Autoimmune hepatitis in the setting of human immunodeficiency virus infection: A case series.
Liver injury in the setting of human immunodeficiency virus (HIV) infection is more commonly attributed to viral hepatitis or highly active antiretroviral treatment (HAART) toxicity. The severity of liver injury is an important cause of morbidity and mortality. The emergence of autoimmune diseases, particularly autoimmune hepatitis (AIH) in the setting of HIV infection, is rare. Previous reports indicate that elevated liver enzymes are a common denominator amongst these patients. We present two patients with HIV infection, on HAART, with virological suppression. Both patients presented with elevated liver enzymes, and following liver biopsies, were diagnosed with AIH. The clinical course of these patients underscore the therapeutic value of corticosteroids, and in some cases, addition of immunosuppression for AIH treatment.


Screening older adults for executive dysfunction.
Studies suggest that executive cognitive dysfunction can more reliably predict loss of autonomy than memory impairment can. Executive cognitive function allows for abstract thought, the planning and taking of actions toward a goal, and adaptation to the unexpected. And because executive function and memory operate in distinct regions of the brain, executive dysfunction can occur even when memory isn't impaired. The detection of executive dysfunction is essential to helping a patient remain as safe and independent as possible. Watch a free video demonstrating best practices for evaluating executive dysfunction in older adults at http://links.lww.com/A326.


Synergistic formal ring contraction for the enantioselective synthesis of spiropyrazolones.
The rapid generation of molecular complexity from simple reactants is a key challenge in organic synthesis. Spiro compounds, underrepresented 3D motifs in chemical libraries, represent a challenge due to the creation of spiro quaternary carbon and the need to control the 3D shape in one step. Herein, we report the first ring contraction/formal [6 + 2] cycloaddition using synergistic Pd(0)/secondary amine catalysis, obtaining [5,5]-spiropyrazolone derivatives in excellent yields and stereoselectivities. We demonstrate that this reaction has a broad scope of early and late stage derivatization that will benefit the creation of highly valuable chemical libraries using spiropyrazolone motifs. We detected the key palladium activated intermediate in its protonated form by mass spectrometry and characterized its structure by infrared spectroscopy and DFT calculations, allowing us to propose a conceivable mechanistic pathway for this reaction.


Bilateral total retinal detachment at birth: a case report of Walker-Warburg syndrome.
Walker-Warburg syndrome (WWS) is a disorder characterized by ocular and brain malformations, and congenital muscular dystrophy. Retinal malformations are common in WWS; however, bilateral retinal detachment is a rare occurrence. We present a case of a newborn baby delivered at 36+3 weeks, who was the first living child of consanguineous parents of Turkish origin. On antenatal anomaly scans, the fetus had hydrocephalus that had increased throughout pregnancy, and a diagnosis of hydrancephaly was made at 36 weeks of gestation. Hypotonia, cleft lip and palate, poor suck and absent gag reflex were noted at birth. Ophthalmic examination at the age of 2 days revealed bilateral funnel retinal detachment. B-scan ultrasonography confirmed these findings, and magnetic resonance imaging (MRI) of the brain was performed at the age of 13 days to establish a diagnosis. The MRI showed lissencephaly, hydrocephalus and thin rim of brain parenchyma, with a cobblestone appearance of the cortex and pontine and cerebellar hypoplasia, consistent with the diagnosis of WWS. The infant deteriorated and died at 39 days of age from complications associated with the brain anomalies. In summary, bilateral retinal detachment is extremely rare and in association with hydrocephalus and posterior fossa anomalies strongly suggests the diagnosis of WWS.


Adherence to artemisinin-based combination therapy for the treatment of malaria: a systematic review of the evidence.
Increasing access to and targeting of artemisinin-based combination therapy (ACT) is a key component of malaria control programmes. To maximize efficacy of ACT and ensure adequate treatment outcomes, patient and caregiver adherence to treatment guidelines is essential. This review summarizes the current evidence base on ACT adherence, including definitions, measurement methods, and associated factors. A systematic search of the published literature was undertaken in November 2012 and updated in April 2013. Bibliographies of manuscripts were also searched and additional references identified. Studies were included if they involved at least one form of ACT and reported an adherence measurement. The search yielded 1,412 records, 37 of which were found to measure adherence to ACT. Methods to measure adherence focused on self-report, pill counts and bioassays with varying definitions for adherence. Most studies only reported whether medication regimens were completed, but did not assess how the treatment was taken by the patient (i.e. timing, frequency and dose). Adherence data were available for four different ACT formulations: artemether-lumefantrine (AL) (range 39-100%), amodiaquine plus artesunate (AQ + AS) (range 48-94%), artesunate plus sulphadoxine-pyrimethamine (AS + SP) (range 39-75%) and artesunate plus mefloquine (AS + MQ) (range 77-95%). Association between demographic factors, such as age, gender, education and socio-economic status and adherence to ACT regimens was not consistent. Some evidence of positive association between adherence and patient age, caregiver education levels, drug preferences, health worker instructions, patient/caregiver knowledge and drug packaging were also observed. This review highlights the weak evidence base on ACT adherence. Results suggest that ACT adherence levels varied substantially between study populations, but comparison between studies was challenging due to differences in study design, definitions, and methods used to measure adherence. Standardising methodologies for both self-report and bioassays used for evaluating adherence of different formulations across diverse contexts would improve the evidence base on ACT adherence and effectiveness; namely, specific and measurable definitions for adherence are needed for both methodologies. Additionally, further studies of the individual factors and barriers associated with non-adherence to ACT are needed in order to make informed policy choices and to improve the delivery of effective malaria treatment.


Characterization of an Amphetamine Interference from Gabapentin in an LC-HRMS Method.
An amphetamine interference was observed during the development of an liquid chromatography-high-resolution mass spectrometry (LC-HRMS) multi-class confirmation method for the determination of 47 drugs and metabolites in urine. The interference passed all qualitative criteria for amphetamine leading to potential false-positive results. Upon investigation, it was found that the amphetamine interference was correlated with the presence of high levels of gabapentin. Gabapentin is routinely detected in patient urine specimens at levels in excess of 1 mg/mL as it is widely prescribed at high doses and does not undergo significant metabolism. The source of the interference was identified as a gabapentin in-source fragment isomeric with protonated amphetamine. Here we describe the characterization of this interference and how its effect was mitigated in the LC-HRMS method.


[Radiographic differential diagnosis of surgical diseases of the lungs: diagnostic errors and their causes].
This study examines the reasons for complete divergences between the results of complex radiation study and the morphological verification of a diagnosis. A hundred and fifty cases with peripheral and central diseases of the lung were examined. There were 16 (10.7%) divergences of CT and X-ray conclusions with the histological verification of a diagnosis. The reasons of errors of complex radiation diagnosis were due both to the same type of symptoms, their latency and subjective ideas when the symptoms were analyzed. The greatest differentially diagnostic difficulties arose when peripheral formations were estimated.


Regeneration of the enteric nervous system in the sea cucumber Holothuria glaberrima.
Among higher metazoans, echinoderms exhibit the most impressive capacity for regeneration. Holothurians, or sea cucumbers, respond to adverse stimuli by autotomizing and ejecting their visceral organs, which are then regenerated. Neuronal fibers and cell bodies are present within the viscera, but previous regeneration studies have not accounted for the nervous component. We used light microscopic immunocytochemistry and ultrastructural studies to describe the regeneration of the enteric nervous system in the sea cucumber Holothuria glaberrima. This study provides evidence that the enteric nervous system of this echinoderm regenerates after evisceration and that in 3-5 weeks the regenerated system is virtually identical to that of noneviscerated animals. The regeneration of the enteric nervous system occurs parallel to the regeneration of other organ components. Nerve fibers and cells are observed within the mesenterial thickenings that give rise to the new intestine and within the internal connective tissue prior to lumen formation. We also used bromodeoxyuridine incorporation to show that proliferation of the neuronal population occurs in the regenerating intestine. The regeneration of the nervous system commands high interest because members of the closely related phylum Chordata either lack or have a very limited capacity to regenerate their nervous system. Thus, holothurians provide a model system to study enteric nervous system regeneration in deuterostomes.


Iontronic Neuromorphic Signaling with Conical Microfluidic Memristors.
Experiments have shown that the conductance of conical channels, filled with an aqueous electrolyte, can strongly depend on the history of the applied voltage. These channels hence have a memory and are promising elements in brain-inspired (iontronic) circuits. We show here that the memory of such channels stems from transient concentration polarization over the ionic diffusion time. We derive an analytic approximation for these dynamics which shows good agreement with full finite-element calculations. Using our analytic approximation, we propose an experimentally realizable Hodgkin-Huxley iontronic circuit where micrometer cones take on the role of sodium and potassium channels. Our proposed circuit exhibits key features of neuronal communication such as all-or-none action potentials upon a pulse stimulus and a spike train upon a sustained stimulus.


[Non-sedative antihistaminics and binding to central and peripheral H1 histamine receptors].
Four non-sedating antihistamines (astemizole, cetirizine, loratadine and terfenadine) were investigated for in vitro and ex vivo binding to histamine-H1 receptors in guinea-pig cerebellum and lung. In vitro, all the drugs dissociated slowly from H1 receptors (half-times greater than or equal to 100 min), Ki,app-values decreased with longer incubation times for potent lipophylic agents (astemizole and terfenadine) Ki,app-values were lower with more dilute tissue suspensions. In optimized assay conditions astemizole showed a Ki,app-value of 0.2 microM. Terfenadine, cetirizine and loratadine bound with 30-, 80- and 100-times lower affinity to H1 receptors. The occupancy of lung and cerebellar H1 receptors was investigated after oral administration of various dosages of the drugs and at several times after drug administration, using ex vivo binding techniques. Astemizole was a very potent compound showing complete differentiation between lung and cerebellar receptor occupation (with 0.63 mg/kg: 70% of lung H1 receptors were occupied, with less than 10% of cerebellar H1 receptor occupancy). A 7-times higher dose of terfenadine was required to induce the same effect. Astemizole produced a rapid and complete occupancy of lung receptors, which was maintained up to 72 h after administration. In contrast, terfenadine produced a peak effect at 1 h and was completely eliminated from lung receptors in 24 h. Loratadine and cetirizine only poorly differentiated between lung and cerebellar receptor occupancy (at 2.5 mg/kg: 70 and 60% of lung receptor occupancy, 50 and 70% of cerebellar receptor occupancy).(ABSTRACT TRUNCATED AT 250 WORDS)


A case of cerebral nocardiosis successfully treated with trimethoprim-sulfamethoxazole.
Nocardiosis is an opportunistic infection that often occurs in patients who are in an immunosuppressive state. It is often difficult to treat and the mortality is high. We report on an immunocompromised patient who suffered from cerebral nocardiosis with multiple brain abscesses which was successfully treated with trimethoprim-sulfamethoxazole (TMP-SMX) for a period of 6 months. The resolution of the brain abscesses with this treatment was documented by serial CT scans. Our experience indicates that a short course of TMP-SMX in a low dose may not be effective in preventing the spread of nocardiosis to the central nervous system (CNS). We recommend a prolonged course of a high dose of TMP-SMX in the treatment of CNS nocardiosis.


Effects of a novel dihydropyridine calcium antagonist on venous capacitance in Wistar-Kyoto rats.
Calcium antagonists are potent dilators of resistance vessels but do not dilate capacitance vessels. CD832 is a novel dihydropyridine calcium antagonist which has a nitrate moiety in its chemical structure. The authors examined the effects of CD832 on venous capacitance in anesthetized rats. Venous capacitance was assessed by measuring mean circulatory filling pressure (MCFP) at three levels of blood volume. Nitroglycerin decreased and phenylephrine increased MCFP. CD832 did not alter MCFP. After treatment with hexamethonium to prevent reflex venoconstriction, CD832 significantly decreased MCFP but nicardipine (another dihydropyridine calcium antagonist) did not. The magnitude of hypotension caused by CD832 and nicardipine was comparable. The results suggest that CD832 is a unique calcium antagonist which has a venodilator effect.


Review of techniques and studies characterizing the release of carbon nanotubes from nanocomposites: Implications for exposure and human health risk assessment.
Composites made with engineered nanomaterials (nanocomposites) have a wide range of applications, from use in basic consumer goods to critical national defense technologies. Carbon nanotubes (CNTs) are a popular addition in nanocomposites because of their enhanced mechanical, thermal, and electrical properties. Concerns have been raised, though, regarding potential exposure and health risks from nanocomposites containing CNTs because of comparisons to other high aspect ratio fibers. Assessing the factors affecting CNT release from composites is therefore paramount for understanding potential exposure scenarios that may occur during product handling and manipulation. Standardized methods for detecting and quantifying released CNTs, however, have not yet been developed. We therefore evaluated experimental approaches deployed by various researchers, with an emphasis on characterizing free versus composite bound CNTs. From our analysis of published studies characterizing CNT releases from nanocomposites, we found that the qualitative and quantitative methods used across studies varied greatly, thus limiting the ability for objective comparison and evaluation of various release factors. Nonetheless, qualitative results indicated that factors such as composite type, CNT functionalization, and energy input during manipulation (i.e., grinding) may affect CNT release. Based on our findings, we offer several recommendations for future product testing and assessment of potential exposure and health risks associated with CNT nanocomposites.


Characterization of palytoxin binding to HaCaT cells using a monoclonal anti-palytoxin antibody.
Palytoxin (PLTX) is the reference compound for a group of potent marine biotoxins, for which the molecular target is Na+/K+-ATPase. Indeed, ouabain (OUA), a potent blocker of the pump, is used to inhibit some PLTX effects in vitro. However, in an effort to explain incomplete inhibition of PLTX cytotoxicity, some studies suggest the possibility of two different binding sites on Na+/K+-ATPase. Hence, this study was performed to characterize PLTX binding to intact HaCaT keratinocytes and to investigate the ability of OUA to compete for this binding. PLTX binding to HaCaT cells was demonstrated by immunocytochemical analysis after 10 min exposure. An anti-PLTX monoclonal antibody-based ELISA showed that the binding was saturable and reversible, with a K(d) of 3 × 10-10 M. However, kinetic experiments revealed that PLTX binding dissociation was incomplete, suggesting an additional, OUA-insensitive, PLTX binding site. Competitive experiments suggested that OUA acts as a negative allosteric modulator against high PLTX concentrations (0.3-1.0 × 10-7 M) and possibly as a non-competitive antagonist against low PLTX concentrations (0.1-3.0 × 10-9 M). Antagonism was supported by PLTX cytotoxicity inhibition at OUA concentrations that displaced PLTX binding (1 × 10-5 M). However, this inhibition was incomplete, supporting the existence of both OUA-sensitive and -insensitive PLTX binding sites.


Gut microbiota dysbiosis increases the risk of visceral gout in goslings through translocation of gut-derived lipopolysaccharide.
We investigated the gut-kidney interaction in goslings with gout and tried to decipher the probable mechanisms through which gut dysbiosis leads to the progression of renal injury and inflammation. A total of 15 goslings (Anser cygnoides), with typical visceral gout symptoms, were screened and compared with 15 healthy goslings. We determined the signatures of the microbiome in the cecum chyme of goslings in the 2 groups by 16S sequencing, and analyzed the changes in intestinal permeability, levels of serum lipopolysaccharide (LPS), and the induced inflammatory response of Toll-like receptors (TLRs). We found the existence of gut dysbiosis in goslings with gout as a result of interactions among the multitude of bacteria present in the gut, and the proliferation of a specific pathogenic genus, Proteobacteria, played a decisive role in this process. Moreover, the permeability increased not only in the intestinal epithelium but also in the renal endothelium, providing possibilities for gut-derived LPS to enter the blood circulation and damage the kidneys. The systemic LPS concentration was increased in the gout group and exhibited a positive correlation with the degree of renal injury. In addition, we also found that inflammatory disorders concurrently existed in the gut and kidney of goslings with gout, and the LPS/TLR4/MyD88 (Myeloid differentiation primary response gene 88) inflammatory signaling was activated. These results indicate that the loss of intestinal barrier as a result of gut dysbiosis causes the translocation of gut-derived LPS, which can play an important role in the development of gout in goslings through interference with kidney functions.


[There's not only Alzheimer's disease].
We report the case of a 59 year old man with a rapidly progressive cognitive decline, neurologic symptoms and recurrent falls. One of the most important differential diagnoses was the lithiumintoxication with normal lithium blood levels. After reducing the lithiumdosis the neurological symptoms regressed completely, and only few cognitive impairments persisted.


Rectal delivery system for insulin.
The purpose of this investigation was to first screen for potential effectiveness several rectal gels as insulin delivery systems and to select one promising dosage form as candidate for further evaluation in rabbits and man. Criteria for effectiveness were the "pharmacologic availability", determined as the ratio between the total area under the percent glucose reduction versus time curves upon rectal administration and the standard (I.V. for rabbits and S.C. for man), the maximum reduction in glucose blood concentration, the time to reach the maximum and the mean residence time of glucose reduction. The rectal gels consisted of emulsion systems prepared from pH 8 buffer solution containing insulin, an oleaginous phase, a surface active agent (bile salts, Myrj or Brij), and a viscosity increasing agent. The finally selected rectal gel was tested in rabbits both in a parallel and a crossover design in nondiabetic and diabetic animals. The selected rectal gel in nondiabetic and diabetic rabbits resulted in a pharmacologic availability of about 25%. By addition of Azone the pharmacologic availability was further increased, although not significantly (small n). In nondiabetic man the pharmacologic availability was about 32%, whereas the bioavailability (measured from plasma insulin) was only about 11%. Drugs undergoing hepatic first-pass metabolism and for which the liver is the biophase, should show increased pharmacologic availability with decreased bioavailability (if the latter one is due to first-pass effect).


Long-term outcomes following a diagnosis of ovarian cancer at the time of preventive oophorectomy among BRCA1 and BRCA2 mutation carriers.
Preventive bilateral salpingo-oophorectomy is the most effective means of reducing the risk of ovarian cancer among women with an inherited BRCA1 or BRCA2 mutation. Some women are diagnosed with an invasive cancer (ovarian or fallopian tube) at the time of preventive surgery, referred to as an 'occult' cancer. The survival experience of these women is not known. We estimated the 10-year survival for 52 BRCA mutation carriers diagnosed with an occult ovarian or fallopian tube cancer at the time of preventive bilateral salpingo-oophorectomy. The mean age at diagnosis was 51.6 (range 33-69) years. All were serous cancers (although 14 were missing information on histologic subtype). Of the 20 cases with information available on stage at diagnosis, 10 were stage I, 1 was stage II, and 9 were stage III (n=32 missing). After a mean of 6.8 years, 12 women died (23%). The 10-year all-cause survival was 74%. Although based on only 52 cases, these findings suggest a more favorable prognosis for BRCA mutation carriers diagnosed with an occult rather than incident disease.


Perylene bisimide dyes as versatile building blocks for functional supramolecular architectures.
Perylene bisimide dyes and their organization into supramolecular architectures through hydrogen-bonding, metal ion coordination and pi-pi-stacking is discussed; further self-assembly leading to nano- and meso-scopic structures and liquid-crystalline compounds is also addressed.


A sacrificial millipede altruistically protects its swarm using a drone blood enzyme, mandelonitrile oxidase.
Soldiers of some eusocial insects exhibit an altruistic self-destructive defense behavior in emergency situations when attacked by large enemies. The swarm-forming invasive millipede, Chamberlinius hualienensis, which is not classified as eusocial animal, exudes irritant chemicals such as benzoyl cyanide as a defensive secretion. Although it has been thought that this defensive chemical was converted from mandelonitrile, identification of the biocatalyst has remained unidentified for 40 years. Here, we identify the novel blood enzyme, mandelonitrile oxidase (ChuaMOX), which stoichiometrically catalyzes oxygen consumption and synthesis of benzoyl cyanide and hydrogen peroxide from mandelonitrile. Interestingly the enzymatic activity is suppressed at a blood pH of 7, and the enzyme is segregated by membranes of defensive sacs from mandelonitrile which has a pH of 4.6, the optimum pH for ChuaMOX activity. In addition, strong body muscle contractions are necessary for de novo synthesis of benzoyl cyanide. We propose that, to protect its swarm, the sacrificial millipede also applies a self-destructive defense strategy-the endogenous rupturing of the defensive sacs to mix ChuaMOX and mandelonitrile at an optimum pH. Further study of defensive systems in primitive arthropods will pave the way to elucidate the evolution of altruistic defenses in the animal kingdom.


Dual liquid-liquid extraction followed by LC-MS/MS method for the simultaneous quantification of melatonin, cortisol, triiodothyronine, thyroxine and testosterone levels in serum: Applications to a photoperiod study in rats.
Hypothalamic Pituitary (PH) axes directly affects the functionality of the thyroid gland, the adrenal gland, and the gonads and their alteration has been related to several pathologies. Therefore, the global analysis of representative hormones from each axis, together with melatonin, would be a very good strategy for therapeutic diagnosis. Hence, an accurate, economic and effective analytical method has been developed and validated for the simultaneous measurement of the melatonin, cortisol, triiodothyronine (T3), thyroxine (T4) and testosterone levels in serum. The protocol consists in two liquid-liquid extractions followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analysis with electrospray ionization in positive mode. The isotopically labelled internal standards melatonin-D4, cortisol-D4, l-thyroxine-13C6 and testosterone-13C3 were added to serum samples. Multiple reaction monitoring (MRM) mode was performed to target fragment ions for the hormones and internal standards. Excellent linearity (r2 ≥ 0.993) of this method was observed within the concentration range of 0.004-0.5 ng/mL for melatonin and 0.4-50 ng/mL for cortisol, T3, T4 and testosterone in rat sera. The mean recovery of all compounds ranged from 51.3% to 76.7%. The relative standard deviations (RSDs) of intra-day and inter-day precision were within the acceptable limits of ±15% at all of the concentrations tested. The method developed here has been successfully applied to study the changes of these hormones induced by the duration of light exposure in rat serum, as a physiological model of HP axes modulation. The results obtained from rat sera showed the suitability of this analytical strategy.


A Random Forest approach to predict the spatial distribution of sediment pollution in an estuarine system.
Modeling the magnitude and distribution of sediment-bound pollutants in estuaries is often limited by incomplete knowledge of the site and inadequate sample density. To address these modeling limitations, a decision-support tool framework was conceived that predicts sediment contamination from the sub-estuary to broader estuary extent. For this study, a Random Forest (RF) model was implemented to predict the distribution of a model contaminant, triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) (TCS), in Narragansett Bay, Rhode Island, USA. TCS is an unregulated contaminant used in many personal care products. The RF explanatory variables were associated with TCS transport and fate (proxies) and direct and indirect environmental entry. The continuous RF TCS concentration predictions were discretized into three levels of contamination (low, medium, and high) for three different quantile thresholds. The RF model explained 63% of the variance with a minimum number of variables. Total organic carbon (TOC) (transport and fate proxy) was a strong predictor of TCS contamination causing a mean squared error increase of 59% when compared to permutations of randomized values of TOC. Additionally, combined sewer overflow discharge (environmental entry) and sand (transport and fate proxy) were strong predictors. The discretization models identified a TCS area of greatest concern in the northern reach of Narragansett Bay (Providence River sub-estuary), which was validated with independent test samples. This decision-support tool performed well at the sub-estuary extent and provided the means to identify areas of concern and prioritize bay-wide sampling.


Positron Emission Tomography Tracer Design of Targeted Synthetic Peptides via 18F-Sydnone Alkyne Cycloaddition.
Chemically synthesized, small peptides that bind with high affinity and specificity to CD8-expressing (CD8+) tumor-infiltrating T cells, yet retain the desirable characteristics of small molecules, hold valuable potential for diagnostic molecular imaging of immune response. Here, we report the development of 18F-labeled peptides targeting human CD8α with nanomolar affinity via the strain-promoted sydnone-alkyne cycloaddition with 4-[18F]fluorophenyl sydnone. The 18F-sydnone is produced in one step, in high radiochemical yield, and the peptide labeling proceeds rapidly. A hydrophilic chemical linker results in a tracer with favorable pharmacokinetic properties and improved image contrast, as demonstrated by in vivo PET imaging studies.


All-trans retinoic acid suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and metastasis in esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is the second common cancer in Henan province and is well-known for aggressiveness and dismal prognosis. Adjuvant therapies, chemotherapy, radiotherapy and endoscopic treatment have not improved survival rates in patients with late stage esophageal carcinoma. All-trans retinoic acid (ATRA) is the active ingredient of Vitamin A and affects a wide spectrum of biological processes including development, growth, neural function, immune function, reproduction, and vision. It is one of the most potent therapeutic agents used for treating cancers, especially lung adenocarcinomas. ATRA inhibits metastatic potential and angiogenesis in several tumor models. We investigated the effects of ATRA on the expression of angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2) and receptor Tie-2 in EC1 cells in vitro. We also assessed the growth and migration of EC1 cells in vitro. ATRA treatment caused 29.5% and 40.3% reduction of the growth of EC1 cells after 24 hours and 48 hours, relative to the control. ATRA plus fluorouracil treatment reduced the viability more strongly than either drug alone, indicating an additive effect. Moreover, ATRA decreased EC1 migration by 87%. Furthermore, ATRA treatment led to a marked decrease of the transcript levels of Ang-1, Ang-2, Tie-2, VEGF, and VEGF receptors, as assessed by real-time RT-PCR. Importantly, the protein levels of Ang-1, Ang-2 and Tie-2 were reduced by ATRA treatment. In vivo, we found ATRA treatment suppressed the tumor growth and improved the cachexia of mice. Importantly, ATRA treatment decreased the expression of CD31, Ang-1, Ang-2 and Tie-2 in subcutaneous tumors of EC1 cells. Collectively, our findings demonstrate that ATRA exhibits a dose- and temporal-dependent effect on the metastatic behavior, suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and the progression of xenograft tumors of EC1 cells.


Identification of effective natural PIK3CA H1047R inhibitors by computational study.
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with a poor prognosis and a high recurrence rate. PIK3CA gene is frequently mutated in breast cancer, with PIK3CA H1047R as the hotspot mutation reported in TNBC. We used the ZINC database to screen natural compounds that could be structurally modified to develop drugs targeting the PIK3CA H1047R mutant protein in the PI3K pathway. The LibDock module showed that 2,749 compounds could strongly bind to the PIK3CA H1047R protein. Ultimately, the top 20 natural ligands with high LibDock scores were used for further analyses including assessment of ADME (absorption, distribution, metabolism, and excretion), toxicity, stability, and binding affinity. ZINC000004098448 and ZINC000014715656 were selected as the safest drug candidates with strong binding affinity to PIK3CA H1047R, no hepatotoxicity, less carcinogenicity, better plasma protein binding (PPB) properties, and enhanced intestinal permeability and absorption than the two reference drugs, PKI-402 and wortmannin. Moreover, their lower potential energies than those of PIK3CA H1047R confirmed the stability of the ligand-receptor complex under physiological conditions. ZINC000004098448 and ZINC000014715656 are thus safe and stable leads for designing drugs against PIK3CA H1047R as part of a targeted therapeutic approach for patients with TNBC.


Synthesis of imidazo and benzimidazo[2,1-a]isoquinolines by rhodium-catalyzed intramolecular double C-H bond activation.
The rhodium-catalyzed intramolecular direct arylation of imidazole and benzimidazole derivatives via double C-H bond activation is described. This approach provides new access to a wide range of imidazo and benzimidazo[2,1-a]isoquinoline derivatives in moderate to high yields. This reaction provides an alternative method to the known Pd-catalyzed intramolecular oxidative cross-coupling reactions.


C-Met expression and mechanical activation of satellite cells on cultured muscle fibers.
Single-fiber cultures can be used to model satellite cell activation in vivo. Although technical deficiencies previously prevented study of stretch-induced events, here we describe a method developed to study satellite cell gene expression by in situ hybridization (ISH) using protocol modifications for fiber adhesion and fixation. The hypothesis that mechanical stretching activates satellite cells was tested. Fiber cultures were established from normal flexor digitorum brevis muscles and plated on FlexCell dishes with a layer of Vitrogen. After 2 hr of stretch in the presence of BrdU, satellite cells on fibers attached to Vitrogen were activated above control levels. In the absence of activating treatments or mechanical stretch, ISH studies showed 0-6 c-Met+ satellite cells per fiber. Time course experiments demonstrated stable quiescence in the absence of stretch and significant peaks in activation after 30 min and 2 hr of stretch. Frequency distributions for unstretched fiber cultures showed a significantly greater number of quiescent c-Met+ satellite cells than were activated by stretching, suggesting that typical activation stimuli did not trigger cycling in the entire c-Met+ population of satellite cells. These methods have a strong potential to further dissect the nature of stretch-induced activation and gene expression among characterized populations of individual quiescent and activated satellite cells.


Metabolic Engineering Strategies in Diatoms Reveal Unique Phenotypes and Genetic Configurations With Implications for Algal Genetics and Synthetic Biology.
Diatoms are photosynthetic microeukaryotes that dominate phytoplankton populations and have increasing applicability in biotechnology. Uncovering their complex biology and elevating strains to commercial standards depends heavily on robust genetic engineering tools. However, engineering microalgal genomes predominantly relies on random integration of transgenes into nuclear DNA, often resulting in detrimental "position-effects" such as transgene silencing, integration into transcriptionally-inactive regions, and endogenous sequence disruption. With the recent development of extrachromosomal transgene expression via independent episomes, it is timely to investigate both strategies at the phenotypic and genomic level. Here, we engineered the model diatom Phaeodactylum tricornutum to produce the high-value heterologous monoterpenoid geraniol, which, besides applications as fragrance and insect repellent, is a key intermediate of high-value pharmaceuticals. Using high-throughput phenotyping we confirmed the suitability of episomes for synthetic biology applications and identified superior geraniol-yielding strains following random integration. We used third generation long-read sequencing technology to generate a complete analysis of all transgene integration events including their genomic locations and arrangements associated with high-performing strains at a genome-wide scale with subchromosomal detail, never before reported in any microalga. This revealed very large, highly concatenated insertion islands, offering profound implications on diatom functional genetics and next generation genome editing technologies, and is key for developing more precise genome engineering approaches in diatoms, including possible genomic safe harbour locations to support high transgene expression for targeted integration approaches. Furthermore, we have demonstrated that exogenous DNA is not integrated inadvertently into the nuclear genome of extrachromosomal-expression clones, an important characterisation of this novel engineering approach that paves the road to synthetic biology applications.


Role of cytidine deaminase in toxicity and efficacy of nucleosidic analogs.
Nucleosidic analogs such as pyrimidine and purine derivatives are mainstay in the field of treating cancers, both in adults and in children. All these drugs act as antimetabolite compounds, that is, they interfere with the ability of cancer cells to synthesize the nucleosides or the nucleotides necessary for proliferation and progression. As with most cytotoxics, maintaining patients in their therapeutic window is challenging, and predicting changes in drug exposure is critical to ensure an optimal efficacy/toxicity balance. Among the antimetabolites, a small but widely prescribed number of drugs (i.e., gemcitabine, capecitabine, cytarabine, azacytidine) share a same metabolic pattern driven by a liver enzyme, cytidine deaminase (CDA), coded by a gene displaying several genetic and epigenetic polymorphisms. Consequently, CDA activity is erratic, ranging from deficient to ultra-rapid deaminator patients, with subsequent impact on drug pharmacokinetics and pharmacodynamics eventually. This review provides an update on the variety of clinical studies and case-reports investigating on CDA status as a marker for clinical outcome in cancer patients treated with nucleosidic analogs. Whereas sorting patients on the basis of their CDA genotype remains tricky because of unclear genotype-to-phenotype relationships, developing functional strategies (i.e., phenotype-based status determination) could help to use CDA status as a biomarker for developing adaptive dosing strategies with nucleosidic analogs.


Interprofessional education as part of becoming a doctor or physiotherapist in a competency-based curriculum.
Interprofessional learning is a critical pre-requisite for future interprofessional work. Structural adaptations in education offer possibilities to introduce new concepts. Rheumatic and musculoskeletal diseases (RMD) are both prevented and treated by physicians and physiotherapists but the development of interprofessional roles is seldom part of curricula. A complex, longitudinal interprofessional educational approach for future doctors and physiotherapists was designed and implanted at various stages (anatomy, physical examination, pathology, therapy). Most segments of the RMD curriculum are now based on interprofessional classes. Student satisfaction with learning is continually and comparatively evaluated. Learning success is assessed with practical and written exams. Interprofessional teaching was first introduced in 2013 for 420 first-year and 360 fourth-year medical students, along with 40 first- and third-year physiotherapy majors. The satisfaction with teaching and learning is high and distinctly above average for all teaching areas (satisfaction RMD rated as 2.4; average for all is 3.3). The percentage of those who pass the final exam is 94%. 100% of the students surveyed support the continuation of this interprofessional unit. Interprofessional teaching of RMD can be successfully implemented for future physicians and physiotherapists at different learning levels.


Role of interleukin 6 and its soluble receptor on the diffusion barrier dysfunction of alveolar tissue.
During respiratory infection, barrier dysfunction in alveolar tissue can result from "cytokine storm" caused by overly reactive immune response. Particularly, interleukin 6 (IL-6) is implicated as a key biomarker of cytokine storm responsible for and further progression to pulmonary edema. In this study, alveolar-like tissue was reconstructed in a microfluidic device with: (1) human microvascular lung endothelial cells (HULEC-5a) cultured under flow-induced shear stress and (2) human epithelial cells (Calu-3) cultured at air-liquid interface. The effects of IL-6 and the soluble form of its receptor (sIL-6R) on the permeability, electrical resistance, and morphology of the endothelial and epithelial layers were evaluated. The diffusion barrier properties of both the endothelial and epithelial layers were significantly degraded only when IL-6 treatment was combined with sIL-6R. As suggested by recent review and clinical studies, our results provide unequivocal evidence that the barrier dysfunction occurs through trans-signaling in which IL-6 and sIL-6R form a complex and then bind to the surface of endothelial and epithelial cells, but not by classical signaling in which IL-6 binds to membrane-expressed IL-6 receptor. This finding suggests that the role of both IL-6 and sIL-6R should be considered as important biomarkers in developing strategies for treating cytokine storm.


Cardiac microinjury measured by troponin T predicts collagen metabolism in adults aged >=65 years with heart failure.
Repeated myocardial microinjuries lead to collagen deposition and fibrosis, thereby increasing the risk of clinical heart failure. Little is known about the longitudinal association between increases in myocardial injury and the biology of collagen synthesis and deposition. Repeated measures of highly sensitive cardiac troponin T (cTnT) were obtained in participants of the Cardiovascular Health Study (N=353; mean age, 74±6 years; 52% women) at baseline and at 3 years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I, carboxyterminal telopeptide of type I collagen, and aminoterminal propeptide of procollagen III. Multivariable linear regression analyses were used to examine the association between baseline cTnT and changes in cTnT with collagen metabolism markers at follow-up adjusting for demographics, heart failure status, and cardiovascular risk factors. Results indicated that cTnT increases over 3-years were significantly associated with higher levels of carboxyterminal telopeptide of type I collagen (β=0.22, P<0.001) and aminoterminal propeptide of procollagen III (β=0.12, P=0.035) at follow-up when adjusting for demographic, clinical, and biochemical covariates including baseline cTnT. These associations were stronger in patients with heart failure than in control subjects. Conclusions- Increases in myocardial microinjury measured by changes in cTnT adversely affect markers of collagen metabolism. These findings are important to the biology of myocardial fibrosis and tissue repair. Serial evaluation of cTnT combined with collagen metabolism markers may further elucidate the pathophysiology of heart failure.


[How healthy are and behave men? Differences in health status and health behavior between the two sexes in the Canton of Zurich].
Men have not been the focus of health monitoring and reporting in German-speaking Switzerland so far and are a largely neglected target group of governmental preventive efforts. Without good reason. Men have a substantial preventive potential regarding health, health behavior and use of health and medical services, as can be seen in the recently published global health report of the Canton Zurich. Men have a shorter life expectancy compared to women and a significantly higher mortality with regard to strongly behavior-related chronic diseases as well as fatal traffic accidents and suicides. Men also show comparably unfavourable health behavior and a reduced utilization of health services. The stronger, but also less healthy and less healthy behaving sex should increasingly be the focus of health reporting and health monitoring in the future.


Fatigue due to compassion in health professionals and coping strategies: a scoping review.
to identify the current state of knowledge on compassion fatigue in the work context of healthcare professionals; and how coping strategies are established in this scenario. a scoping review with search applied to the databases: MEDLINE, LILACS, CINAHL, Scopus. Temporal limit: 2009 to 2019. The data was analyzed and synthesized in narrative form. thirty articles were selected, synthesized into two categories: a) Health work and compassion fatigue: conceptual analysis, context, and manifestations; b) Coping strategies for compassion fatigue. this study presented: a descriptive and general panorama about compassion fatigue in healthcare professionals, identifying a greater consolidation of the concept between 2015 and 2018; and some coping strategies. The association between health and spirituality is highlighted as one of the strategies in this scenario, enabling new research to be conducted in view of the importance of the theme in life, health work.


CANADIAN THALIDOMIDE EXPERIENCE.
Data are presented on 115 children, including three sets of twins, born in Canada in 1961 and 1962 with congenital malformations associated with the use of thalidomide by their mothers in early pregnancy. The epidemiological method is described. Of the 115 children, 74 were alive at the time of reporting, 41 of these being severely handicapped; 8 had been stillborn; 33 had died. Limb involvement was usually bilateral, affecting the upper limbs alone in 42 cases, and the upper and lower limbs in 41. Of 112 mothers, only 60 had had the drug prescribed by the physician providing maternity care; 87 were estimated to have first taken the drug before their last menstrual period or within 56 days thereafter. A plea is made for the development of better methods of collecting information on the occurrence of congenital malformations, with the aid of practising physicians.


Ceftaroline for Severe Methicillin-Resistant Staphylococcus aureus Infections: A Systematic Review.
Ceftaroline is approved by the Food and Drug Administration for acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia, including cases with concurrent bacteremia. Use for serious methicillin-resistant Staphylococcus aureus (MRSA) infections has risen for a multitude of reasons. The aim of this article is to review the literature evaluating clinical outcomes and safety of ceftaroline prescribed for serious MRSA infections. We conducted a literature search in Ovid (Medline) and PubMed for reputable case reports, clinical trials, and reviews focusing on the use of ceftaroline for treatment of MRSA infections. Twenty-two manuscripts published between 2010 and 2016 met inclusion criteria. Mean clinical cure was 74% across 379 patients treated with ceftaroline for severe MRSA infections. Toxicities were infrequent. Ceftaroline treatment resulted in clinical and microbiologic cure for severe MRSA infections. Close monitoring of hematological parameters is necessary with prolonged courses of ceftaroline.


Commentary on Iraqi health and culture.
Respect for the inherent dignity of each human is one of the most fundamental requirements for the delivery of culturally competent health care (National Organization of Nurse Practitioner Faculties, 2006). The inclusion of the worldviews, historical events, and differing belief systems of others is a characteristic of cultural competence. The following interview conducted with Colonel John P. McGuinness, MD, an Army medical officer who served in Iraq from April, 2003-April 2004 and December 2005-March 2006, gives insight to the Iraqi culture.


Does a screening trial for spinal cord stimulation in patients with chronic pain of neuropathic origin have clinical utility and cost-effectiveness (TRIAL-STIM)? A randomised controlled trial.
Spinal cord stimulation (SCS) is an established treatment of chronic neuropathic pain. Although a temporary SCS screening trial is widely used to determine whether a patient should receive permanent SCS implant, its evidence base is limited. We aimed to establish the clinical utility, diagnostic accuracy, and cost-effectiveness of an SCS screening trial. A multicentre single-blind, parallel two-group randomised controlled superiority trial was undertaken at 3 centres in the United Kingdom. Patients were randomised 1:1 to either SCS screening trial strategy (TG) or no trial screening strategy (NTG). Treatment was open label, but outcome assessors were masked. The primary outcome measure was numerical rating scale (NRS) pain at 6-month follow-up. Between June 2017 and September 2018, 105 participants were enrolled and randomised (TG = 54, NTG = 51). Mean numerical rating scale pain decreased from 7.47 at baseline (before SCS implantation) to 4.28 at 6 months in TG and from 7.54 to 4.49 in NTG (mean group difference: 0.2, 95% confidence interval [CI]: -1.2 to 0.9, P = 0.89). We found no difference between TG and NTG in the proportion of pain responders or other secondary outcomes. Spinal cord stimulation screening trial had a sensitivity of 100% (95% CI: 78-100) and specificity of 8% (95% CI: 1-25). The mean incremental cost-effectiveness ratio of TG vs NTG was £78,895 per additional quality-adjusted life-year gained. In conclusion, although the SCS screening trial may have some diagnostic utility, there was no evidence that an SCS screening TG provides superior patient outcomes or is cost-effective compared to a no trial screening approach.


Visualization of pronuclei in living bovine zygotes.
Bovine embryos were surgically collected from the oviducts of superovulated crossbred heifers 48 h postonset of estrus. The one-celled ova were treated with 4'-6'-diamidino-2-phenylindole (DAPI) and observed under ultraviolet light by fluorescence microscopy. Both male and female pronuclei were visualized, identified and subjected to micromanipulation.


Experimental simulation of quantum graphs by microwave networks.
We present the results of experimental and theoretical study of irregular, tetrahedral microwave networks consisting of coaxial cables (annular waveguides) connected by T joints. The spectra of the networks were measured in the frequency range 0.0001-16 GHz in order to obtain their statistical properties such as the integrated nearest neighbor spacing distribution and the spectral rigidity Delta(3) (L). The comparison of our experimental and theoretical results shows that microwave networks can simulate quantum graphs with time reversal symmetry. In particular, we use the spectra of the microwave networks to study the periodic orbits of the simulated quantum graphs. We also present experimental study of directional microwave networks consisting of coaxial cables and Faraday isolators for which the time reversal symmetry is broken. In this case our experimental results indicate that spectral statistics of directional microwave networks deviate from predictions of Gaussian orthogonal ensembles in random matrix theory approaching, especially for small eigenfrequency spacing s, results for Gaussian unitary ensembles. Experimental results are supported by the theoretical analysis of directional graphs.


Use and Perception of Contraception among Genders in Santo Domingo, Dominican Republic.
The prevalence of contraception in the Dominican Republic is among the highest of Latin American countries. Prior research has assessed the general perception of contraception in Latin America, examined determinants of contraceptive use among Dominican women, and explored their perceived reproductive control. Little research has explored the specific role each sexual partner, male and female, has in determining the use of contraception in Latin American countries. This study aims to address the gap in research regarding the specific role each sexual partner has in determining the contraception use in Latin American countries by evaluating male and female perception and use of contraception, and their perceived reproductive control. A one-time survey was administered to adult patients of two short-term medical missions located in Santo Domingo, Dominican Republic. The difference in overall responses to dichotomous questions and ordinal questions were tested using binomial Z-test and nonparametric Chi-Square Goodness-of-Fit test. Bivariate analyses were conducted using cross tabulation with Chi-Square test. The majority of participants of both genders are in favor of contraception use, believe they have the power to avoid an unplanned pregnancy, and view their partners' wishes regarding the use of contraception as important. However, significantly more females than males are in favor of contraception use (p-value = 0.01). Specific subgroups of men and women answered the survey in ways that suggest traditional values may be at odds with individuals' willingness to use contraception. There is an overall acceptance of contraception use and perception of reproductive control among both genders in our population, with a greater proportion of females in favor of contraception use than males (p-value = 0.01). Changing cultural norms may be coming into conflict with established beliefs and practices in the Dominican Republic, such as its machismo culture.


Effects of albendazole/metronidazole or tetracycline/folate treatments on persisting symptoms after Giardia infection: a randomized open clinical trial.
After an epidemic of giardiasis, some patients experienced persisting abdominal symptoms despite becoming Giardia-negative in stool samples after metronidazole treatment. The study aimed to determine if these patients were suffering from treatment refractory, chronic, cryptic giardiasis. The design was a prospective randomized open clinical trial with 1 arm receiving anti-Giardia treatment in the form of albendazole and metronidazole (A/M) for 7 d (n=12) and the other arm receiving tetracycline and folic acid (T/F) for 28 d (n=13). Symptom scores and global improvement were outcome measures. Symptom scores were analysed regarding time and treatment using mixed linear modelling. In both groups total symptom scores improved at the end of treatment; the improvement was significant for the T/F group. Bloating decreased significantly in both groups at the end of treatment. One month after treatment, 3 patients in the T/F group (23.1%) and 1 patient (8.3%) in the A/M group reported global symptom improvement. Symptoms recurred in all of these, and after 1 y total symptom scores were unchanged from baseline in either group. Treatment of post-giardiasis persistent abdominal symptoms with T/F or A/M resulted in only temporary symptom relief, possibly due to the anti-inflammatory effect of both treatments. Cryptic chronic giardiasis was not the explanation for the persistent symptoms.


Meningoencephalocele of the temporal bone: pictorial essay on transmastoid extradural-intracranial repair.
A spontaneous meningoencephalocele of the temporal bone may present with effusion in the middle ear, a cerebrospinal fluid leak, hearing loss, or rarely otitic meningitis. Repair of spontaneous encephaloceles in the temporal bone has been performed using transmastoid and transcranial middle fossa approaches or a combination of the two with varied results. The authors present a technical paper on the transmastoid extradural intracranial approach for the management of temporal lobe encephaloceles. Case reports and cadaver dissections are used to provide a pictorial essay on the technique. Advantages and disadvantages compared with alternative surgical approaches are discussed. Traditional transmastoid approaches are less morbid compared with a transcranial repair as they avoid brain retraction. However, in the past, there has been a higher risk of graft failure and hearing loss due to downward graft migration and a potential need for ossicular disarticulation. For the appropriate lesion, the transmastoid extradural intracranial approach lesion offers a stable meningoencephalocele repair without the comorbidity of brain retraction. The authors describe a transmastoid extradural intracranial technique via case reports and cadaver dissections for the repair of spontaneous meningoencephalocele defects larger than 2 cm. This approach provides more support to the graft compared to the conventional transmastoid repair.


The impact of intellectual property rights on health care in Canada.
Advances in biotechnology can lead to promising disease treatments and medicines. In order for these advances to reach fruition, however; there must be an incentive to incur the significant costs associated with the developments. Intellectual Property ("IP") regimes, particularly patents, are crucial in this regard. The limited monopolies offered by patent rights serve as an incentive to develop technology. The benefits of securing future advancements need, however, to be balanced with the exclusivity of IP protection and any potential "chill" on the use and/or development of health care technology. This article explores the relationship between IP, innovation and public health and examines how all these factors are balanced within a biotechnologically focused economy.


Recognition of filtered words in noise at higher-than-normal levels: decreases in scores with and without increases in masking.
To examine spectral effects on declines in speech recognition in noise at high levels, word recognition for 18 young adults with normal hearing was assessed for low-pass-filtered speech and speech-shaped maskers or high-pass-filtered speech and speech-shaped maskers at three speech levels (70, 77, and 84 dB SPL) for each of three signal-to-noise ratios (+8, +3, and -2 dB). An additional low-level noise produced equivalent masked thresholds for all subjects. Pure-tone thresholds were measured in quiet and in all maskers. If word recognition was determined entirely by signal-to-noise ratio, and was independent of signal levels and the spectral content of speech and maskers, scores should remain constant with increasing level for both low- and high-frequency speech and maskers. Recognition of low-frequency speech in low-frequency maskers and high-frequency speech in high-frequency maskers decreased significantly with increasing speech level when signal-to-noise ratio was held constant. For low-frequency speech and speech-shaped maskers, the decline was attributed to nonlinear growth of masking which reduced the "effective" signal-to-noise ratio at high levels, similar to previous results for broadband speech and speech-shaped maskers. Masking growth and reduced "effective" signal-to-noise ratio accounted for some but not all the decline in recognition of high-frequency speech in high-frequency maskers.


[EEG changes in patients undergoing on-pump coronary artery bypass grafting].
We studied the changes of electroencephalograms (EEG) related to on-pump coronary artery bypass grafting (CABG) in 28 right-handed male patients with coronary heart disease (CHD), 10 from which had accompanying moderated (30-50%) carotid artery (CA) stenoses. All EEG studies were performed 3-5 days before and 7-11 days after CABG. EEG data of healthy age-matched males (n=14) were examined. Before surgery, the CHD patients differed from the control group by less expressed theta2 and beta1 rhythm power asymmetry. The differences demonstrated worse conditions for cognitive processes in CHD patients. After CABG, the higher power of teta1 and 2 rhythms, predominantly in the frontal lobe of the left hemisphere which was mostly expressed in patients with CA stenosis, was observed in all CHD patients. This effect can be considered as the appearance of ischemic neuronal injury caused by on-pump CABG. The localization of changes in the frontal cortex of the left hemisphere can be related to a high vulnerability of these regions. The deficit of cerebral blood flow in these regions will define a clinical picture of cognitive decline after CABG.


EIF5A expression and its role as a potential diagnostic biomarker in hepatocellular carcinoma.
Introduction and objectives: Eukaryotic translation initiation factor 5A (EIF5A) is a member of the identified eIF family and played an important role in cell proliferation. There are few studies about the correlation between EIF5A and hepatocellular carcinoma (HCC). Materials and methods: We evaluated the expression of the EIF5A in human HCC cell lines and tissues by western blot analysis. Immunohistochemistry analysis of EIF5A was performed on a tissue microarray including 10 normal liver samples and 90 pathological section of HCC. Receiver operating characteristic (ROC) was introduced to obtain an optimal cut-off score for EIF5A positive expression. Results: Western blot results showed that EIF5A was highly expressed in HCC cell lines and tissues. Based on ROC curve analysis, 1/10 (10.0%) of normal hepatic tissues and 67/90 (74.4%) of HCC tissues were tested positive for EIF5A expression, which indicated that EIF5A were significantly up-regulated in HCC tissues compared with normal liver tissues (χ2=17.177, P<0.001). Furthermore, expression of EIF5A was significantly correlated with histological grade (P=0.048), clinical stage (P=0.003) and pT stage (P=0.003) but not correlated with sex (P=0.617) and age (P=0.831). Conclusions: In our study, we demonstrated the expression of EIF5A is closely correlated with HCC. In consideration of its relationship with clinicopathological parameters including histological grade, clinical stage and pT stage of HCC, EIF5A could be a potential biomarker.


Timing of first cannulation and vascular access failure in haemodialysis: an analysis of practice patterns at dialysis facilities in the DOPPS.
Optimal waiting time before first use of vascular access is not known. Two practices-first cannulation time for fistulae and grafts, and blood flow rate-were examined as potential predictors of vascular access failure in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Access failure (defined as time to first failure or first salvage intervention) was modelled using Cox regression. Among 309 haemodialysis facilities, 2730 grafts and 2154 fistulae were studied. For grafts, first cannulation typically occurred within 2-4 weeks at 62% of US, 61% of European and 42% of Japanese facilities. For fistulae, first cannulation occurred <2 months after placement in 36% of US, 79% of European and 98% of Japanese facilities. Overall, the relative risk (RR) of graft failure in Europe was lower compared with the USA (RR = 0.69, P = 0.04). The RR of graft failure (reference group = first cannulation at 2-3 weeks) was 0.84 with first cannulation at <2 weeks (P = 0.11), 0.94 with first cannulation at 3-4 weeks (P = 0.48) and 0.93 with first cannulation at >4 weeks (P = 0.48). The RR of fistula failure was 0.72 with first cannulation at <4 weeks (P = 0.08), 0.91 at 2-3 months (P = 0.43) and 0.87 at >3 months (P = 0.31) (reference group = first cannulation at 1-2 months). Facility median blood flow rate was not a significant predictor of access failure. Earlier cannulation of a newly placed vascular access at the haemodialysis facility level was not associated with increased risk of vascular access failure. Potential for confounding due to selection bias cannot be excluded, implying the importance of clinical judgement in determining time to first use of vascular access.


Strontium-doped calcium silicate bioceramic with enhanced in vitro osteogenic properties.
Gehlenite (GLN, Ca2SiAl2O7) is a bioceramic that has been recently shown to possess excellent mechanical strength and in vitro osteogenic properties for bone regeneration. Substitutional incorporation of strontium in place of calcium is an effective way to further enhance biological properties of calcium-based bioceramics and glasses. However, such strategy has the potential to affect other important physicochemical parameters such as strength and degradation due to differences in the ionic radius of strontium and calcium. This study is the first to investigate the effect of a range of concentrations of strontium substitution of calcium at 1, 2, 5, 10 mol% (S1-GLN, S2-GLN, S5-GLN and S10-GLN) on the physicochemical and biological properties of GLN. We showed that up to 2 mol% strontium ion substitution retains the monophasic GLN structure when sintered at 1450 °C, whereas higher concentrations resulted in presence of calcium silicate impurities. Increased strontium incorporation resulted in changes in grain morphology and reduced densification when the ceramics were sintered at 1450 °C. Porous GLN, S1-GLN and S2-GLN scaffolds (∼80% porosity) showed compressive strengths of 2.05 ± 0.46 MPa, 1.76 ± 0.79 MPa and 1.57 ± 0.52 MPa respectively. S1-GLN and S2-GLN immersed in simulated body fluid showed increased strontium ion release but reduced calcium and silicon ion release compared to GLN without affecting overall weight loss and pH over a 21 d period. The bioactivity of the S2-GLN ceramics was significantly improved as reflected in the significant upregulation of HOB proliferation and differentiation compared to GLN. Overall, these results suggest that increased incorporation of strontium presents a trade-off between bioactivity and mechanical strength for GLN bioceramics. This is an important consideration in the development of strontium-doped bioceramics.


Properties of Isoaccepting tRNALys, tRNAGlu and tRNAGln from rabbit Reticulocytes and liver. Multiplicity, Codon Recognition and Inactivation by Iodine.
The three tRNA species from rabbit liver and reticulocytes, each corresponding to the codons XAA and XAG(X equals A, G, C) were investigated. The elution patterns of the isoaccepting tRNA subspecies after separation by reversedphase chromatography followed by determination of amino acid acceptance have common and differing characteristics. Three subspecies of tRNALys, two of tRNAGlu and three of tRNAGln have been found in reticulocytes, wheras two subspecies of tRNALys, three of tRNAGlu and four of tRNAGln have been determined in rabbit liver. Examination of codon recognition by means of a ribosome binding assay showed that each subspecies binds exclusively in the presence of only one of the two possible triplets; i.e. wobbling was not found. It has been assumed that this high specificity, which is not to be expected according to the "wobble hypothesis", is due to a 2-thiouracil base in the first position of the anticodon. This was supported by oxidation experiments with iodine. Treatment with iodine significantly reduces the aminoacylation capacity of all subspecies that show specific binding with triplets ending in adenosine. We describe and compare for the first time the characteristics of eucaryotic tRNA species which occupy homologous positions in the codon table. Thus it can be seen that all the investigated subspecies have rigorously specific codon recognition in common, wherby "wobbling" can probably be excluded by a principle that is valid for all the investigated species.


A rhythmic movement disorder in REM sleep: a case report.
The case of a 34-year-old woman in good health with a complaint of diurnal fatigue and chronic repetitive rocking body movements during sleep is reported. Repeated polygraphic and video recordings during sleep allowed for a detailed analysis of rhythmic patterns of head and body rolling movements preferentially occurring during rapid eye movement sleep. The contribution of severe psychopathology or neurologic disorder was carefully examined and ruled out with personality testing, structured psychiatric interview, neurological examination with electroencephalogram, cerebral computerized tomography, magnetic resonance imaging and position emission tomography scans.


Exploring the Structural Importance of the C3=C4 Double Bond in Plant Alkaloids Harmine and Harmaline on Their Binding Interactions with Hemoglobin.
Harmine and harmaline are two structurally similar heterocyclic β-carboline plant alkaloids with various therapeutic properties, having a slight structural difference in the C3=C4 double bond. In the present study, we have reported the nature of the interaction between hemoglobin (Hb) with harmine and harmaline by employing several multispectroscopic, calorimetric, and molecular docking approaches. Fluorescence spectroscopic studies have shown stronger interaction of harmine with Hb compared to that of almost structurally similar harmaline. Steady-state anisotropy experiments further show that the motional restriction of harmine in the presence of Hb is substantially higher than that of the harmaline-Hb complex. Circular dichroism (CD) study demonstrates no conformational change of Hb in the presence of both alkaloids, but CD study in 1-cm cuvette path length also demonstrates stronger affinity of harmine toward Hb compared to harmaline. From the thermal melting study, it has been found that both harmine and harmaline slightly affect the stability of Hb. From isothermal titration calorimetry (ITC), we have found that the binding process is exothermic and enthalpy driven. Molecular docking studies indicated that both harmine and harmaline prefer identical binding sites in Hb. This study helps us to understand that slight structural differences in harmine and harmaline can alter the interaction properties significantly, and this key information may help in the drug discovery processes.


Comparison of in vitro effects of triflusal and acetysalicylic acid on nitric oxide synthesis by human neutrophils.
Recent studies have suggested that the protective anti-ischemic effects of acetylsalicylic acid are stronger than the inhibition of platelet thromboxane A2 synthesis. Since ischemic events still occur in acetylsalicylic acid-treated patients, the development of new drugs with more powerful protective effects is needed. We compared the effects of a new platelet antiaggregating drug, 2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and of acetylsalicylic acid on the interaction between human neutrophils and platelets, examining the capability of neutrophils to generate nitric oxide (NO). Triflusal, in the presence of neutrophils, showed a greater antiplatelet potency than acetylsalicylic acid to inhibit thrombin-induced platelet activation. Significant stimulation of NO-mediated mechanisms in the presence of acetylsalicylic acid or triflusal was demonstrated by the following findings: (1) increased metabolism of arginine to citrulline, (2) increase of cGMP in the platelet/neutrophil system and (3) the inhibitory action of the L-arginine (L-Arg) competitive analogue, NG-nitro-L-arginine-methyl ester (L-NAME), which was reversed by L-Arg. Triflusal increased the stimulation of NO synthesis by neutrophils more than did of acetylsalicylic acid. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB), alone or in combination with acetylsalicylic acid, did not modify NO production by neutrophils. Therefore, the whole molecule of triflusal is needed to stimulate NO production by neutrophils. Our results show that, in the presence of neutrophils, triflusal exerts an antiplatelet effect greater than that of acetylsalicylic acid, demonstrating a more powerful stimulation of the NO/cGMP system. The present results indicate that it is possible to develop new and more potent acetylsalicylic acid-related antiplatelet drugs for the prevention of the myocardial ischemic/reperfusion processes.


Should uncooperative trauma patients with suspected head injury be intubated?
In trauma patients with a suspicion for traumatic brain injury (TBI), a head computed tomography (CT) scan is imperative. However, uncooperative patients often cannot undergo imaging without sedation and may need to be intubated. Our hypothesis was that among mildly injured trauma patients, in whom there is a suspicion of a head injury, uncooperative patients have higher rates of TBI and intubation should be considered to obtain a CT scan. We found that uncooperative patients intubated for diagnostic purposes were more likely to have moderate to severe TBI than nonintubated patients (21.4 vs. 8.4%, P < 0.0001) and uncooperative behavior leading to intubation was an independent predictor of TBI (odds ratio, 2.5; 95% confidence interval, 1.5 to 4.5). Of patients with brain injury, intubated patients more often had a head abbreviated injury scale score of 4 (20.8 vs. 7.9%, P = 0.04). Uncooperative intubated patients had longer hospital stays (3.6 vs. 2.6 days, P = 0.003) and higher mortality (0.9 vs. 0.2%, P = 0.02) than nonintubated patients. Uncooperative behavior may be an early warning sign of TBI and the trauma surgeon should consider intubating uncooperative trauma patients if there is suspicion for brain injury based on the mechanism of their trauma.


Detachable Porous Organic Polymers Responsive to Light and Heat.
Stimuli-responsive porous materials have captured much attention due to the on-demand tunable properties. Most reported stimuli-responsive porous materials are based on molecule isomerism or host-guest interaction, and it is highly desired to develop new types based on different responsive mechanism. Herein, inspired by natural cells which have the ability to fuse and divide induced by external stimulation, we report a new type of stimuli-responsive porous material based on detachment mechanism. A detachable porous organic polymer, namely DT-POP-1, is fabricated from the polymerization of anthracene-containing monomer (AnMon) when irradiated by 365 nm UV light. DT-POP-1 can detach into the monomer AnMon when irradiated with 275 nm UV light or heat. Such polymerization/detachment is reversible. The detachment results in a big difference in porosity and adsorption capacity, making the present detachable porous polymer highly promising in adsorptive separation and drug delivery.


Design of abdominal retractor.
The purpose of this paper is to present the development and design of an abdominal retractor which allows a single person to perform operations and the fixation of the operation instruments can be done with one hand. The additional devices make the operation more comfortable for surgeons. Conventional measuring devices have been designed and applied for determining axial forces in a surgeon's forearm during operations. The same forces must be transmitted by the frame of the retractor. Thus a simple truss structure of a retractor was done. Several types of fixations have been proposed and tested using the rapid prototyping. Finally, the abdominal retractor was manufactured from stainless steel. The simple-to-use abdominal retractor was built. The standard surgery instruments were modified due to the fixation system of the frame. A wide variety of additional useful devices, such as a lamp, video camera etc., were also proposed. The present abdominal retractor is user-friendly and all components are easily sterilized by conventional methods (Fig. 7, Ref. 6) Keywords: abdominal retractor, stainless steel retractor, standard surger, fixation system of the frame, lamp, video camera, conventional methods.


Effect of alcohol dehydrogenase-1B and -7 polymorphisms on blood ethanol and acetaldehyde concentrations in healthy subjects with a history of moderate alcohol consumption.
This study aims to evaluate the effect of ADH1B and ADH7 genotypes on blood acetaldehyde and ethanol levels after alcohol ingestion, and to measure the genotoxic effect of smoking and ethanol on the buccal cells, also controlling for ADH variants. We recruited healthy Italian subjects with at least a moderate history of alcohol consumption. All subjects were given an alcoholic drink of 0.4 g ethanol /kg of body weight. Blood venous samples were collected at baseline, and 30, 60, 90, and 120 minutes after ingestion. Buccal cells were collected before ethanol ingestion. Sixty subjects were enrolled in the study. Individuals with the ADH1B GG genotype had median ethanol levels of 5.0mM (IQR 3.4-7.2), and those with the ADH1B GT/TT genotype had 4.7mM (IQR 4.2-4.8). Corresponding acetaldehyde levels were 1.5μM (IQR 0.7-2.6) for ADH1B GG genotype and 1.6μM (IQR 1.5-1.7) for ADH1B CG/GG genotype. Individuals with the ADH7 CC genotype had median ethanol levels of 5.0mM (IQR 3.3-7.2), while 5.0mM (IQR 4.7-5.6) was in those with the ADH7 CG/GG genotype. Corresponding acetaldehyde levels were 1.5 μM (IQR 0.7-2.6) for ADH7 CC genotype and 1.5 μM (IQR 1.4-1.6) for ADH7 CG/GG genotypes. A non-significant increase in the frequency of karyolitic and pyknotic cells was found in the group of heavy drinkers and current smokers, when compared to the moderate drinkers and the non-smokers. Our study does not support the hypothesis that ADH1B and ADH7 genotypes affect blood ethanol and acetaldehyde concentration.


HIF-1α inhibition by diethylstilbestrol and its polyacetal conjugate in hypoxic prostate tumour cells: insights from NMR metabolomics.
In this study, we have employed 1H NMR metabolomics to assess the metabolic responses of PC3 prostate tumour cells to hypoxia and to pharmacological HIF-1α inhibition by DES or its polyacetal conjugate tert-DES. Oxygen deprivation prompted a number of changes in intracellular composition and metabolic activity, mainly reflecting upregulated glycolysis, amino acid catabolism and other compensatory mechanisms used by hypoxic cells to deal with oxidative imbalance and energy deficit. Cell treatment with a non-cytotoxic concentration of DES, under hypoxia, triggered significant changes in 17 metabolites. Among these, lactate, phosphocreatine and reduced glutathione, whose levels showed opposite variations in hypoxic and drug-treated cells, emerged as possible markers of DES-induced HIF-1α inhibition. Furthermore, the free drug had a much higher impact on the cellular metabolome than tert-DES, particularly concerning polyamine and pyrimidine biosynthetic pathways, known to be tightly involved in cell proliferation and growth. This is likely due to the different cell pharmacokinetics observed between free and conjugated DES. Overall, this study has revealed a number of unanticipated metabolic changes that inform on DES and tert-DES direct cellular effects, providing further insight into their mode of action at the biochemical level.


Potential of supervised machine learning algorithms for estimating the impact of water efficient scenarios on solids accumulation in sewers.
Understanding the negative effects of widespread implementation of optimal water efficient solutions may have on existing centralised sewer systems is still limited - one of these effects is the accumulation of solids in sewer pipes. Predicting these effects requires setting up and simulating complex detailed hydraulic sewer network models. Often, precise details of the sewer network layout and diurnal patterns of the wastewater flows are not available, limiting the applicability of using model predictions for such phenomena. In this study, the applicability of supervised machine learning (ML) algorithms for the development of a simplified surrogate model to predict solid accumulation in sewer pipes was investigated. A large number of highly variable sewer networks were synthetically generated and used to produce results that can be generalizable within the limitations of the current study. A hydrodynamic sewer model was set up and simulated for each synthetic sewer network and various scenarios in which different water-efficient solutions were considered. Simulation results indicated that the most impacts are expected to occur in the upstream part of the sewer networks, and that with 50% reduction in (waste-)water flows, 3-20% more pipes are expected to accumulate solids. It was further found that ML algorithms can be used to successfully predict locations of solids accumulation in sewer pipes without using hydrodynamic models. A simple tool based on the findings of this study, sparing the need to conduct complex hydraulic simulations, was developed. It allows the user to enter a set of pipe characteristics and the proportion of flow that is reduced due to the implementation of water efficient solutions, and it predicts whether the pipe will accumulate solids or not. The study results and the proposed ML algorithms can support the implementation of optimal water-efficient solutions that will promote designing and managing the water sensitive cities of the future.


Is there a difference between women with or without detrusor overactivity complaining of symptoms of overactive bladder?
What's known on the subject? and what does the study add?: Overactive bladder syndrome (OAB) is a highly prevalent medical condition, which is linked to the urodynamic observation of detrusor overactivity (DO). Urodynamics detect DO in about half of female patients with OAB. Our study detects significant differences between female patients with OAB with and without DO. DO could be considered as a more severe form in the wide OAB spectrum and the two terms should not be used interchangeably. The detected differences should be taken into account in the design of studies for the assessment of new selective or combination treatments of OAB and in the provision of treatment in everyday clinical practice. To determine if there are differences between female patients complaining of symptoms of overactive bladder (OAB) with and without detrusor overactivity (DO). The present study was a cross-sectional study of consecutive women attending a one-stop urodynamic assessment clinic with OAB symptoms. The King's Health Questionnaire (KHQ) and a 3-day bladder diary incorporating the Patient's Perception of Intensity of Urgency Scale (PPIUS) were used to assess symptoms and health-related quality of life (HRQoL). The participants underwent multichannel urodynamics (UDS) according to the International Continence Society (ICS) recommendations. Patients whose symptom of urgency was not reproduced during the laboratory test underwent a 4-h ambulatory UDS test. Of the 556 patients who were included in the study, 43% were diagnosed with DO by either laboratory (227/556) or ambulatory UDS (11/39). There was no difference between the groups in age, body mass index (BMI), menopausal status or the presence of prolapse. Patients with DO had a smaller functional bladder capacity (P < 0.001), higher urgency episode frequency (P < 0.001) and larger maximum and mean urge ratings (P < 0.001). No significant differences were found in daytime or nocturnal micturitions between the groups. The presence of DO had a more negative impact on the quality of life, with a statistically significant difference between the groups in six of the domains of the KHQ. The present study detects objective and subjective differences between female patients with OAB with and without DO. Women with DO experience more significant impairment to their quality of life and have a greater degree of bladder dysfunction.


First principles simulation of the UV absorption spectrum of ethylene using the vertical Franck-Condon approach.
A new method which we refer to as vertical Franck-Condon is proposed to calculate electronic absorption spectra of polyatomic molecules. In accord with the short-time picture of spectroscopy, the excited-state potential energy surface is expanded at the ground-state equilibrium geometry and the focus of the approach is more on the overall shape of the spectrum and the positions of the band maxima, rather than the precise position of the 0-0 lines. The Born-Oppenheimer approximation and the separability of the excited-state potential energy surface along the excited-state normal mode coordinates are assumed. However, the potential surface is not necessarily approximated as harmonic oscillator potentials along the individual normal modes. Instead, depending upon the nature of the potential surface along a particular normal mode, it is treated either in the harmonic approximation or the full one-dimensional potential is considered along this mode. The vertical Franck-Condon approach is applicable therefore even in cases where the excited state potential energy surface is highly anharmonic and the conventional harmonic Franck-Condon approach is inadequate. As an application of the method, the ultraviolet spectrum of ethylene between 6.2 eV (50,000 cm(-1)) and 8.7 eV (70,000 cm(-1)) is simulated, using the Similarity Transformed Equation of Motion Coupled-Cluster method to describe the required features of the potential energy surfaces. The spectrum is shown to be a result of sharp doublet structures stemming from the pi --> 3s (Rydberg) state superimposed on top of a broad band resulting from the pi --> pi* (valence) state. For the Rydberg state, the symmetric C=C stretch and the torsion mode contribute to the spectrum, while the broad valence band results from excitation into the C=C stretch, CH2 scissors, and the torsion mode. For both states, the potential along the torsion mode is highly anharmonic and the full treatment of the potential along this mode in the vertical Franck-Condon method is required.


Transplantation in miniature swine. VIII. Recombination within the major histocompatibility complex of miniature swine.
Offspring of heterozygous parents derived from three herds of miniature swine, each of which is homozygous at the major histocompatibility complex (MHC), were screened for recombination within the MHC. The swine were typed serologically at weaning and later typed by mixed lymphocyte reaction (MLR). Two intra-MHC recombinants were discovered, both of which involved the exchange of D region specificities without apparent dissociation of ABC region specificities, confirming the localization of the SLA-D region outside of the SLA-ABC regions. The first recombinant was the offspring of an SLAc/d (cd) by dd mating and typed serologically as cd but typed by MLR as dd. The second recombinant was the offspring of a cd by cd mating. It typed serologically as cc but stimulated cc in one-way MLR and retained its reactivity to dd, thus suggesting a possible recombination within the D region. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of 3H-leucine-labeled lymphocyte surface antigens demonstrated that corresponding Ia antigens were also exchanged during these recombinant events supporting the hypothesis that genes coding for Ia antigens are identical or closely linked to D region genes encoding the MLR specificities.


Hippocampal damage causes retrograde but not anterograde memory loss for context fear discrimination in rats.
There is a substantial body of evidence that the hippocampus (HPC) plays and essential role in context discrimination in rodents. Studies reporting anterograde amnesia (AA) used repeated, alternating, distributed conditioning and extinction sessions to measure context fear discrimination. In addition, there is uncertainty about the extent of damage to the HPC. Here, we induced conditioned fear prior to discrimination tests and rats sustained extensive, quantified pre- or post-training HPC damage. Unlike previous work, we found that extensive HPC damage spares context discrimination, we observed no AA. There must be a non-HPC system that can acquire long-term memories that support context fear discrimination. Post-training HPC damage caused retrograde amnesia (RA) for context discrimination, even when rats are fear conditioned for multiple sessions. We discuss the implications of these findings for understanding the role of HPC in long-term memory.


Morphological wave attenuation of the nature-based flood defense: A case study from Chongming Dongtan Shoal, China.
The risk of coastal storm flooding is deteriorating under global warming, especially for the heavily urbanized deltaic cities, like Shanghai. The Nature-Based Flood Defense (NBFD), as an eco-friendly design alternative for hard infrastructure against coastal flooding, is gaining attention. Nevertheless, the vulnerability of saltmarsh due to the biological instability, resulting in the uncertainties on coastal protection, is considered the bottleneck challenge that hinders the broad application of the NBFD concept. We argue that except for direct wave attenuations by the above-ground vegetation during storms, the gradual sediment trapping and consolidating during the non-storm period is a more crucial function of coastal saltmarsh, which mitigates storm waves by forming a broader and higher intertidal morphology. This benefit is an important value of saltmarsh-based coastal protection but is largely neglected in many NBFD studies. Taking Chongming Dongtan Shoal (CDS) as a case study, we demonstrated that over 2/3th wave attenuation during storms is contributed by the saltmarsh morphology, and less than 1/3th is from the saltmarsh vegetation. The relative contribution of the saltmarsh morphology on wave mitigation is even enhanced under the increasing storm grades from 100 yrs. to 5000 yrs. return levels. To promote this idea for broader application, the cost-benefit analysis of three artificial NBFD solutions (e.g., submerged breakwater, timber piles, and sand nourishment) are compared. We identified an optimal measure of the submerged breakwater for CDS, which minimizes the ecological impact and maximizes the cost-benefit. Moreover, the wave-free zone behind the breakwater increases the chance of vegetation establishment, helps suspended sediment trapping, hence fostering a beneficent cycle for saltmarsh restoration. In summary, ignoring the contribution of saltmarsh morphology on wave attenuation largely underestimated the benefits of vegetation-based coastal protection, which should be greatly emphasized to provide a solid basis for developing NBFD.


Nucleoside monophosphates recognition using macrocyclic polyamine bonded phase in capillary electrochromatography.
An open-tubular wall-coated macrocyclic polyamine capillary column (70 cm x 75 microm ID) with 50 cm effective length for the separation of nucleoside monophosphates is described. Some parameters with respect to concentration, pH, composition of the buffer, and voltage in order to optimize the separation were studied. The coated capillary showed reversed electroosmotic flow (EOF), allowing anions to be separated in the co-EOF mode. Baseline separations were achieved for the eight nucleotides in less than 26 min using a background electrolyte consisting of H(3)PO(4)-NaH(2)PO(4) (30 mM, pH 3.10), an applied voltage of -15 kV, and detection at 254 nm. The macrocyclic polyamine on the capillary wall introduced anion coordination for the interaction with the analytes, the strength of which could be moderated by the type and concentration of the competing ion used in the background electrolyte (BGE). With a low concentration of the competing ion (phosphate ion), the migration behavior followed that obtained in the electrophoretic system. Increasing the concentration of the competing ion resulted in a faster migration and more complete elution of the analyte. The method established was also employed for the analysis of nucleotides in mushrooms. Aqueous extracts of mushrooms from different species and various extraction methods were injected directly for the analysis. Uridine 5'-monophosphate, guanosine 5'-monophosphate, adenosine 5'-monophosphate, and cytidine 5'-monophosphate, were found in the sample tested.


Energetics of ligand-induced conformational flexibility in the lactose permease of Escherichia coli.
Isothermal titration calorimetry has been applied to characterize the thermodynamics of ligand binding to wild-type lactose permease (LacY) and a mutant (C154G) that strongly favors an inward facing conformation. The affinity of wild-type or mutant LacY for ligand and the change in free energy (DeltaG) upon binding are similar. However, with the wild type, the change in free energy upon binding is due primarily to an increase in the entropic free energy component (TDeltaS), whereas in marked contrast, an increase in enthalpy (DeltaH) is responsible for DeltaG in the mutant. Thus, wild-type LacY behaves as if there are multiple ligand-bound conformational states, whereas the mutant is severely restricted. The findings also indicate that the structure of the mutant represents a conformational intermediate in the overall transport cycle.


First Report of Fusarium solani Species Complex Causing Vascular Wilt on Cauliflower in China.
Cauliflower (Brassica oleracea var. botrytis L.), which belongs to the family Cruciferae, is a cool-season vegetable with green leaves around a large hard white head of flowers. China is the leading cauliflower and broccoli producing country in the world, with approximately 10.71 MT production (FAOSTAT 2019). During September 2018 to July 2019, wilting symptoms were observed on cauliflower in several commercial fields, with approximately 45% to 65% disease incidence in Shen county (115°48'E, 35°98N) of Liaocheng city, Shandong province, China. Plant stunting, leaves yellowing and wilting, and dark brown, hollow appearance of vascular stem tissues were the symptoms prominently observed. To isolate the causal organism, nine symptomatic tissues were collected and cut into small pieces (5 × 5 mm), disinfected in 75% ethanol for 30 s, rinsed three times in sterile water, transferred onto potato dextrose agar (PDA) medium. The plates were then incubated in air-conditioned room at 26°C with an artificial 12 h light-dark cycle provided by incandescent lamp. In total, 15 single-spore isolates were obtained and morphological characterization of 15 isolates was done on both PDA and carnation leaf agar (CLA; Leslie and Summerell 2006). The mycelia on PDA were initially white, fluffy, later becoming brown, and the underside of the colonies were light brown. Typical macroconidia were abundant on CLA. Macroconidia were hyaline, slightly curved, one to five septa, both ends were smooth, measuring 3.7 to 6.4 μm × 23.7 to 38.1 μm (n = 40). Microconidia were oval to cylindrical, hyaline, zero to one septate, measuring 2.0 to 4.1 × 4.3 to 10.3 μm (n = 40). Chlamydospores were terminal or intercalary, solitary or in pairs, globose to oval, thick wall, smooth or rough, 6.3 to 9.8 μm. Based on morphological characteristics, all of the 15 isolates were identified as Fusarium solani (Leslie and Summerell 2006). The isolates were further identified based on PCR amplification. The ITS, mtSSU, EF-1α and RPB2 genes were amplified using primers ITS1/ITS4, NSM1/NSM2 (Li et al. 1994), EF-1 Ha/EF-2Tb (O'Donnell et al. 1998) and RPB2-5F2/fRPB2-7cR (O'Donnell et al. 2008). BLAST analysis showed that 15 isolates were highly similar to F. solani species complex, with 100% similarity for ITS (AB470904.1), mtSSU (KF125009.1), EF-1α (KF372878.1), and RPB2 (MK048113.1), respectively. The sequences of isolate HYC1410080102 had been deposited in GenBank with accessions MT378292.1 for ITS, MT383122.1 for mtSSU, OK595059.1 for EF-1α and OK595060.1 for RPB2, respectively. Pathogenicity of the 15 isolates were conducted on 4-true-leaf seedlings cv. Jinsong by dipping the roots into a conidial suspension (107 conidia/mL) for 10 min. The conidial was prepared from 7-day old cultures grown on CLA at 26°C and suspended in sterilized water. Control plants were dipped in sterile distilled water. All treated seedlings were planted in 5.0 cm diameter plastic pots containing pasteurized soil matrix. Then the plants were kept in a greenhouse at 15°C (night)/26°C (day) and 80%RH with natural daylight. Twelve days later, brown lesions appeared on stem bases in all inoculated cauliflowers, and finally, the plants wilted, similar to those observed in the field. The control plants remained healthy. Re-isolation of the infected tissues showed same morphological characteristics of F. solani as the original isolates, which were verified using PCR. To our knowledge, this is the first report of F. solani causing cauliflower wilt in China and the world (Farr and Rossman 2021). F. solani is a destructive pathogen with a broad host range worldwide and is responsible for significant crop losses, prevention and control measures should be considered.


Probabilistic assessment of the cumulative dietary exposure of the population of Denmark to endocrine disrupting pesticides.
The four pesticides epoxiconazole, prochloraz, procymidone and tebuconazole, are commonly used pesticides, all suspected of acting as endocrine disrupters. In the present study, we assessed the acute cumulative dietary exposure to the women of child bearing age and the general population of Denmark to these pesticides from the intake of fruit and vegetables. The assessment was carried out using the probabilistic approach combined with the relative potency factor (RPF) approach. Residue data for prochloraz, procymidone, and tebuconazole were obtained from the Danish monitoring programme 2006-2009, while residue data for epoxiconazole were obtained from the Swedish monitoring programme carried out in the period 2007-2009. Food consumption data were obtained from the Danish nationwide dietary survey conducted in 2000-2002. Relative potency factors for the four pesticides were obtained from rat studies. Prochloraz was used as the index compound. All four pesticides increased nipple retention in male offspring, and epoxiconazole, prochloraz, and tebuconazole also increased the gestation period in pregnant rat dams. For women of childbearing age, the high-end cumulative exposure (99.9th percentile) was calculated to 9% of the Adjusted Reference Value (ARV) for the effect on nipple retention and to 1% of the ARV for the effect on increased gestation period.


Fetal growth in the offspring of epileptic women: results of an Italian multicentric cohort study.
An historical cohort study of the association between maternal epilepsy, anticonvulsant drugs and fetal growth was carried out among 47 hospitals collaborating in the Italian Multicentric Registry on Birth Defects (IPIMC). Birth weight, head circumference and body length were studied in 164 babies of epileptic women and compared to 185 controls. Seventy-nine epileptic women were treated by monotherapy, 59 by polytherapy and 26 took no anticonvulsant during pregnancy. An intrauterine growth retardation and a smaller head circumference was observed among babies of epileptic women. No effect was evident for body length. When specific anticonvulsant therapies were taken into account, only phenobarbital showed an effect on birth weight and head circumference; a reduction in head circumference was observed also in the babies of untreated epileptic women. The other antiepileptics (carbamazepine and valproic acid) showed no influence on the outcome considered. The observed effects on fetal growth can be interpreted as a result of an interaction between the effect of the maternal disease and that of the anticonvulsants.