX3, thiazolium tribromocadmate(ii) (1), in which thiazolium cations are situated in the space between the one-dimensional chains of face-sharing CdBr(6) octahedra, has been successfully synthesized. Systematic characterizations including differential scanning calorimetry measurements, variable-temperature structural analyses, and dielectric measurements reveal that it undergoes two structural phase transitions, at 180 and 146 K. These phase transitions are accompanied by remarkable dielectric relaxation and anisotropy. The thiazolium cations remain orientationally disordered during the two phase transition processes. The origins of the phase transitions at 180 and 146 K are ascribed to the slowing down and reorientation of the molecular motions of the cations, respectively. Moreover, the dielectric relaxation process well described by the Cole-Cole equation and the prominent dielectric anisotropy are also connected with the dynamics of the dipolar thiazolium cations.


Survival of Schwann cells in chronically denervated skeletal muscles.
It is well established that over time Schwann cells disappear from the endoneurial space of the distal stump of a chronically transected sciatic nerve trunk. Nevertheless, the status of the Schwann cells within terminal branches of the transected sciatic nerve remains poorly understood. To elucidate this issue we examined the endoneurial space of the intramuscular nerves in rat hindlimb skeletal muscles, which had been denervated for a 25-month period. Based on specific ultrastructural characteristics, we identified a small population of viable Schwann cells within the intramuscular nerve trunks. The surviving Schwann cells continued to be immunopositive for both S-100 protein and neural cell adhesion molecule. In addition, reverse transcription-polymerase chain reaction and/or Western blot analyses have shown that at least two molecules, brain-derived neurotrophic factor and a non-catalytic truncated form of tyrosine protein kinase receptor B, which could potentially participate in the process of nerve repair, were detectable in chronically denervated skeletal muscle. Our results demonstrate that Schwann cells can survive inside the intramuscular nerve trunks of denervated skeletal muscle for a 25-month period without axonal contact.


Inhibition of factor XIII activation by an anti-peptide monoclonal antibody.
As the final enzyme in the coagulation cascade, activated fibrin stabilizing factor or factor XIII catalyzes the intermolecular cross-linking of fibrin chains. To study this enzyme in plasma, we derived a monoclonal antibody (MAb 309) against a peptide sequence (NH2-G-V-N-L-Q-E-F-C-COOH) in the thrombin activation site of factor XIII. Radioimmunoassays indicate that MAb 309 binds specifically to both platelet and plasma factor XIII. Peptide inhibition studies demonstrate that the MAb binds equally well to the factor XIII (FXIII) zymogen and the active form of FXIII (FXIIIa). In immunoblots of whole platelet lysates, MAb 309 binds only to FXIII and does not cross-react with other proteins. In saturation binding studies, the antibody shows a binding avidity of (1.75 +/- 0.35) x 10(9) M-1. MAb 309 also inhibited 99% of apparent FXIIIa activity in a standard transglutaminase assay. SDS-PAGE analysis of fibrin clots showed that MAb 309 inhibited fibrin gamma-gamma cross-linking. Moreover, MAb 309 accelerated the lysis of plasma clots, consistent with inhibition of fibrin-fibrin and fibrin-alpha 2-antiplasmin cross-linking. Immunoblotting experiments revealed that MAb 309 affected apparent FXIIIa activity by inhibiting the thrombin activation of the FXIII zymogen. In addition to its utility as a specific probe for the FXIII a-subunit, the strategy used to obtain MAb 309 may be used to generate MAbs that inhibit the activation of other coagulation factor zymogens.


Comparative genomics on SLIT1, SLIT2, and SLIT3 orthologs.
SLIT1 gene at human chromosome 10q24.1, SLIT2 gene at 4p15.31, and SLIT3 gene at 5q34-q35.1 encode large secreted proteins functioning as ligands for Roundabout (Robo) receptors. SLIT-ROBO signaling pathway is implicated in neurogenesis, angiogenesis, and immune response through the regulation of axonal guidance, endothelial cell migration, and denderitic cell migration, respectively. GREMLIN (CKTSF1B1 or GREM1) and DANTE (CKTSF1B3 or GREM3) are secreted antagonists for BMPs and SLITs. Here, comparative integromics analyses on SLIT1, SLIT2, and SLIT3 orthologs were performed by using bioinformatics. Rat Slit2 gene, consisting of 36 exons, was located within rat genome sequences AC098362.4 and AC111627.6. Mouse Slit3 complete coding sequence was determined by assembling BB634238 EST, AF144629 cDNA, and AK129223 cDNA. Leucine-rich repeats with nine conserved cysteine (LRRCC) domains and SLIT C-terminal cysteine-rich (SLITCCR) domain were identified in this study. CPxxCxCxxxxVxCxxxxLxxxPxxxPx(10~58) Nx(19,20)LxxNx(9)Fx(8)LxLxxNxxxCxxxxxFxxLxxx xxLxLxxNx(9)Fx(13)NxxxCxCxxxWLx(15)CxxPx(17)C was the consensus sequence of LRRCC domain. Mammalian SLIT1, SLIT2 and SLIT3 orthologs were large secreted proteins with four LRRCC domains, nine EGF domains, Laminin G (LamG) domain, and SLITCCR domain. SLIT1 mRNA was expressed in fetal brain, infant brain, anaplastic oligodendroglioma, and Jurkat T cells. SLIT2 and SLIT3 mRNAs were co-expressed in embryonic stem (ES) cells with embryoid body formation, and diffuse type gastric cancer with signet ring cell features. Double TCF/LEF and bHLH-binding sites were conserved among mammalian SLIT1 promoters. FOXJ2, E47, ETS1, and FOXA2-binding sites and CCAAT box were conserved among mammalian SLIT3 promoters. Mammalian SLIT1 orthologs were identified as evolutionarily conserved targets of the WNT/beta-catenin signaling pathway.


Optical Ultrastructure of Large Mammalian Hearts Recovers Discordant Alternans by In Silico Data Assimilation.
Understanding and predicting the mechanisms promoting the onset and sustainability of cardiac arrhythmias represent a primary concern in the scientific and medical communities still today. Despite the long-lasting effort in clinical and physico-mathematical research, a critical aspect to be fully characterized and unveiled is represented by spatiotemporal alternans patterns of cardiac excitation. The identification of discordant alternans and higher-order alternating rhythms by advanced data analyses as well as their prediction by reliable mathematical models represents a major avenue of research for a broad and multidisciplinary scientific community. Current limitations concern two primary aspects: 1) robust and general-purpose feature extraction techniques and 2) in silico data assimilation within reliable and predictive mathematical models. Here, we address both aspects. At first, we extend our previous works on Fourier transformation imaging (FFI), applying the technique to whole-ventricle fluorescence optical mapping. Overall, we identify complex spatial patterns of voltage alternans and characterize higher-order rhythms by a frequency-series analysis. Then, we integrate the optical ultrastructure obtained by FFI analysis within a fine-tuned electrophysiological mathematical model of the cardiac action potential. We build up a novel data assimilation procedure demonstrating its reliability in reproducing complex alternans patterns in two-dimensional computational domains. Finally, we prove that the FFI approach applied to both experimental and simulated signals recovers the same information, thus closing the loop between the experiment, data analysis, and numerical simulations.


A role for immune modulation in achieving functional cure for chronic hepatitis B among current changes in the landscape of new treatments.
Chronic hepatitis B (CHB) is rarely cured using available treatments. Barriers to cure are: 1) persistence of reservoirs of hepatitis B virus (HBV) replication and antigen production (HBV DNA); 2) high burden of viral antigens that promote T cell exhaustion with T cell dysfunction; 3) CHB-induced impairment of immune responses. We discuss options for new therapies that could address one or more of the barriers to functional cure, with particular emphasis on the potential role of immunotherapy. Ideally, a sterilizing cure for CHB would translate into finite therapies that result in loss of HBV surface antigen and eradication of HBV DNA. Restoration of a functional adaptive immune response, a key facet of successful CHB treatment, remains elusive. Numerous strategies targeting the high viral DNA and antigen burden and aiming to restore the host immune responses will enter clinical development in coming years. Most patients are likely to require combinations of several drugs, personalized according to virologic and disease characteristics, patient preference, accessibility, and affordability. The management of CHB is a global health priority. Expedited drug development requires collaborations between regulatory agencies, scientists, clinicians, and within the industry to facilitate testing of the best drug combinations.


Insertion of CS2 into a Phosphorus-Arsenic Single Bond and Investigations on Phosphane Arsanyldithiocarboxylates.
The synthesis and reactivity of sterically demanding phosphaarsanes TerR1P-AsR2 (3) is described. These species were selectively synthesized via metathesis reactions of Ter-stabilized [Ter = 2,6-bis(2,4,6-trimethylphenyl)phenyl] potassium phosphides TerR1PK (1) with the N-heterocyclic chloroarsane ClAs{N(tBu)CH2}2 (2). Conversion of the n-butyl-substituted phosphaarsane 3c with the reactive heterocumulene CS2 leads to an insertion into the P-As bond, yielding the phosphane arsanyldithiocarboxylate TerR1P-C(S)S-AsR2 (4c) as a new structural motif. Because full conversion of 3c with CS2 requires long reaction times, an alternative synthetic route is reported herein, involving the conversion of 2 with phosphane dithiocarboxylates TerR1-C(S)SK (5), enabling synthetic access to a wider range of phosphane arsanyldithiocarboxylates. These interpnictogen dithiocarboxylates show an interesting bonding situation with a significantly elongated As-S bond due to negative hyperconjugation within the molecule. All products along the reaction path were fully characterized.


Patupilone and ixabepilone: the effect of a point structural change on the exo-endo conformational profile.
The natural product patupilone (epothilone B) and its synthetic aza-analogue, ixabepilone, are effective agents against a broad range of human cancers. A detailed conformational analysis was conducted on the basis of single-point MP2 energy calculations for density functional theory (DFT) geometries at the MP2/6-31+G(d,p)//B3LYP/6-31+G(d,p) level. In a vacuum, patupilone exclusively adopts compact exo conformations due to short, near-linear hydrogen bonding between the 3-hydroxyl group and the side-chain thiazole. In contrast, ixabepilone can be described as a competitive mixture of exo and endo conformers with a large population of the above-mentioned compact exo conformations. The stability of the endo form is consistent with the cooperativity of hydrogen bonds. The relative energies of some patupilone and ixabepilone conformers were found to be sensitive to solvent effects within the integral equation formalism polarizable continuum model (IEF-PCM). This study contributes to a better understanding of the important structural features of patupilone and ixabepilone. This conformational analysis lends support to previous observations concerning their different pharmaceutical profiles.


Studying the collective motions of the adenosine A2A receptor as a result of ligand binding using principal component analysis.
Adenosine receptors (ARs) belong to family A of GPCRs that are involved in many diseases, including cerebral and cardiac ischemic diseases, immune and inflammatory disorders, etc. Thus, they represent important therapeutic targets to treat these conditions. Computational techniques such as molecular dynamics (MD) simulations permit researchers to obtain structural information about these proteins, and principal component analysis (PCA) allows for the identification of collective motions. There are available structures for the active form (3QAK) and the inactive form (3EML) of A2AR which permit us to gain insight about their activation/inactivation mechanism. In this work, we have proposed an inverse strategy using MD simulations where the active form was coupled to the antagonist caffeine and the inactive form was coupled to adenosine agonist. Moreover, we have included four reported thermostabilizing mutations in the inactive form to study A2AR structural differences under different conditions. Some observations stand out from the PCA studies. For instance, the apo structures showed remarkable similarities, and the principal components (PCs) were rearranged in a ligand-dependent manner. Additionally, the active conformation was less stable compared to the inactive one. Some PCs inverted their direction in the presence of a ligand, and comparison of the PCs between 3EML and 3EML_ADN showed that adenosine induced major changes in the structure of A2AR. Rearrangement of PCs precedes and drives conformational changes that occur after ligand binding. Knowledge about these conformational changes provides important insights about the activity of A2AR.


Reduced-port robotic total mesorectal resection for rectal cancer using a single-port access: a technical note.
Single-port laparoscopic surgery has some advantages, including improved cosmetic outcomes and minimized parietal trauma. However, pure single-port laparoscopic rectal cancer surgery is challenging because of the difficulties in creating triangulation and applying the laparoscopic staplers with sufficient distal margins in the narrow pelvic cavity. Recently, a reduced-port robotic operation with a robotic single-port access plus one wristed robotic arm for colon cancer was introduced to overcome the limitations of single-port laparoscopic rectal surgery. Single-port laparoscopic surgery has some advantages, including improved cosmetic outcomes and minimized parietal trauma. However, the pure single-port laparoscopic rectal cancer operation is challenging. Recently, a reduced-port robotic operation with a robotic single-port access plus one wristed robotic arm for colon cancer was introduced to overcome the limitations of single-port laparoscopic rectal surgery. We performed a single-port plus an additional port robotic operation using a robotic single-port access through the umbilical incision, and the wristed robotic instruments were inserted through an additional robotic port in the right lower quadrant. The total operative and docking times were 310 min and 25 min, respectively. The total number of lymph nodes harvested was 12, and the proximal and distal resection margins were 11.1 and 2 cm, respectively. The patient was discharged on postoperative day 12 uneventfully. Based on a representative case, reduced-port robotic total mesorectal excision for rectal cancer using the single-port access appears to be feasible and safe. This approach could overcome the limitations of single-port laparoscopic rectal surgery.


CD8+ T cell exhaustion, suppressed gamma interferon production, and delayed memory response induced by chronic Brucella melitensis infection.
Brucella melitensis is a well-adapted zoonotic pathogen considered a scourge of mankind since recorded history. In some cases, initial infection leads to chronic and reactivating brucellosis, incurring significant morbidity and economic loss. The mechanism by which B. melitensis subverts adaptive immunological memory is poorly understood. Previous work has shown that Brucella-specific CD8(+) T cells express gamma interferon (IFN-γ) and can transition to long-lived memory cells but are not polyfunctional. In this study, chronic infection of mice with B. melitensis led to CD8(+) T cell exhaustion, manifested by programmed cell death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) expression and a lack of IFN-γ production. The B. melitensis-specific CD8(+) T cells that produced IFN-γ expressed less IFN-γ per cell than did CD8(+) cells from uninfected mice. Both memory precursor (CD8(+) LFA1(HI) CD127(HI) KLRG1(LO)) and long-lived memory (CD8(+) CD27(HI) CD127(HI) KLRG1(LO)) cells were identified during chronic infection. Interestingly, after adoptive transfer, mice receiving cells from chronically infected animals were able to contain infection more rapidly than recipients of cells from acutely infected or uninfected donors, although the proportions of exhausted CD8(+) T cells increased after adoptive transfer in both challenged and unchallenged recipients. CD8(+) T cells of challenged recipients initially retained the stunted IFN-γ production found prior to transfer, and cells from acutely infected mice were never seen to transition to either memory subset at all time points tested, up to 30 days post-primary infection, suggesting a delay in the generation of memory. Here we have identified defects in Brucella-responsive CD8(+) T cells that allow chronic persistence of infection.


Effects of land use on arbuscular mycorrhizal fungal communities in Estonia.
Arbuscular mycorrhizal (AM) fungal communities vary across habitat types, as well as across different land use types. Most relevant research, however, has focused on agricultural or other severely human-impacted ecosystems. Here, we compared AM fungal communities across six habitat types: calcareous grassland, overgrown ungrazed calcareous grassland, wooded meadow, farmyard lawn, boreonemoral forest, and boreonemoral forest clear-cut, exhibiting contrasting modes of land use. AM fungi in the roots of a single host plant species, Prunella vulgaris, and in its rhizosphere soil were identified using 454-sequencing from a total of 103 samples from 12 sites in Estonia. Mean AM fungal taxon richness per sample did not differ among habitats. AM fungal community composition, however, was significantly different among habitat types. Both abandonment and land use intensification (clearcutting; trampling combined with frequent mowing) changed AM fungal community composition. The AM fungal communities in different habitat types were most similar in the roots of the single host plant species and most distinct in soil samples, suggesting a non-random pattern in host-fungal taxon interactions. The results show that AM fungal taxon composition is driven by habitat type and land use intensity, while the plant host may act as an additional filter between the available and realized AM fungal species pool.


Genome sequencing reveals evidence of adaptive variation in the genus Zea.
Maize is a globally valuable commodity and one of the most extensively studied genetic model organisms. However, we know surprisingly little about the extent and potential utility of the genetic variation found in wild relatives of maize. Here, we characterize a high-density genomic variation map from 744 genomes encompassing maize and all wild taxa of the genus Zea, identifying over 70 million single-nucleotide polymorphisms. The variation map reveals evidence of selection within taxa displaying novel adaptations. We focus on adaptive alleles in highland teosinte and temperate maize, highlighting the key role of flowering-time-related pathways in their adaptation. To show the utility of variants in these data, we generate mutant alleles for two flowering-time candidate genes. This work provides an extensive sampling of the genetic diversity of Zea, resolving questions on evolution and identifying adaptive variants for direct use in modern breeding.


When psychologists take a stand: Barriers to trauma response services and advocacy for American Indian communities.
American Indians and other Indigenous groups face numerous traumas resulting from civil rights infractions. Often, these infractions began in historical contexts and continue into modern experiences. The Dakota Access Pipeline (DAPL) and subsequent activist response at Standing Rock are a prime example of how movements asserting human rights are met with resistance from dominant majority groups. Generally, this resistance turns violent as police and security responses from the dominant culture escalate despite the peaceful nature of demonstrations. This impacts mental health among oppressed populations. As #NoDAPL progressed, Indigenous psychologists felt moved to "Stand with Standing Rock" by supporting Water Protectors in need of trauma services. This was met with institutional and systemic barriers to treatment and lack of support from key professional organizations. This article addresses barriers faced by mental health professionals providing services on the frontlines and lists potential resolutions including the development of a crisis response team, infrastructure for communication with individuals onsite, culturally congruent healing, community-building, and prayer. The article serves as a case study for trauma provision among American Indian communities in crisis and is a reminder of the resilience and empowerment that occurs when Indigenous peoples from all over the world come together for a shared cause. This case study format can be a guiding example for service providers choosing to take a stand with marginalized communities asserting social change.


The Nature-Inspired Metaheuristic Method for Predicting the Creep Strain of Green Concrete Containing Ground Granulated Blast Furnace Slag.
The aim of this study was to develop a nature-inspired metaheuristic method to predict the creep strain of green concrete containing ground granulated blast furnace slag (GGBFS) using an artificial neural network (ANN)model. The firefly algorithm (FA) was used to optimize the weights in the ANN. For this purpose, the cement content, GGBFS content, water-to-binder ratio, fine aggregate content, coarse aggregate content, slump, the compaction factor of concrete and the age after loading were used as the input parameters, and in turn, the creep strain (εcr) of the GGBFS concrete was considered as the output parameters. To evaluate the accuracy of the FA-ANN model, it was compared with the well-known genetic algorithm (GA), imperialist competitive algorithm (ICA) and particle swarm optimization (PSO). Results indicated that the ANNs model, in which the weights were optimized by the FA, were more capable, flexible and precise than other optimization algorithms in predicting the εcr of GGBFS concrete.


Long-term Clinical Outcome of Antibody Replacement Therapy in Humoral Immunodeficient Adults With Respiratory Tract Infections.
In severe humoral immunodeficiency the indication for antibody replacement therapy (ART) is clear, and supported by several large studies. However, for milder forms of humoral immunodeficiency, the indication for ART is less clear. This is a retrospective cohort study of 87 adults with recurrent respiratory tract infections who received ART. The patients had severe or mild humoral immunodeficiency, and were followed up for a median of 62months. Infection frequency, pharmacy-registered antibiotics use and hospital admissions significantly decreased under ART compared to the year prior to starting ART (median 5.50 (anamnestically)-0.82 (physician-confirmed) infections/year, p<0.001; median 4.00-2.05antibioticscourses/year, p<0.001; mean 0.75-0.44hospitaladmissions/year, p=0.009). These beneficial effects of ART were seen in both severe and mild immunodeficiency. Bronchiectasis was present in 27 patients when ART was started, but was not associated with clinical outcomes. An increase in hospital admissions under ART, observed in some patients, was significantly associated with pulmonary emphysema and current smoking. In conclusion, this study shows that ART is a long-term effective therapy in adults with recurrent respiratory tract infections with severe as well as with milder forms of humoral immunodeficiency.


Renal clearance and daily excretion of cortisol and adrenal androgens in patients with rheumatoid arthritis and systemic lupus erythematosus.
In rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), patients demonstrate low levels of adrenal hormones. To investigate whether increased renal clearance and daily excretion contribute to this phenomenon. Thirty patients with RA, 32 with SLE, and 54 healthy subjects (HS) participated. Serum and urinary levels of cortisol, cortisone, 17-hydroxyprogesterone (17OHP), androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulphate (DHEAS) were measured. Clearance of DHEAS and DHEA was lower in patients than in HS, and clearance of androstenedione was somewhat higher in patients than in HS, but daily excretion of this latter hormone was low. Clearance of cortisol, cortisone, and 17OHP was similar between the groups. The total molar amount per hour of excreted DHEA, DHEAS, and androstenedione was lower in patients than HS (but similar for cortisol). Serum DHEAS levels correlated with urinary DHEAS levels in HS and patients, whereby HS excreted 5-10 times more of this hormone than excreted by patients. Low serum levels of adrenal androgens and cortisol in patients as compared with HS were confirmed, and proteinuria was not associated with changes of measured renal parameters. This study in patients with RA and SLE demonstrates that low serum levels of adrenal androgens and cortisol are not due to increased renal clearance and daily loss of these hormones. Decreased adrenal production or increased conversion or conjugation to downstream hormones are the most likely causes of inadequately low serum levels of adrenal hormones in RA and SLE.


Snake venom toxin from Vipera lebetina turanica induces apoptosis of colon cancer cells via upregulation of ROS- and JNK-mediated death receptor expression.
Abundant research suggested that the cancer cells avoid destruction by the immune system through down-regulation or mutation of death receptors. Therefore, it is very important that finding the agents that increase the death receptors of cancer cells. In this study, we demonstrated that the snake venom toxin from Vipera lebetina turanica induce the apoptosis of colon cancer cells through reactive oxygen species (ROS) and c-Jun N-terminal kinases (JNK) dependent death receptor (DR4 and DR5) expression. We used cell viability assays, DAPI/TUNEL assays, as well as western blot for detection of apoptosis related proteins and DRs to demonstrate that snake venom toxin-induced apoptosis is DR4 and DR5 dependent. We carried out transient siRNA knockdowns of DR4 and DR5 in colon cancer cells. We showed that snake venom toxin inhibited growth of colon cancer cells through induction of apoptosis. We also showed that the expression of DR4 and DR5 was increased by treatment of snake venom toxin. Moreover, knockdown of DR4 or DR5 reversed the effect of snake venom toxin. Snake venom toxin also induced JNK phosphorylation and ROS generation, however, pretreatment of JNK inhibitor and ROS scavenger reversed the inhibitory effect of snake venom toxin on cancer cell proliferation, and reduced the snake venom toxin-induced upregulation of DR4 and DR5 expression. Our results indicated that snake venom toxin could inhibit human colon cancer cell growth, and these effects may be related to ROS and JNK mediated activation of death receptor (DR4 and DR5) signals.


Temporomandibular joint disorder in systemic sclerosis: a case report.
Systemic sclerosis have several effects on the orofacial region such as widening of the periodontal ligament space, xerostomia and bone resorption of the mandible. We report a case of systemic sclerosis with temporomandibular joint involvement in a 45-year-old female patient accompanied by severe limited mouth opening and pain in the right and left preauricular regions and tenderness in masseter muscles with a morning stiffness of jaws.Magnetic resonance imaging showed a resorption of mandibular condylar process, with disk and joint abnormalities.


Porous-surfaced dental implants in the partially edentulous maxilla: assessment for subclinical mobility.
Fifty patients received 151 short, porous-surfaced implants in the partially edentulous maxilla. Periotest values (PTV) were recorded at baseline and after 6 months and 1 and 2 years. For this, prostheses were removed and a standard abutment attached and tightened (20-Ncm force) to each implant. Data analysis indicated significant relationships between time in function vs PTV and implant diameter (3.5, 4.1, or 5.0 mm) vs PTV There was no relationship between PTV and implant length. PTVs were more favorable in the posterior than anterior maxilla, and better PTVs were obtained with nonsplinted as opposed to splinted implants.


Effective treatment with chemotherapy and surgery for advanced small cell carcinoma of the esophagus.
A 78-year-old man reported a persistent midthoracic pain, mild dysphagia, and an abdominal distention. An abdominal computed tomography scan showed massive ascites, extensive paracardial mass, a large mass which invaded the pancreas, and a mass of multiple para-aortic lymphadenopathies which involved the superior mesenteric artery. An upper gastrointestinal endoscopic study revealed an infiltrative, ulcerating tumor of the lower esophagus. Histological study of the biopsy specimens from esophageal tumor showed small cell carcinoma. After combination chemotherapy, an abdominal computed tomography scan showed a disappearance of asites, a partial response reduction of paragastric mass, peripancreatic mass and para-aortic lymphadenopathies. Histological study of the biopsy specimens from esophageal tumor showed a viable small cell carcinoma. In June 2001, the patient underwent lower esophagectomy and proximal gastrectomy combined with splenectomy and distal pancreatectomy through an abdominal approach. Histological findings of the resected specimen showed that the esophageal tumor was a small cell carcinoma which invaded into the submucosal layer, and both paracardial and peripancreatic tumors, and all lymph nodes had no cancer cells. The patient's postoperative recovery was uneventful and discharged without aggressive chemotherapy postoperatively. However, he eventually died of progression of the metastasis 21 months after first detection of the carcinoma. Patients with esophageal small cell carcinoma treated with surgery following chemotherapy and/or radiotherapy have been reported to survive longer than those treated with chemotherapy and/or radiotherapy. Therefore, surgical resection may be recommended as the second therapy that occasionally produces long-term remission and possibly long-term survival for patients with small cell carcinoma of the esophagus.


The tumour suppressing role of the circadian clock.
The circadian clock and the ~24 h rhythms it generates are essential in maintaining regular tissue functioning. At the molecular level, the circadian clock comprises a core set of rhythmically expressed genes and gene products that are able to drive rhythmic expression of other genes to generate overt circadian rhythms. It has recently come to light that perturbations of circadian rhythms contribute to the development of pathological states such as cancer, and altered expression and/or regulation of circadian clock genes has been identified in multiple tumour types. This review summarises the important role the circadian system plays in regulating cellular processes, including the cell cycle, apoptosis, DNA repair, the epithelial-to-mesenchymal transition, metabolism and immunity and how its dysregulation has widespread implications and could be a critical player in the development of cancer. Understanding its role in cancer development is important for the field chronotherapy, where the timing of chemotherapy administration is optimised based on differences in circadian clock functioning in normal and cancer cells. This has been found to influence the patient response, minimising the side effects commonly associated with chemotherapy. © 2019 IUBMB Life, 2019.


[Educational trajectories of the endocrinological service: the results of a survey].
Given the socio-economic, political and epidemiological changes in the regions of the Russian Federation, the issue of modernizing the training of medical personnel and planning to provide medical organizations with qualified specialists has remained extremely important for several years. The analysis of the survey showed that at present the highly topical issue of staffing the population with endocrinologists and pediatric endocrinologists does not have an unambiguous effective solution. The above measures to reorganize the educational environment require additional revision and correction for the most effective work in the field of medical education. Ultimately, these activities will have an impact on improving the level of training of specialists, improving the personnel situation in the constituent entities of the Russian Federation and improving the quality of medical care for the population of the country.


Cetuximab reduces the accumulation of radiolabeled bevacizumab in cancer xenografts without decreasing VEGF expression.
Bevacizumab and cetuximab are approved for the treatment of cancer. However, in advanced colorectal cancer, addition of cetuximab to chemotherapy with bevacizumab did not improve survival. The reason for the lack of activity remains unclear. The aim of this study was to determine the effect of cetuximab on VEGF expression and targeting of bevacizumab to the tumor. Mice with subcutaneous SUM149 or WiDr xenografts were treated with cetuximab, bevacizumab, or a combination of the two. Before the start of cetuximab treatment and after 7 and 21 days of treatment, the uptake of radiolabeled bevacizumab in the tumor was measured by immunoSPECT/CT. Tumor growth of SUM149 xenografts was significantly inhibited by cetuximab, bevacizumab, or their combination, whereas growth of WiDr xenografts was not affected. Cetuximab caused a significant reduction of bevacizumab uptake in SUM149 xenografts, whereas tumor-to-blood ratios in mice with WiDr xenografts did not change. Biodistribution studies with an irrelevant antibody in the SUM149 model also showed significantly reduced tumor-to-blood ratios. Cetuximab treatment did not decrease VEGF expression. Without decreasing VEGF levels, cetuximab reduces tumor targeting of bevacizumab. This could, at least partly, explain why the combination of bevacizumab and cetuximab does not result in improved therapeutic efficacy.


Experimental Study on the Fracture Toughness of Bamboo Scrimber.
In the past decade, bamboo scrimber has developed rapidly in the field of building materials due to its excellent mechanical properties, such as high toughness and high tensile strength. However, when the applied stress exceeds the ultimate strength limit of bamboo scrimber, cracks occur, which affects the performance of bamboo scrimber in structural applications. Due to the propensity of cracks to propagate, it reduces the load-bearing capacity of the bamboo scrimber material. Therefore, research on the fracture toughness of bamboo scrimber contributes to determining the material's load-bearing capacity and failure mechanisms, enabling its widespread application in engineering failure analysis. The fracture toughness of bamboo scrimber was studied via the single-edge notched beam (SENB) experiment and compact compression (CC) method. Nine groups of longitudinal and transverse samples were selected for experimental investigation. The fracture toughness of longitudinal bamboo scrimber under tensile and compressive loadings was 3.59 MPa·m1/2 and 2.39 MPa·m1/2, respectively. In addition, the fracture toughness of transverse bamboo scrimber under tensile and compressive conditions was 0.38 MPa·m1/2 and 1.79 MPa·m1/2, respectively. The results show that, for this material, there was a significant distinction between longitudinal and transverse. Subsequently, three-point bending tests and simulations were studied. The results show that the failure mode and the force-displacement curve of the numerical simulation were highly consistent compared with the experimental results. It could verify the correctness of the test parameters. Finally, the flexural strength of bamboo scrimber was calculated to be as high as 143.16 MPa. This paper provides data accumulation for the numerical simulation of bamboo scrimber, which can further promote the development of bamboo scrimber parameters in all aspects of the application.


High resolution propagation-based imaging system for in vivo dynamic computed tomography of lungs in small animals.
We have developed an x-ray imaging system for in vivo four-dimensional computed tomography (4DCT) of small animals for pre-clinical lung investigations. Our customized laboratory facility is capable of high resolution in vivo imaging at high frame rates. Characterization using phantoms demonstrate a spatial resolution of slightly below 50 μm at imaging rates of 30 Hz, and the ability to quantify material density differences of at least 3%. We benchmark our system against existing small animal pre-clinical CT scanners using a quality factor that combines spatial resolution, image noise, dose and scan time. In vivo 4DCT images obtained on our system demonstrate resolution of important features such as blood vessels and small airways, of which the smallest discernible were measured as 55-60 μm in cross section. Quantitative analysis of the images demonstrate regional differences in ventilation between injured and healthy lungs.


[Dangerous dogs in Berlin in comparison to the dog population--ways to reduce the dangerousness of dogs].
The law for handling and control of dogs in Berlin of September 29, 2004 was enacted to prevent the risks for humans and animals when ever they have contact with dogs. "Dangerous dogs" are defined by this law. There are 10 breeds of dogs supposed to be dangerous due to specific characteristics of their breed ("listed breeds"). The dangerousness of a dog's breed is not identical with the dangerousness of an individual dog. The subject of this study is to examine the potential dangerousness of dog breeds and not the individual dangerousness of a dog. This study refers to statistics of incidents between dogs and humans in Berlin for the years 1998 to 2004. The population density of a breed is based on the dogs assessed for tax purposes in Berlin of January 1, 2005 and on the dog registrations maintained at veterinary hospitals. The fourfold-table-test was used to compare the quantity of the recorded incidents of two statistically independent dog breeds. Of the total population of 107,804 tax assessed dogs in Berlin in 2004, 0.9% was documented as dogs involved in incidents with humans. The incidents per year decreased in the "listed breeds"about 68% and in the "unlisted breeds" about 41% during the last 7 years in Berlin. Therefore, the probability (the odds ratio) of a breed to be conspicuous was analysed. The values for the calculation of this probability were the number of dogs of a breed having been involved in incidents compared to the population of this breed based on tax records. The comparison of the probability of a breed with another to be conspicuous was used to compile a cluster of breeds which had the same probability to be conspicuous in 2004. A cluster was assessed for dogs of the following breeds: Sheep dogs, Rottweiler, Doberman, Pitbull Terrier and American Staffordshire Terrier. A listing of breeds is not the right way to reduce the potential dangerousness of a dog, especially in the private domain of their owners. Most incidents with dogs occur in the private domain which normally is not recorded in the statistics of incidents. Therefore, it is more effective to support activities which include the training of abilities of the dog owners. Training by experts can enable dog owners to avoid conflict situations with their dog, or in case of conflict, to take appropriate actions.


Hydrocytium expands the phylogenetic, morphological, and genomic diversity of the poorly known green algal order Chaetopeltidales.
Chaetopeltidales is a small, understudied order of the green algal class Chlorophyceae, that is slowly expanding with the occasional discoveries of novel algae. Here we demonstrate that hitherto unrecognized chaetopeltidaleans also exist among previously described but neglected and misclassified species. Strain SAG 40.91 of Characium acuminatum, shown by previous preliminary evidence to have affinities with the orders Oedogoniales, Chaetophorales, and Chaetopeltidales (together constituting the OCC clade), was investigated with light and electron microscopy to characterize its morphology and ultrastructure. Sequence assemblies of the organellar and nuclear genomes were obtained and utilized in bioinformatic and phylogenetic analyses to address the phylogenetic position of the alga and its salient genomic features. The characterization of strain SAG 40.91 and a critical literature review led us to reinstate the forgotten genus Hydrocytium A.Braun 1855, with SAG 40.91 representing its type species, Hydrocytium acuminatum. Independent molecular markers converged on placing H. acuminatum as a deeply diverged lineage of the order Chaetopeltidales, formalized as the new family Hydrocytiaceae. Both chloroplast and mitochondrial genomes shared characteristics with other members of Chaetopeltidales and were bloated by repetitive sequences. Notably, the mitochondrial cox2a gene was transferred into the nuclear genome in the H. acuminatum lineage, independently of the same event in Volvocales. The nuclear genome data from H. acuminatum and from another chaetopeltidalean that was reported by others revealed endogenized viral sequences corresponding to novel members of the phylum Nucleocytoviricota. The resurrected genus Hydrocytium expands the known diversity of chaetopeltidalean algae and provides the first glimpse into their virosphere.


The effect of torsional shoe sole stiffness on knee moment and gross efficiency in cycling.
Altering torsional stiffness of cycling shoe soles may be a novel approach to reducing knee joint moments and overuse injuries during cycling. We set out to determine if the magnitude of three-dimensional knee moments were different between cycling shoe soles with different torsional stiffnesses. Eight trained male cyclists cycled at 90% lactate threshold power output in one of two cycling shoe conditions in a randomized crossover design. The shoe sole was considered torsionally flexible (FLEX) compared to a relatively stiffer (STIFF) sole. Gross efficiency (GE) and knee joint moments were quantified. No significant effect of shoe condition was seen in GE (21.4 ± 1.1% and 20.9 ± 1.6% for FLEX and STIFF, respectively, P = 0.12), nor in three-dimensional knee moments. 4 of the 8 subjects had reduced knee moments in at least 2 of the 3 moment directions. These "responders" were significantly shorter (1.73 ± 0.02 m vs 1.81 ± 0.04 m, P = 0.017) and had a higher relative maximal aerobic power (MAP) (4.6 ± 0.3 W∙kg-1 vs 3.9 ± 0.3 W∙kg-1, P = 0.024) compared to non-responders. These results suggest that certain shoe characteristics may influence certain individuals differently because these participants belong to different "functional groups"; certain individuals may respond positively to FLEX, while others may not. Further studies should test this proposed hypothesis.


Fatigue Threshold R-Curves for Dental Lithium Disilicate Glass-Ceramics.
Chemical and mechanical fatigue degradation in ceramic materials is generally inconspicuous yet ubiquitous, to the effect that clinical fractures still consist of the main cause of failure in all-ceramic restorations. Implications of this span wide, from a reduced survival prognosis for the affected teeth, including more frequent and increasingly invasive procedural interventions, to the financial burden borne by individuals and health care systems. To suffice as an effective corrective, restoration lifetimes need only to be extended so to outlive the patient. That opens a box of problems from a materials science standpoint, entailing inherent deficiencies of brittle materials to resist mechanical and environmental challenges. Efforts in developing more damage-tolerant and fatigue-resistant restoratives go thus hand in hand with understanding intrinsic mechanisms of crack growth behavior under conditions that simulate the oral environment. Here we developed experiments using size-relevant sharp precracked specimens with controlled size and geometry (truncated semielliptical crack in the surface-crack-in-biaxial-flexure method) to establish a relationship between crack size and strength. The tangent method was used to construct envelopes for the quasi-static resistance curves (R-curves), which served as template for deriving residual cyclic R-curve analogs. By means of experimentally obtained stress-cycle curves, lifetime and fatigue parameters were employed within a mechanistic framework to reveal constitutive toughening mechanisms during subcritical growth under cyclic loading in a wet environment. Using 3 modern dental lithium disilicate glass-ceramics, we demonstrate the extent of R-curve degradation up to a threshold of 10 million cycles (~30 y in service) and draw parallels between the scope of fatigue degradation and the size of the microstructural units responsible for toughening mechanisms in glass-ceramic materials. Our results indicate that larger microstructural elements endow glass-ceramics with a higher reaching quasi-static R-curve at the onset but degrading more rapidly to comparable levels of lithium disilicates having submicrometric and nanometric crystal phases.


Single-molecule FRET observes opposing effects of urea and TMAO on structurally similar meso- and thermophilic riboswitch RNAs.
Bacteria live in a broad range of environmental temperatures that require adaptations of their RNA sequences to maintain function. Riboswitches are regulatory RNAs that change conformation upon typically binding metabolite ligands to control bacterial gene expression. The paradigmatic small class-I preQ1 riboswitches from the mesophile Bacillus subtilis (Bsu) and the thermophile Thermoanaerobacter tengcongensis (Tte) adopt similar pseudoknot structures when bound to preQ1. Here, we use UV-melting analysis combined with single-molecule detected chemical denaturation by urea to compare the thermodynamic and kinetic folding properties of the two riboswitches, and the urea-countering effects of trimethylamine N-oxide (TMAO). Our results show that, first, the Tte riboswitch is more thermotolerant than the Bsu riboswitch, despite only subtle sequence differences. Second, using single-molecule FRET, we find that urea destabilizes the folded pseudoknot structure of both riboswitches, yet has a lower impact on the unfolding kinetics of the thermodynamically less stable Bsu riboswitch. Third, our analysis shows that TMAO counteracts urea denaturation and promotes folding of both the riboswitches, albeit with a smaller effect on the more stable Tte riboswitch. Together, these findings elucidate how subtle sequence adaptations in a thermophilic bacterium can stabilize a common RNA structure when a new ecological niche is conquered.


Non-reciprocal robotic metamaterials.
Non-reciprocal transmission of motion is potentially highly beneficial to a wide range of applications, ranging from wave guiding to shock and vibration damping and energy harvesting. To date, large levels of non-reciprocity have been realized using broken spatial or temporal symmetries, yet mostly in the vicinity of resonances, bandgaps or using nonlinearities, thereby non-reciprocal transmission remains limited to narrow ranges of frequencies or input magnitudes and sensitive to attenuation. Here, we create a robotic mechanical metamaterials wherein we use local control loops to break reciprocity at the level of the interactions between the unit cells. We show theoretically and experimentally that first-of-their-kind spatially asymmetric standing waves at all frequencies and unidirectionally amplified propagating waves emerge. These findings realize the mechanical analogue of the non-Hermitian skin effect. They significantly advance the field of active metamaterials for non hermitian physics and open avenues to channel mechanical energy in unprecedented ways.


Is simultaneous hamstring lengthening necessary when performing distal femoral extension osteotomy and patellar tendon advancement?
Crouch gait is common in individuals with cerebral palsy. Recently published data has shown that distal femoral extension osteotomy with patellar tendon advancement (DFEO/PTA) is an effective procedure to correct crouch gait in the presence of a knee flexion contracture and quadriceps insufficiency. Short length and slow lengthening rate (velocity) of the hamstrings are indications for hamstrings surgery. We empirically believed that hamstrings surgery would not be necessary to improve hamstring function when DFEO/PTA are performed. This hypothesis was examined in a retrospective review of hamstrings length and velocity before and after DFEO/PTA. 51 limbs in 32 individuals with a diagnosis of CP who underwent DFEO/PTA without concomitant hamstring surgery were included in the study. Pre and post-operative peak medial hamstring length and velocity z-scores were calculated using a musculoskeletal model. A subset of limbs with pre-operative values above or below two SD from the control mean emerged and were called long or short respectively. Members of this subset would often be considered candidates for hamstrings surgery. Categorical length outcomes were derived, with analogous categories for velocity. The mean peak hamstring length z-score improved pre- to post-operatively from -2.2 to -0.76 (p<0.001). The mean peak velocity z-score improved from -3.1 to -1.5 (p<0.001) [Figure 1]. DFEO/PTA surgery without concomitant hamstrings surgery led to significantly longer or faster hamstrings. Specifically, we saw 94% good or neutral results for length correction and 80% good or neutral results for velocity correction. Because crouch improved without posterior pelvic tilting, and because both hamstring length and velocity increased substantially, we conclude that concomitant hamstring surgery is rarely needed when performing DFEO/PTA.


CoMiniGut-a small volume in vitro colon model for the screening of gut microbial fermentation processes.
Driven by the growing recognition of the influence of the gut microbiota (GM) on human health and disease, there is a rapidly increasing interest in understanding how dietary components, pharmaceuticals and pre- and probiotics influence GM. In vitro colon models represent an attractive tool for this purpose. With the dual objective of facilitating the investigation of rare and expensive compounds, as well as an increased throughput, we have developed a prototype in vitro parallel gut microbial fermentation screening tool with a working volume of only 5 ml consisting of five parallel reactor units that can be expanded with multiples of five to increase throughput. This allows e.g., the investigation of interpersonal variations in gut microbial dynamics and the acquisition of larger data sets with enhanced statistical inference. The functionality of the in vitro colon model, Copenhagen MiniGut (CoMiniGut) was first demonstrated in experiments with two common prebiotics using the oligosaccharide inulin and the disaccharide lactulose at 1% (w/v). We then investigated fermentation of the scarce and expensive human milk oligosaccharides (HMOs) 3-Fucosyllactose, 3-Sialyllactose, 6-Sialyllactose and the more common Fructooligosaccharide in fermentations with infant gut microbial communities. Investigations of microbial community composition dynamics in the CoMiniGut reactors by MiSeq-based 16S rRNA gene amplicon high throughput sequencing showed excellent experimental reproducibility and allowed us to extract significant differences in gut microbial composition after 24 h of fermentation for all investigated substrates and fecal donors. Furthermore, short chain fatty acids (SCFAs) were quantified for all treatments and donors. Fermentations with inulin and lactulose showed that inulin leads to a microbiota dominated by obligate anaerobes, with high relative abundance of Bacteroidetes, while the more easily fermented lactulose leads to higher relative abundance of Proteobacteria. The subsequent study on the influence of HMOs on two infant GM communities, revealed the strongest bifidogenic effect for 3'SL for both infants. Inter-individual differences of infant GM, especially with regards to the occurrence of Bacteroidetes and differences in bifidobacterial species composition, correlated with varying degrees of HMO utilization foremost of 6'SL and 3'FL, indicating species and strain related differences in HMO utilization which was also reflected in SCFAs concentrations, with 3'SL and 6'SL resulting in significantly higher butyrate production compared to 3'FL. In conclusion, the increased throughput of CoMiniGut strengthens experimental conclusions through elimination of statistical interferences originating from low number of repetitions. Its small working volume moreover allows the investigation of rare and expensive bioactives.


Ontological turns, turnoffs and roundabouts.
There has been much talk of an 'ontological turn' in Science and Technology Studies. This commentary explores some recent work on multiple and historical ontologies, especially articles published in this journal, against a background of constructivism. It can be tempting to read an ontological turn as based and promoting a version of perspectivism, but that is inadequate to the scholarly work and opens multiple ontologies to serious criticisms. Instead, we should read our ontological turn or turns as being about multiplicities of practices and the ways in which these practices shape the material world. Ontologies arise out of practices through which people engage with things; the practices are fundamental and the ontologies derivative. The purchase in this move comes from the elucidating power of the verbs that scholars use to analyze relations of practices and objects--which turn out to be specific cases of constructivist verbs. The difference between this ontological turn and constructivist work in Science and Technology Studies appears to be a matter of emphases found useful for different purposes.


Evidence-informed capacity building for setting health priorities in low- and middle-income countries: A framework and recommendations for further research.
Priority-setting in health is risky and challenging, particularly in resource-constrained settings. It is not simply a narrow technical exercise, and involves the mobilisation of a wide range of capacities among stakeholders - not only the technical capacity to "do" research in economic evaluations. Using the Individuals, Nodes, Networks and Environment (INNE) framework, we identify those stakeholders, whose capacity needs will vary along the evidence-to-policy continuum. Policymakers and healthcare managers require the capacity to commission and use relevant evidence (including evidence of clinical and cost-effectiveness, and of social values); academics need to understand and respond to decision-makers' needs to produce relevant research. The health system at all levels will need institutional capacity building to incentivise routine generation and use of evidence. Knowledge brokers, including priority-setting agencies (such as England's National Institute for Health and Care Excellence, and Health Interventions and Technology Assessment Program, Thailand) and the media can play an important role in facilitating engagement and knowledge transfer between the various actors. Especially at the outset but at every step, it is critical that patients and the public understand that trade-offs are inherent in priority-setting, and careful efforts should be made to engage them, and to hear their views throughout the process. There is thus no single approach to capacity building; rather a spectrum of activities that recognises the roles and skills of all stakeholders. A range of methods, including formal and informal training, networking and engagement, and support through collaboration on projects, should be flexibly employed (and tailored to specific needs of each country) to support institutionalisation of evidence-informed priority-setting. Finally, capacity building should be a two-way process; those who build capacity should also attend to their own capacity development in order to sustain and improve impact.


The Information Available to a Moving Observer on Shape with Unknown, Isotropic BRDFs.
Psychophysical studies show motion cues inform about shape even with unknown reflectance. Recent works in computer vision have considered shape recovery for an object of unknown BRDF using light source or object motions. This paper proposes a theory that addresses the remaining problem of determining shape from the (small or differential) motion of the camera, for unknown isotropic BRDFs. Our theory derives a differential stereo relation that relates camera motion to surface depth, which generalizes traditional Lambertian assumptions. Under orthographic projection, we show differential stereo may not determine shape for general BRDFs, but suffices to yield an invariant for several restricted (still unknown) BRDFs exhibited by common materials. For the perspective case, we show that differential stereo yields the surface depth for unknown isotropic BRDF and unknown directional lighting, while additional constraints are obtained with restrictions on the BRDF or lighting. The limits imposed by our theory are intrinsic to the shape recovery problem and independent of choice of reconstruction method. We also illustrate trends shared by theories on shape from differential motion of light source, object or camera, to relate the hardness of surface reconstruction to the complexity of imaging setup.


Isotropic-nematic spinodal decomposition kinetics.
The initial stage of isotropic-nematic spinodal demixing kinetics of suspensions of very long and thin, stiff, repulsive rods is analyzed on the basis of the N-particle Smoluchowski equation. Equations of motion for the reduced probability density function of the position and orientation of a rod are expanded up to second order in spatial gradients and leading order in orientational order parameter. The resulting equation of motion is solved analytically, from which the temporal evolution of light-scattering patterns are calculated. It is shown that inhomogeneities in number density are enslaved by the temporal development of inhomogeneities in orientational order. Furthermore, demixing due to rotational diffusion is shown to be much faster as compared to translational diffusion. This results in an instable mode that is rotational, for which the corresponding eigenvector remains finite at zero wave vector. The scattered intensity nevertheless exhibits a maximum at a finite wave vector due to the wave-vector dependence of time-exponential prefactors. The wave vector where the intensity exhibits a maximum is therefore predicted to be a function of time even during the initial stage of demixing.


Identifying the Incidence, Predictors, Outcomes, and Prevention of Stent Thrombosis (ST) in Post-percutaneous Coronary Revascularization Patients With Drug-Eluting Stents (DES): A Systematic Review.
Stent thrombosis (ST) is a rare but catastrophic event to happen to a stented coronary artery. The incidence of ST has greatly been reduced after the advent of modern drug-eluting stent (DES) implants, which have become the most preferred treatment option in the stenting category for coronary artery disease (CAD). Although the risk reduction by newer category implant provides substantial benefits, the possibility of thrombosis still exists mostly during the early stage of DES implantation. The development of ST after percutaneous coronary intervention (PCI) can be predicted by multiple factors, but advancements in early diagnostic techniques and modified stent types have greatly reduced the occurrence of this complication. Mortality, which is one of the complications of ST, is primarily influenced by patient-related factors such as incomplete treatment duration of dual antiplatelet therapy (DAPT). The duration of DAPT after DES implantation in patients with acute coronary syndrome (ACS) is determined based on individual characteristics, mainly considered in view of bleeding or ischemia risk. Risk evaluation systems like DAPT/precise-DAPT scores help tailor and personalize the duration of DAPT for each individual patient. This systematic review contains pertinent articles extracted from the PubMed database. We retrieved articles from various study categories, encompassing publications from the period spanning 2014 to 2022. Our analysis highlighted results from studies investigating different aspects contributing to ST development. The most favorable prevention option was the use of customized DAPT intervention based on patient-specific predictable factors. Several complications associated with ST were identified, including recurrent ST, major adverse cardiovascular events (MACE) encompassing all-cause mortality (including cardiac and non-cardiac mortality), cerebrovascular accidents (CVA) or transient ischemic attacks (TIA), hospitalization due to heart failure, and myocardial infarction requiring revascularization. Mortality was also observed as a significant outcome. The umbrella term of ST includes multiple causative factors. Although DES has improved patient survival rates vastly with its usage, careful risk factor assessment and required follow-up, in each individual being stented, further guarantee a more promising reduction in late adverse outcomes.


ToxRead: a tool to assist in read across and its use to assess mutagenicity of chemicals.
Life sciences, and toxicology in particular, are heavily impacted by the development of methods for data collection and data analysis; they are moving from an analytical approach to a modelling approach. The scarce availability of experimental data is a known bottleneck in assessing the properties of new chemicals. Even when a model is available, the resulting predictions have to be assessed by close scrutiny of the chemicals and the biological properties of the compounds concerned. To avoid unnecessary testing, a read across strategy is often suggested and used. In this paper we discuss how to improve and standardize read across activity using ad hoc visualization and data search methods which use similarity measures and fragment search to organize in a chart a picture of all the relevant information that the expert needs to make an assessment. We show in particular how to apply our system to the case of mutagenicity.


[Efficiency of nebulised magnesium sulphate in infective exacerbations of chronic obstructive pulmonary disease].
Conflicting results has been achieved in a small number of clinical studies evaluating the efficiency of magnesium sulphate (MS) in COPD exacerbations. We aimed to investigate the efficiency of nebulised MS in COPD exacerbations. Twenty patients who met the study criteria were randomized into two groups. All patients were treated with O2, antibiotics and oral corticosteroids. Additionally one group received ipratropium bromide (IB) 500 µg together with MS 151 mg/dose, while the other group received IB together with placebo. The patients were followed-up with forced expiratory volume in 1 second (FEV1) and visual analogue scale dyspnea scores for 48 hours. Peak expiratory flow rates (PEFRs) were measured before and 10, 30, 60 and 120 minutes after each nebule treatment. The baseline characteristics of the patients in both groups were similar. The FEV1 values measured at 24 and 48 hours did not show significant changes compared to baseline in both groups. Dyspnea scores in both groups decreased significantly in the first day, and in only MS group in the second day. The % change in the dyspnea score at the end of first day was significantly more in the MS group [-23.8% (13.6)] compared with the placebo group [-9.4% (12.9)] (p= 0.002). The % changes in PEFRs at 10 minutes [4.7 (7.5) and -3.5 (6.0), p= 0.005] and 30 minutes [8.2 (6.7) and 1.3 (5.5), p= 0.03] were significantly greater in the MS group compared with the placebo group on the first day. No side effects developed due to MS. Nebulised MS is a cheap, feasible and safe drug that can be added to the standart bronchodilator treatment since it provides additional relief of dyspnea in patients with COPD exacerbations. This needs to be evaluated in future clinical studies including greater number of patients.


Pulmonary meningothelial-like nodules: new insights into a common but poorly understood entity.
Although pulmonary meningothelial-like nodules (MLNs) have been recognized for decades, their nature and significance remain uncertain. This study was undertaken to evaluate MLNs in a wide range of specimens to clarify their incidence, distribution, relation to age and underlying disease, and histogenesis. Five hundred surgical lung biopsies, 25 extensively sampled lobectomies, 20 resections for pneumothoraces in persons younger than 30 years, and 92 pediatric autopsies were examined. Immunohistochemistry was performed in selected cases. One hundred eighty-six MLNs were identified in 81 cases, including 69 of 500 (13.8%) surgical biopsies and 12 of 25 (48%) lobectomies. No MLNs were found in pneumothorax resections or pediatric autopsies. Patients ranged from 22 to 84 years (mean, 62), with only 4 younger than 40 years. There were 56 women and 25 men (female:male=2.2:1). The highest incidence of MLNs was in thromboembolic disease/infarcts (5/12; 42%) and respiratory bronchiolitis-associated interstitial lung disease/desquamative interstitial pneumonia (9/35; 26%). MLNs were randomly distributed in alveolar septa with no consistent relation to small blood vessels. Immunohistochemistry demonstrated positivity for CD56 (18/18) in addition to progesterone receptor (18/18), epithelial membrane antigen (11/11), and vimentin (2/2). The high incidence of MLNs in our study may be related to underlying chronic lung disease. The finding of MLNs in almost half of extensively sampled lobectomies suggests that they may be present in all abnormal lungs if sufficiently sampled. Their absence in infants and children indicates that they are not congenital rests. The positive staining for CD56 is novel, and as CD56 has been reported in meningiomas, this finding supports meningothelial differentiation.


Self-Harm, Methadone Use and Drug-Related Deaths amongst Those Registered As Being of No Fixed Abode or Homeless in Ireland.
This work aims to contribute to the evidence base regarding the health of those who experience homelessness in Ireland by collating data on methadone use, drug-related deaths and emergency department presentations due to self-harm. Data from the Central Methadone Treatment List (CTL), National Self-Harm Registry Ireland and the National Drug-Related Deaths Index were analysed. The percentage on the CTL registered as being of no fixed abode (NFA) or homeless increased from 2% to 7% from 2011-2014. The absolute number of presentations with deliberate self-harm from those of NFA increased by 49% from 2007-2014. The number of drug-related deaths amongst those of NFA or homeless and who died in Dublin fluctuated from 2004-13 with an overall upward trend. There is an urgent need to adequately resource and coordinate those services which aim to address factors (social and health inequalities, mental ill-health and addiction) which lead people into - and prevent them exiting from - homelessness.


[Prenatal diagnosis of an adenomatoid malformation of the lung. Apropos of 2 cases].
Two cases of pulmonary cystic adenomatoid malformation are presented. The first case presented with bilateral pulmonary cystic involvement associated with oligoamnios and feto-placental anasarca. A peculiar feature of this case was the elevated level of alphafetoprotein in the amniotic fluid. In the second case, the pulmonary involvement was limited to one lobe. There was coexistent aplasia of the diaphragm. Premature rupture of the amniotic membranes necessitated a therapeutic abortion at 21 weeks of pregnancy. In connection with these two cases, a discussion based on the data in the literature.


JNC-IV and the evolution of stepped care to individualized treatment of hypertension.
There have been many changes in the treatment of hypertension over the past few decades. The Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC) has published four reports since 1977. The first three highlighted diuretic therapy as the main ingredient of stepped care for hypertensive patients. In the fourth report, this position has been revised to a patient-oriented, or individualized, approach. The shift reflects the results of many studies on hypertensive patients treated with a variety of approaches and drugs, including diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, sympatholytics, and calcium channel blockers. After analyzing the patient's history, physical, and laboratory findings, the report recommends making choices from the various agents, based on patient demographics, sequelae, concomitant diseases, and other risk factors such as cholesterol levels.


Patients Taking Antihistamines and Their Effects on Driving.
Sleepiness is known as one of the side effects of antihistamines, and impaired performance caused by these drugs has become problematic. Among the 13 second-generation antihistamines causing sleepiness to some extent, the package inserts of 8 drugs prohibit driving, 3 stress driving with care, and 2 give no driving-related warning. It was confirmed that the description did not necessarily reflect the results of the standard deviation of lateral position measurement study, which is considered the most effective study for evaluating the effects of drugs on automobile driving. Do these descriptions reflect actual patients' sleepiness? According to a questionnaire survey involving 2000 individuals taking second-generation antihistamines, 7.3% of respondents answered that they had always become sleepy after taking antihistamines (3.1-12.5% according to the type of antihistamine), 32.8% (27.8-45.8%) had become sleepy sometimes, 9.1% (3.1-15.8%) had previously become sleepy but not anymore, and 40.9% (27.1-49.1%) had never become sleepy. In addition, 10.3% (2.4-21.1%) reported intolerable sleepiness. Patients who had experience of receiving pharmaceutical education from pharmacists numbered 1296 (64.8%), and 80.2% of them had also received driving-related explanations, which included the prohibition of driving (32.8%), stressing the need to drive with care (54.7%), and the prohibition of medication before driving (12.0%). Concerning these explanations, the proportion who paid attention on a daily basis, paid slight attention, and paid no attention was 36.7, 31.2, and 32.1%, respectively. To provide effective and safe pharmacotherapy for the increasing number of patients taking antihistamines, pharmacists should ideally improve pharmaceutical education.


Simultaneous determination of spinosad, temephos, and piperonyl butoxide in animal-derived foods using LC-MS/MS.
Pesticides, which are used as plant protection products, can enter the food chain, and exposure to these xenobiotics can cause a wide array of health problems in humans. Therefore, the objective of the present study was to develop an analytical method for the simultaneous determination of residual spinosad (sum of spinosyn A and D), temephos and piperonyl butoxide in porcine muscle, egg, milk, eel, flatfish and shrimp (sampling period: February to June 2018) using liquid chromatography-triple quadrupole tandem mass spectrometry (LC-MS/MS). The target analytes were extracted with a combination of acidified acetonitrile and ethyl acetate and subsequently purified with original QuEChERS kits (composed of magnesium sulfate and sodium chloride) as well as n-hexane. All analytes were separated on a reversed-phase analytical column using a mobile phase of (A) 0.1% formic acid containing 10 mm ammonium formate in distilled water and (B) methanol. Good linearity (R2 ≥ 0.980) was achieved over the tested concentration range (3.5-35 μg/kg for spinosyn A; 1.5-15 μg/kg for spinosyn D; 5-50 μg/kg for temephos and piperonyl butoxide) in matrix-matched standard calibrations. Fortified samples at three spiking levels yielded recoveries in the range of 71-105% with relative standard deviations ≤9.2%. The applicability of the method was evaluated via evaluating samples collected from a large wholesale market located in Seoul, and none of the samples contained any of the target analytes. In conclusion, the current approach is simple, efficient and reliable and can successfully determine the residual levels of spinosad, temephos and piperonyl butoxide in complex animal-derived food products.


Fullerene cyanation does not always increase electron affinity: an experimental and theoretical study.
The electron affinities of C70 derivatives with trifluoromethyl, methyl and cyano groups were studied experimentally and theoretically using low-temperature photoelectron spectroscopy (LT PES) and density functional theory (DFT). The electronic effects of these functional groups were determined and found to be highly dependent on the addition patterns. Substitution of CF3 for CN for the same addition pattern increases the experimental electron affinity by 70 meV per substitution. The synthesis of a new fullerene derivative, C70(CF3)10(CN)2, is reported for the first time.


Significance and impact of urinary incontinence.
All nurses can play an important role in the detection of urinary incontinence (UI) in both community as well as institutional populations. With their advanced practice assessment and patient management skills, NPs are assuming a major role in the diagnosis and treatment of UI in primary and acute care settings, in home care, and in the management of chronic incontinence in long-term care. A strong commitment by the nursing community to emerge as a leading health care provider of incontinence assessment and management will be a major contribution to providing long awaited assistance for the 10 million incontinence sufferers in the United States. This article reviews the significance and impact of UI across all settings.


Multisite electrophysiological recordings by self-assembled loose-patch-like junctions between cultured hippocampal neurons and mushroom-shaped microelectrodes.
Substrate integrated planar microelectrode arrays is the "gold standard" method for millisecond-resolution, long-term, large-scale, cell-noninvasive electrophysiological recordings from mammalian neuronal networks. Nevertheless, these devices suffer from drawbacks that are solved by spike-detecting, spike-sorting and signal-averaging techniques which rely on estimated parameters that require user supervision to correct errors, merge clusters and remove outliers. Here we show that primary rat hippocampal neurons grown on micrometer sized gold mushroom-shaped microelectrodes (gMμE) functionalized simply by poly-ethylene-imine/laminin undergo self-assembly processes to form loose patch-like hybrid structures. More than 90% of the hybrids formed in this way record monophasic positive action potentials (APs). Of these, 34.5% record APs with amplitudes above 300 μV and up to 5,085 μV. This self-assembled neuron-gMμE configuration improves the recording quality as compared to planar MEA. This study characterizes and analyzes the electrophysiological signaling repertoire generated by the neurons-gMμE configuration, and discusses prospects to further improve the technology.


The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes.
Lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes represent a group of rare genetic disorders of HDL metabolism that have been the subject of a large number of clinical, biochemical, and genetic studies. Of special interest are patients with LCAT-related disorders with severe HDL deficiency and the apparent absence of premature atherosclerosis. This finding is inconsistent with the general concept that low HDL cholesterol levels are an obligate risk factor for atherosclerosis. In this review, we describe 36 natural mutations in the LCAT gene that result in either familial LCAT deficiency (FLD) or the milder phenotype known as fish-eye disease (FED). We propose a new classification of the natural mutations of the LCAT gene that are described to date. The defects are divided into four classes based on both the clinical and biochemical characterization of the patient and data that were obtained from the functional assessment of the mutant proteins. We define FLD-associated mutations that underlie a complete or nearly complete loss of LCAT activity due to null mutations (Class 1), and missense mutations (Class 2), respectively. In addition, we distinguish two classes of FED-associated mutations (Classes 3, 4) that underlie a partial impairment of LCAT activity but differ in their lipoprotein substrate specificity. In addition, we review the evidence of atherosclerosis in subjects with LCAT deficiency syndromes. The observation that 6 (all males) of a total of 19 FED subjects suffered from premature CAD (as defined by < 55 years of age and < 60 years of age for women and men, respectively) challenges the earlier assumption that the FED phenotype is not associated with increased risk of CAD. However, premature CAD remains an unusual clinical complication in FLD subjects.


[Modelling of digestion in the rumen].
The ruminal ecosystem illustrates the main concepts of system analysis. Due to its structure and functional complexity and to its determinant role in ruminant nutrition and feeding, the reticulo-rumen has been the target of modelling works. The proposed models have been static or dynamic. The later have known a recent development but the former have until now largely contributed to the knowledge progress. The complexity of dynamic models is proportional to the number of biological mechanisms taken into account. The simplest models describe, for instance, a degradation or a transit elementary process. The aggregated models take simultaneously into account 2 to 4 processes while the general models aim at describing the digestive behaviour of the ruminal ecosystem by integrating its main functions. These mechanistic models have been studied for about 20 years. They are on the whole satisfactory but they are not sufficiently able to describe some diet differences and some variations in the dynamic properties of feed particles.