Carbon-incorporated Ni2P-Fe2P hollow nanorods as superior electrocatalysts for the oxygen evolution reaction.
A rational design and cost-effective transition metal-based hollow nanostructures are important for sustainable energy materials with high efficiency. This study reports on carbon-incorporated Ni2P-Fe2P hollow nanorods ((Ni,Fe)2P/C HNRs) derived from a self-template approach as efficient electrocatalysts. Initially, a Ni2(BDC)2(DABCO)-MOF (Ni-MOF) is converted to NiFe-PBA hollow nanorods (HNRs) through facile ion exchange which was further converted to (Ni,Fe)2P/C HNRs via a subsequent phosphidation process. The resulting (Ni,Fe)2P/C HNRs exhibit remarkable activity for the oxygen evolution reaction in an alkaline solution requiring a small overpotential of 258 mV to drive a current density of 10 mA cm-2 and long-term stability with little deactivation after 40 h. (Ni,Fe)2P/C HNRs outperform (Ni,Fe)2P/C NPs and commercial RuO2. The unique hollow morphology and interfacial electronic structure substantially increase the active site and charge transfer rate of our electrocatalyst, resulting in excellent OER activity and stability.


Reoperative Mitral Valve Surgery Through Port Access.
Minimally invasive mitral valve surgery (MIMVS) has become the standard approach for mitral valve pathology in many centres. The anterolateral mini thoracotomy access is beneficial in reoperative surgery by avoiding repeat sternotomy associated risks. The aim of this study is to analyse the safety of this technique. All patients undergoing reoperative MIMVS between 2008 and 2019 were studied retrospectively. Primary endpoint was 30-day major complications and mortality; secondary outcome was long term survival, reoperation rate and rate of more than moderate recurrent regurgitation. 146 Patients underwent reoperative MIMVS with a mean age of 68 ± 8 years. The composite outcome of 30-day major complication and mortality was 29.5%. 30-Day mortality was 6.2% and stroke rate 3.4%. Survival for the whole cohort was 89.7 ± 2.5% at 1-year, 71.6 ± 4.3% at 5 year and 50.9 ± 5.9% at 8-year follow up. Cox regression analysis revealed reduced left ventricular function (HR 2.8; 95%CI 1.5 - 5.0), GFR < 60 (HR 2.1; 95%CI 1.2 - 3.7) and active endocarditis (HR 6.4; 95%CI 2.7 - 15.4) as variables associated with reduced long-term survival. The cumulative incidence of re-operation after mitral valve replacement was 11.3 ± 3.2% at 5-year and for repair 16.2 ± 7.5% at 5-year. The cumulative incidence of more than moderate recurrent regurgitation after mitral valve repair was 25.4 ± 9.0% at 3-year. Minimally invasive access in reoperative mitral valve surgery in the current study showed similar 30-day mortality and stroke rate compared to repeat sternotomy results reported in literature.


HOST-PARASITE COEVOLUTION: EVIDENCE FOR RARE ADVANTAGE AND TIME-LAGGED SELECTION IN A NATURAL POPULATION.
In theory, parasites can create time-lagged, frequency-dependent selection in their hosts, resulting in oscillatory gene-frequency dynamics in both the host and the parasite (the Red Queen hypothesis). However, oscillatory dynamics have not been observed in natural populations. In the present study, we evaluated the dynamics of asexual clones of a New Zealand snail, Potamopyrgus antipodarum, and its trematode parasites over a five-year period. During the summer of each year, we determined host-clone frequencies in random samples of the snail to track genetic changes in the snail population. Similarly, we monitored changes in the parasite population, focusing on the dominant parasite, Microphallus sp., by calculating the frequency of clones in samples of infected individuals from the same collections. We then compared these results to the results of a computer model that was designed to examine clone frequency dynamics for various levels of parasite virulence. Consistent with these simulations and with ideas regarding dynamic coevolution, parasites responded to common clones in a time-lagged fashion. Finally, in a laboratory experiment, we found that clones that had been rare during the previous five years were significantly less infectible by Microphallus when compared to the common clones. Taken together, these results confirm that rare host genotypes are more likely to escape infection by parasites; they also show that host-parasite interactions produce, in a natural population, some of the dynamics anticipated by the Red Queen hypothesis.


A New Rabbit-Skin Model to Evaluate Protective Efficacy of Tuberculosis Vaccines.
Background: BCG protection is suboptimal and there is significant interest to develop new tuberculosis (TB) vaccines. However, there are significant limitations of the current vaccine evaluation systems in the mouse model. Here, we developed a BCG-challenge rabbit skin model as a new way to evaluate the protective efficacy of selected TB subunit vaccine candidates. Methods: Rabbits were immunized with subunit vaccines, including EAMM (ESAT6-Ag85B-MPT64<190-198>-Mtb8.4), MH (Mtb10.4-HspX), and LT70 (ESAT6-Ag85B-MPT64<190-198>-Mtb8.4-Rv2626c) three times subcutaneously every 3-weeks and challenged with the attenuated Mycobacterium bovis BCG intradermally 6-weeks after last immunization. The immune response induced by the vaccine candidates was measured, the histopathology induced by the BCG challenge was studied, and the number of bacilli in the liquefied caseum was determined. Results: The subunit vaccines generated high antigen-specific IgG antibodies and fastened the liquefaction and healing process, and significantly reduced the viable BCG load. The subunit vaccine LT70 and EAMM-MH reduced BCG bacterial load in comparison to proteins EAMM, MH, Rv2626c, and also BCG itself. The Koch phenomena induced by the LT70 and combination of EAMM-MH were the same as that produced by BCG itself and were more rapid than those induced by the other proteins and the saline controls. Conclusions: The subunit vaccines LT70 and the combination of EAMM-MH showed promising protective efficacy as expected in the rabbit skin model, which can serve as a visual and convenient new model for evaluating TB vaccines.


Early experience with a new aortic clamping system designed for port access cardiac surgery: the PortaClamp.
We report a clinical study to demonstrate the feasibility and safety of a new aortic crossclamping concept for use in port-access cardiac surgery. The limited access to the aorta in minimally invasive cardiac surgery mandates specific clamping modalities, which entail specific limitations, drawbacks, and costs. Therefore a new autoguided, extravascular, and atraumatic clamping system (PortaClamp) was developed to facilitate port-access surgery while potentially avoiding the complications and costs inherent to endoluminal clamping or "blind" crossclamping. Twenty patients underwent various cardiac operations under cardiopulmonary bypass and aortic crossclamping with the PortaClamp between February and September 2003. The method of aortic clamping is described and the operative course and clinical outcome of the patients are reported as surrogates of feasibility and safety. The average time to position the clamp was 196 +/- 75 seconds. Crossclamping through a 10-mm port or incision was achieved successfully, enabling cardiac arrest throughout the procedure in every patient. No patient presented with cardiovascular accident or transient ischemic attack, aortic dissection, or hematoma. Intensive care unit times were 12 +/- 3 hours; length of stay was 7.2 +/- 1.1 days. From this early experience we conclude that the PortaClamp system is safe and can effectively be used to crossclamp the aorta inexpensively to facilitate port-access cardiac surgery. Further comparative studies with the existing systems are warranted to confirm that the atraumatic design provides further benefit.


Costs of laparoscopic and open liver and pancreatic resection: a systematic review.
To study costs of laparoscopic and open liver and pancreatic resections, all the compiled data from available observational studies were systematically reviewed. A systematic review of the literature was performed using the Medline, Embase, PubMed, and Cochrane databases to identify all studies published up to 2013 that compared laparoscopic and open liver [laparoscopic hepatic resection (LLR) vs open liver resection (OLR)] and pancreatic [laparoscopic pancreatic resection (LPR) vs open pancreatic resection] resection. The last search was conducted on October 30, 2013. Four studies reported that LLR was associated with lower ward stay cost than OLR (2972 USD vs 5291 USD). The costs related to equipment (3345 USD vs 2207 USD) and theatre (14538 vs 11406) were reported higher for LLR. The total cost was lower in patients managed by LLR (19269 USD) compared to OLR (23419 USD). Four studies reported that LPR was associated with lower ward stay cost than OLR (6755 vs 9826 USD). The costs related to equipment (2496 USD vs 1630 USD) and theatre (5563 vs 4444) were reported higher for LPR. The total cost was lower in the LPR (8825 USD) compared to OLR (13380 USD). This systematic review support the economic advantage of laparoscopic over open approach to liver and pancreatic resection.


Morphological and morphometric study of the superior vestibular nerve trunk in guinea pigs.
The guinea pig has been chosen as a research model for otologic or neuropathic studies due to the relative ease of the cochlea, cochlear nerve, and vestibular nerve dissection. Little data have been reported on the normality of these nerves. The vestibular nerve is composed of the superior vestibular, inferior vestibular, and branch nerves. This study aimed to study the microscopic anatomy of the superior vestibular nerve (SVN) of guinea pigs using light microscopy and to search for normality patterns for use in experimental models in basic otologic research. We used eight male albino guinea pigs (Cavia porcellus, English strain), weighing between 400 and 500 g. After anesthetizing, the animals were perfused with a fixative solution of 2.5% glutaraldehyde. Dissection was performed by the access method to the temporal bone, coming to the rock and exposing the cochlea and vestibular nerve. The NVS fragments were removed, postfixed in osmium tetroxide, and embedded in the epoxy plastic resin Poly/Bed 812® (Polysciences Inc., Warrington, PA). Semi-thin transverse serial sections (0.5 μm) were made using a microtome MT6000-XL, RMC, Inc. and stained with toluidine blue. Morphology and morphometry were described and evaluated using the KS 400 application (Kontron 2.0, EchingBei, Munich, Germany) by macro, a computer program specially designed and developed for the study of the VIII nerve. The SVN was found to be devoid of epineurium, with only a thin conjunctive tissue layer. The myelin sheath of guinea pigs is relatively thin compared to the sensory and motor nerves found in mammals. The average fascicular area SVN was 0.19 ± 0.05 mm2 , with the largest area found to be 0.24 mm2 and the lowest was 0.12 mm2 . The average number of fibers was 5,753.00 ± 538 fibers. The density of myelinated fibers reached 32,316.08 ± 11,375.29 fibers/mm2 . Its diameter ranged from 1.0 to 9 μm and its peak was 3 μm. The measured results confirm the results of another study, indicating that the methodology is appropriate and reproducible. These findings are important for the evaluation of injured nerves in experimental models of peripheral neuropathy and basic ear disease.


Impact of IUdR on Rat 9L glioma cell survival for 25-35 keV photon-activated auger electron therapy.
The goal of the current study was to measure the energy dependence of survival of rat 9L glioma cells labeled with iododeoxyuridine (IUdR) that underwent photon-activated Auger electron therapy using 25-35 keV monochromatic X rays, i.e., above and below the K-edge energy of iodine. Rat 9L glioma cells were selected because of their radioresistance, ability to be implanted for future in vivo studies and analogy to radioresistant human gliomas. Survival curves were measured for a 4 MV X-ray beam and synchrotron produced monochromatic 35, 30 and 25 keV X-ray beams. IUdR was incorporated into the DNA at levels of 0, 9 and 18% thymidine replacement for 4 MV and 35 keV and 0 and 18% thymidine replacement for 30 and 25 keV. For 10 combinations of beam energy and thymidine replacement, 62 data sets (3-13 per combination) provided 776 data points (47-148 per combination). Survival versus dose data taken for the same combination, but on different days, were merged by including the zero-dose points in the nonlinear, chi-squared data fitting using the linear-quadratic model and letting the best estimate to the zero-dose plating efficiency for each of the different days be a fitting parameter. When comparing two survival curves, the ratio of doses resulting in 10% survival gave sensitization enhancement ratios (SER10) from which contributions due to linear energy transfer (LET) (SER10,LET), IUdR radiosensitization (SER10,RS), the Auger effect (SER10,AE) and the total of all effects (SER10,T) were determined. At 4 MV and 35, 30 and 25 keV, SER10,LET values were 1.00, 1.08 ± 0.03, 1.22 ± 0.02 and 1.37 ± 0.02, respectively. At 4 MV SER10,RS values for 9 and 18% IUdR were 1.28 ± 0.02 and 1.40 ± 0.02, respectively. Assuming LET effects were independent of percentage IUdR and radiosensitization effects were independent of energy, SER10,AE values for 18% IUdR at 35, 30 and 25 keV were 1.35 ± 0.05, 1.06 ± 0.03 and 0.98 ± 0.03, respectively. The value for 9% IUdR at 35 keV was 1.01 ± 0.04. First, we found the radioresistant rat 9L glioma cell line exhibited an SER10 due to the Auger effect of 1.35 at (35 keV, 18% IUdR) and an SER10 due to the radiosensitizing effect of 1.40 at (4 MV, 18% IUdR), both significantly less than values for previously reported cell lines. These low individual values emphasize the benefit of their combined value (SER10 of approximately 1.9) for achieving clinical benefit. Second, as expected, we observed that energies below the K-edge of iodine (25 and 30 keV), for which there are L, M and higher shell photoelectric events creating Auger electrons, show no promise for Auger electron therapy. Third, to proceed with future in vivo studies, additional data from 35-65 keV are needed to determine the optimal X-ray energy for IUdR Auger electron therapy. Only then can there be an answer to the question, how well the energy dependence of in vitro survival data supports the potential for photon-activated Auger electron therapy with IUdR in cancer radiotherapy.


Antidepressants and anti-inflammatory drugs differentially reduce the release of NGF and BDNF from rat platelets.
Platelets store serotonin and brain-derived neurotrophic factor (BDNF) as well as amyloid precursor protein and nerve growth factor (NGF), thus platelets are of special interest in depression and Alzheimer's disease, respectively. Both diseases are associated with inflammation and release of NGF or BDNF from platelets may play a potent role. Platelets were isolated from adult Sprague-Dawley rats and were incubated with anti-inflammatory drugs (ibuprofen and indomethacin) and antidepressants (citalopram, paroxetine and sertraline) (final concentration: 0.3 µM) with or without 2 mM calcium chloride. The release of NGF and BDNF was analyzed in comparison to serotonin release from rat platelets after 10 or 60 min. Spontaneous release of serotonin and BDNF was approximately 10-15% of total serotonin or BDNF content in platelets, but nearly all NGF was released within 10 min. All antidepressants increased the serotonin release from rat platelets. NGF release was reduced by sertraline, paroxetine and ibuprofen, but only when calcium was present, except for sertraline after 10 min. BDNF release was only reduced by ibuprofen when calcium was added. We conclude that antidepressants and anti-inflammatory drugs differentially influence the NGF and BDNF release, in a time-, dose- and calcium-specific pattern.


P014 Postoperative Recurrence in Crohn's Disease Patients Treated with Adalimumab versus Infliximab: A Systematic Review and Meta-Analysis.
Up to 80% of patients with Crohn's disease (CD) undergo intestinal resection at one point. However, the risk of post-operative recurrence (POR) increases with time, with half of these patients developing recurrence at five years after surgery. Treatment with anti-tumor necrosis factor (anti-TNF) agents has been shown to decrease the risk of clinical and endoscopic recurrence post-operatively. This meta-analysis aims to compare the rate of the two mostly commonly used anti-TNF agents (infliximab (IFX) and adalimumab (ADA)) and their efficacy in maintaining clinical and endoscopic remission in CD patients who were treated with adalimumab versus infliximab after surgery. A comprehensive search of Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Scopus was conducted from each database's inception to May 29th 2021. Comparative studies assessing the efficacy and safety of infliximab and adalimumab for postoperative CD patients were included. Primary outcomes included postoperative clinical and endoscopic remission. Secondary outcome was the risk of adverse events due to anti-TNF agents. Pooled event rates were calculated per person-year of follow-up. Four studies with total of 361 CD patients were included in the final analysis. Our meta-analysis showed no statistically significant difference in maintaining clinical and endoscopic remission rates between patients treated with infliximab and those with adalimumab (Pooled incidence rate ratio of 0.75 (95% CI 0.43-1.3), and 0.94 (95% CI 0.71-1.2), respectively) (Figure 1A, 2A). There were low to moderate heterogeneities (I2 = 57.1% for clinical remission and I2 = 0% for endoscopic remission). The funnel plot in each analysis indicated no publication bias, which was supported by Begg's and Egger's tests (Figure 1B, 2B). There was also no significant difference in the risk of adverse events between the two groups (RR= 0.56, 95% CI 0.068-4.5) (Figure 3). Our meta-analysis demonstrated comparable efficacy of infliximab and adalimumab in maintaining post-operative clinical and endoscopic remission in Crohn's disease, with similar rates of adverse events. Our meta-analysis was limited by the small number of total studies and patients included and the lack of randomized controlled trials.


Molecular and morphological characterization of Parabronema skrjabini of sheep and goats at three different geographical zones in Iran.
Parabronema skrjabini is a spirurid nematode of the family Habronematidae that lives in the abomasum of ruminants such as sheep and goats. The purpose of this study was to investigate the molecular and morphological aspects of Parabronema skrjabini in sheep and goats in Iran. The worms were collected from these animal species from three different regions. An internal transcribed spacer 2 ribosomal DNA (ITS2-rDNA) fragment of Parabronema skrjabini was amplified by polymerase chain reaction (PCR) using a pair of specific primers (Para-Ir-R and Para-Ir-F). Morphological studies based on the body length, the frontal shield, spicules of male and egg dimensions were performed. ITS2-rDNA sequences were between 167 and 299 bp in different isolates. ITS2 homology in different isolates was between 68% and 77% compared with the sequence data in GenBank. Morphological results showed that the average length of male and female worms in sheep were 16.5 mm and 36 mm and in goats 16 mm and 35.5 mm, respectively. The average length of the small and large spicules in sheep were 657.5 μm and 304.07 μm and in goats 653.08 μm and 302.66 μm, respectively. To our knowledge, this is the first study in the world exploring the genetic diversity of Parabronema in sheep and goats. Add this sentence in discussion: the low ITS2-rDNA identity in different isolates from Iran as compared to the reference sequence in GenBank (68-77%) raise questions regarding the species identity of the parasites isolated in Iran.


Study of membrane orientation and glycosylated extracellular loops of mouse P-glycoprotein by in vitro translation.
Increased expression of P-glycoprotein (Pgp) has been demonstrated to cause multidrug resistance (MDR) in vitro, and it may be responsible for chemotherapy failure in a number of human cancers. Pgp is a plasma membrane protein thought to function as an energy-dependent drug transporter. From its deduced protein sequence the topology of Pgp was proposed to contain 12 transmembrane domains with six extracellular loops and two cytoplasmic ATP-binding sites. To investigate further the membrane orientation of Pgp, we have expressed a full length cDNA of mouse mdr1, as well as its truncated forms, in a cell-free system supplemented with dog pancreatic microsomal membranes (RM). We determined which domains of the in vitro-synthesized Pgp had transversed the RM membranes by analyzing their resistance to protease digestion and their glycosylation state. To our surprise, this system revealed that a significant portion of in vitro-synthesized Pgp molecules has an additional glycosylated domain in the C-terminal half. Previously, only the first predicted extracellular loop near the N terminus had been thought to be glycosylated. Furthermore, we discovered that Pgp has at least two functional signal recognition particle/docking protein dependent signal sequences, one at the N-terminal half and the other at the C-terminal half. These findings suggest a new topological model for in vitro synthesized P-glycoprotein which may be relevant to its in vivo topology.


Synthesis and Biological Activity of Myricetin Derivatives Containing Pyrazole Piperazine Amide.
In this paper, a series of derivatives were synthesized by introducing the pharmacophore pyrazole ring and piperazine ring into the structure of the natural product myricetin through an amide bond. The structures were determined using carbon spectrum and hydrogen spectrum high-resolution mass spectrometry. Biological activities of those compounds against bacteria, including Xac (Xanthomonas axonopodis pv. Citri), Psa (Pseudomonas syringae pv. Actinidiae) and Xoo (Xanthomonas oryzae pv. Oryzae) were tested. Notably, D6 exhibited significant bioactivity against Xoo with an EC50 value of 18.8 μg/mL, which was higher than the control drugs thiadiazole-copper (EC50 = 52.9 μg/mL) and bismerthiazol (EC50 = 69.1 μg/mL). Furthermore, the target compounds were assessed for their antifungal activity against ten plant pathogenic fungi. Among them, D1 displayed excellent inhibitory activity against Phomopsis sp. with an EC50 value of 16.9 μg/mL, outperforming the control agents azoxystrobin (EC50 = 50.7 μg/mL) and fluopyram (EC50 = 71.8 μg/mL). In vitro tests demonstrated that D1 possessed curative (60.6%) and protective (74.9%) effects on postharvest kiwifruit. To investigate the active mechanism of D1, its impact on SDH activity was evaluated based on its structural features and further confirmed through molecular docking. Subsequently, the malondialdehyde content of D1-treated fungi was measured, revealing that D1 could increase malondialdehyde levels, thereby causing damage to the cell membrane. Additionally, the EC50 value of D16 on P. capsici was 11.3 μg/mL, which was superior to the control drug azoxystrobin (EC50 = 35.1 μg/mL), and the scanning electron microscopy results indicated that the surface of drug-treated mycelium was ruffled, and growth was significantly affected.


Inhaled Corticosteroid use and the Risk of Pneumonia and COPD Exacerbations in the UPLIFT Study.
Unlike many other COPD studies, the 4-year UPLIFT trial permitted inhaled corticosteroid (ICS) use during run-in and treatment phases. This provided the opportunity to prospectively observe the continuing effects of ICS on respiratory events in closely observed COPD population. We aimed to determine rate and number of episodes of pneumonia and exacerbations of COPD in patients entering the study on no ICS, fluticasone proprionate (FP), and other ICS. The UPLIFT dataset was examined retrospectively, and patients were divided into three groups based on their medications at entry: no ICS, FP and other ICS. Poisson regression was used to compare the frequency of respiratory adverse events. At entry, the groups were well matched apart from a higher FEV1% predicted (38 vs. 41%; ICS vs. no ICS, respectively) and prevalence of current smoking (26 vs. 36%; ICS vs. no ICS, respectively). Incidence rates of pneumonia were significantly higher in patients taking ICS compared to no ICS (0.068 vs. 0.056 respectively; p = 0.012). When the FP group was compared to the other ICS, the event rate was even higher (0.077 vs. 0.058, respectively; p < 0.001). COPD exacerbations were more frequent in patients taking ICS, with significantly greater rate in the FP group compared to that seen with other ICS (0.93 vs. 0.84 respectively; p = 0.013). ICS use was associated an increase in respiratory adverse event rates, but whether this was due to more severe illness at entry is unknown. In subgroup analysis, the excess of morbidity in the ICS group appeared to be mainly associated with those receiving FP at randomisation.


Case 252: Acute Hyperammonemic Encephalopathy Resulting from Late-Onset Ornithine Transcarbamylase Deficiency.
History A 19-year-old woman with no pertinent medical history was brought to the emergency department after being found unconscious on her bathroom floor by her roommate. In the preceding weeks, she had reported intractable nausea and vomiting, for which she had been taking ondansetron. No other medications had been prescribed. The day prior to presentation, she had contacted her mother and described increasing confusion. Glasgow coma scale score on arrival in the emergency department was 4. Intravenous naloxone was administered, without immediate response. Initial blood glucose level was 232 mg/dL (12.8 mmol/L) (normal range, 79-140 mg/dL [4.4- 7.7 mmol/L]), and other routine laboratory test results were normal. Urine toxicology results were negative. Cerebrospinal fluid evaluation revealed levels were within normal limits. Neurologic examination revealed dilated pupils, which showed a sluggish response to light, and left lower extremity rigidity with intermittent tremors. Initial unenhanced cranial computed tomographic (CT) findings were negative. Magnetic resonance (MR) imaging of the brain was performed. The patient's condition deteriorated, with increasing cerebral edema over the next week, and she was declared brain dead. Her liver was transplanted into an adult recipient, who subsequently developed cerebral edema and elevated plasma ammonia levels, resulting in death in the immediate postoperative period.


Plasma Sfrp5 levels correlate with determinants of the metabolic syndrome in Chinese adults.
Secreted frizzled-related protein-5 (Sfrp5) is a novel adipokine, and it has been found to link insulin resistance with diabetes. Animal studies have revealed the role of Sfrp5 in regulating lipid and glucose metabolism. The objective of this study was to investigate the relationship between Sfrp5 and the metabolic syndrome (MetS) in a cross-sectional study. We conducted a series of cross-sectional studies of Chinese population including 194 control participants and 90 MetS patients. Circulating Sfrp5 concentrations were determined by ELISA. The relationships between circulating Sfrp5 levels and MetS components were assessed. Circulating Sfrp5 was significantly lower in newly examined MetS patients than in control participants (49.1 ± 17.2 vs 61.6 ± 23.2 μg/L, P < .01). Circulating Sfrp5 correlated negatively with markers of adiposity (waist-to-hip ratio, body mass index, and free fatty acids, P < .001 or P < .05). Furthermore, Sfrp5 levels correlated with fasting insulin, 2 h-ins, fasting blood glucose, 2 h post-glucose load blood glucose, HbA1c , and homeostasis model assessment of insulin resistance. In addition, circulating Sfrp5 levels were closely associated with blood pressure, high-density lipoprotein cholesterol, triglycerides, and atherosclerotic index. Circulating concentrations of Sfrp5 decreased progressively with continued increases in the numbers of MetS components. The analysis of receiver operating characteristic curves revealed that the best cutoff value for circulating Sfrp5 to predict MetS was 46.8 μg/L (sensitivity 70.1 %, specificity 47.8 %, and AUC 0.66). We conclude that Sfrp5 may be an adipokine that is associated with the pathogenesis of MetS in humans.


Fetal pancreatic antigens in the Syrian golden hamster and their relationship to development and carcinogenesis.
A rabbit antiserum raised against pancreatic extracts of newborn Syrian hamsters was used in a histological study of pancreas development. This antiserum, after being rendered specific by appropriate absorption, stained the cytoplasm of acinar cells in neonatal pancreas. The reaction was observed from the 13th day of gestation (3 days before delivery) until the 10th day after birth. This period was characterized by a progressive maturation of the endocrine pancreas. The disappearance of fetal pancreatic antigens coincided with the appearance of Langerhans islets. Adult pancreas was not stained with the antiserum, but a good reaction was observed in chemically induced pancreas adenocarcinomas. All reactions were confirmed by immunochemical studies. Polyacrylamide gel electrophoresis followed by immunodetection on nitrocellulose blots demonstrated the presence of two major fetal antigens. Thus, this study demonstrates the existence of fetal pancreatic antigens associated with development which are reexpressed in pancreatic tumors.


Interventions to Enhance Achievement to Independent Oral Feeds in Premature Infants: A Scoping Review.
To assess the effectiveness of interventions aimed at facilitating the transition from full tube to independent oral feeds in premature infants. Scoping review methodology using the Preferred Reporting items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA_ScR). A search of six databases (EMBASE, MEDLINE, CINAHL, Web of Science, COCHRANE, and OT Seeker), using keywords related to oral feeding and premature infants retrieved 11,870 articles. Full-text screening was completed for 36 articles, and 21 articles were included in this review. Review of the 21 articles revealed five intervention types: oral stimulation (n = 14), swallow/gustatory stimulation (n = 3), olfactory stimulation (n = 2), tactile/kinesthetic stimulation (n = 1), and auditory stimulation (n = 1). Oral stimulation had the most studies with consistent evidence supporting its beneficial effect to facilitate achievement to independent oral feeds, swallow/gustatory stimulation appeared to have some benefit, but evidence for olfactory, tactile/kinesthetic, and auditory stimulation was sparse. Oral stimulation has the most studies with consistent evidence, and thus is suggested as a suitable early intervention strategy that can be used by health providers to facilitate the achievement to independent oral feeds in premature infants. The alternate forms of stimulation have limited evidence and necessitate further studies to confirm their benefits.


Spectrum of antiviral activity and mechanism of action of zidovudine. An overview.
Zidovudine is a potent in vitro inhibitor of human immunodeficiency virus (HIV) with varying efficacy against other retroviruses. With the exception of Epstein-Barr virus, all non-retroviruses tested so far have been insensitive to inhibition by zidovudine. In vivo, efficacy of zidovudine was demonstrated against Rauscher murine leukemia virus and feline leukemia virus. In both experimental models, infections completely resolved in animals when the drug was administered soon after infection. These results suggest that prompt initiation of zidovudine therapy, following a known exposure to HIV, should be considered. Mechanism studies show that zidovudine is phosphorylated to the monophosphate and diphosphate derivatives by the host cell cytosolic thymidine kinase and thymidylate kinase, respectively. The identity of the enzyme that phosphorylates zidovudine diphosphate is not known, but is believed to be the cellular nucleoside diphosphate kinase. The triphosphate of zidovudine appears to be the active form of the drug. Zidovudine triphosphate competes well with thymidine 5'-triphosphate for binding to the HIV reverse transcriptase and also functions as an alternative substrate. Incorporation of zidovudine monophosphate results in chain termination. However, it is not clear which mechanism, chain termination or competition with thymidine 5'-triphosphate, or a combination of both, is responsible for the inhibition of HIV replication.


Identification and characterization of a stage specific membrane protein involved in flagellar attachment in Trypanosoma brucei.
Flagellar attachment is a visibly striking morphological feature of African trypanosomes but little is known about the requirements for attachment at a molecular level. This study characterizes a previously undescribed membrane protein, FLA3, which plays an essential role in flagellar attachment in Trypanosoma brucei. FLA3 is heavily N-glycosylated, locates to the flagellar attachment zone and appears to be a bloodstream stage specific protein. Ablation of the FLA3 mRNA rapidly led to flagellar detachment and a concomitant failure of cytokinesis in the long slender bloodstream form but had no effect on the procyclic form. Flagellar detachment was obvious shortly after induction of the dsRNA and the newly synthesized flagellum was often completely detached after it emerged from the flagellar pocket. Within 12 h most cells possessed detached flagella alongside the existing attached flagellum. These results suggest that proteins involved in attachment are not shared between the new and old attachment zones. In other respects the detached flagella appear normal, they beat rapidly although directional motion was lost, and they possess an apparently normal axoneme and paraflagellar rod structure. The flagellar attachment zone appeared to be disrupted when FLA3 was depleted. Thus, while flagellar attachment is a constitutive feature of the life cycle of trypanosomes, attachment requires stage specific elements at the protein level.


Person-Centered Assessment and Care Planning.
The quality of dementia care rendered to individuals and families is contingent upon the quality of assessment and care planning, and the degree to which those processes are person-centered. This paper provides recommendations for assessment and care planning derived from a review of the research literature. These guidelines build upon previous recommendations published by the Alzheimer's Association, and apply to all settings, types, and stages of dementia. The target audience for these guidelines includes professionals, paraprofessionals, and direct care workers, depending on their scope of practice and training.


A note on the expected biases in conventional iterative health state valuation protocols.
Typical health state valuation exercises use tradeoff methods, such as the time tradeoff or the standard gamble, involving a series of iterated questions so that a value for each health state by each individual respondent is elicited. This iterative process is a source of potential biases, but this has not received much attention in the health state valuation literature. The issue has been researched widely in the contingent valuation (CV) literature, which elicits the monetary value of hypothetical outcomes. The lessons learned in the CV literature are revisited in the context of the design and administration of health state valuations. The article introduces the main known biases in the CV literature and then examines how each might affect conventional iterative health state valuations. Of the 8 main types of biases, starting point bias, range bias, and incentive incompatibility bias are found to be potentially relevant. Furthermore, the magnitude and direction of the bases are unlikely to be uniform and depend on the range of the value (e.g., between 0 and 0.5). Limitation. This is an overview article, and the conclusions drawn need to be tested empirically. Health state valuation studies, like CV studies, are susceptible to a number of possible biases that affect the resulting values. Their magnitude and direction are unlikely to be uniform, and thus empirical studies are needed to diagnose the problem and, if necessary, to address it.


Evaluation of biomechanical properties and biocompatibility: are partially absorbable cords eligible for anterior cruciate ligament reconstruction?
Introduction: Independent augmentation technology based on reinforcing devices has been reported to signifi-cantly reduce the elongation behavior of graft and improve knee stability after anterior cruciate ligament reconstruction (ACLR). Using biodegradable devices could reduce the risk of severe inflammatory reactions due to particle accumulation from foreign bodies. Given the limitations of the mechanical properties of biodegradable materials, partially biodegradable composite devices may offer a compromise strategy. Methods: Three types of partially absorbable core-sheath sutures, including low-absorbable cord (LA-C), medium-absorbable cord (MA-C) and high-absorbable cord (HA-C), were braided using unabsorbable ultra-high molecular weight polyethylene (UHMWPE) yarn and absorbable polydioxanone (PDO) monofil-ament bundle based on the desired configuration. The feasibility of these partially absorbable cords were verified by biomechanical testing, material degradation testing, and cell experiments, all performed in vitro. Results: Reinforcement of an 8 mm graft with the cords decreased dynamic elongation by 24%-76%, was positively related to dynamic stiffness, and increased the failure load by 44%-105%, during which LA-C showed maximum enhancement. Human ligament-derived fibroblasts showed good proliferation and vitality on each cord over 2 weeks and aligned themselves in the direction of the fibers, especially the UHMWPE portion. Discussion: This study supports the potential of partially degradable UHMWPE/PDO cords, particularly LA-C, for graft protection. Nervertheless, a higher proportion of biodegradable material results in lower stiffness, which may impair the protective and lead to mechanical instability during degradation.


G-Protein-coupled modulation of presynaptic calcium currents and transmitter release by a GABAB receptor.
Presynaptic GABAB receptors play a regulatory role in central synaptic transmission. To elucidate their underlying mechanism of action, we have made whole-cell recordings of calcium and potassium currents from a giant presynaptic terminal, the calyx of Held, and EPSCs from its postsynaptic target in the medial nucleus of the trapezoid body of rat brainstem slices. The GABAB receptor agonist baclofen suppressed EPSCs and presynaptic calcium currents but had no effect on voltage-dependent potassium currents. The calcium current-EPSC relationship measured during baclofen application was similar to that observed on reducing [Ca2+]o, suggesting that the presynaptic inhibition generated by baclofen is caused largely by the suppression of presynaptic calcium influx. Presynaptic loading of the GDP analog guanosine-5'-O-(2-thiodiphosphate) (GDPbetaS) abolished the effect of baclofen on both presynaptic calcium currents and EPSCs. The nonhydrolyzable GTP analog guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) suppressed presynaptic calcium currents and occluded the effect of baclofen on presynaptic calcium currents and EPSCs. Photoactivation of GTPgammaS induced an inward rectifying potassium current at the calyx of Held, whereas baclofen had no such effect. We conclude that presynaptic GABAB receptors suppress transmitter release through G-protein-coupled inhibition of calcium currents.


Frequent Eye Examinations Urged for Children with Type 2 Diabetes.
According to this study: Children who had type 2 diabetes developed vision-threatening retinopathy after a shorter duration of diabetes and at a higher rate than children who had type 1 diabetes.Children who have type 2 diabetes may need eye examinations as frequently or more frequently than those who have type 1 diabetes.


Pembrolizumab Approved for Hodgkin Lymphoma.
The FDA has approved pembrolizumab for adults and children with classical Hodgkin lymphoma whose disease is refractory to or has relapsed after at least three prior therapies. The approval marks the first time that a PD-1 inhibitor has been indicated for blood cancers-and for children.


Indole Alkaloids from a Soil-Derived Clonostachys rosea.
Clonorosins A (1) and B (2), two novel indole alkaloids featuring unprecedented 6/5/6/6/5 and 6/5/5 cores, together with seven known indole-linked 2,5-diketopiperazine alkaloids (3-9), were isolated from the soil-derived fungus Clonostachys rosea YRS-06. The new structures were proposed through HR-MS, NMR, and ECD spectroscopic data. They were established by comparing the calculated NMR, ECD, and specific rotation data with the experimental. To assist in determining the absolute configuration of the chiral carbon in the side chain of 2,5-diketopiperazine derivatives, flexible analogues 3i-3iv were synthesized and analyzed. 1 was active against Fusarium oxysporum with an MIC value of 50 μg/mL. 7 and 8 showed excellent activity against human HeLa and HepG2 cells with IC50 values of 0.12-0.60 μM.


Ralfuranones contribute to mushroom-type biofilm formation by Ralstonia solanacearum strain OE1-1.
After invasion into intercellular spaces of tomato plants, the soil-borne, plant-pathogenic Ralstonia solanacearum strain OE1-1 forms mushroom-shaped biofilms (mushroom-type biofilms, mBFs) on tomato cells, leading to its virulence. The strain OE1-1 produces aryl-furanone secondary metabolites, ralfuranones (A, B, J, K and L), dependent on the quorum sensing (QS) system, with methyl 3-hydroxymyristate (3-OH MAME) synthesized by PhcB as a QS signal. Ralfuranones are associated with the feedback loop of the QS system. A ralfuranone productivity-deficient mutant (ΔralA) exhibited significantly reduced growth in intercellular spaces compared with strain OE1-1, losing its virulence. To analyse the function of ralfuranones in mBF formation by OE1-1 cells, we observed cell aggregates of R. solanacearum strains statically incubated in tomato apoplast fluids on filters under a scanning electron microscope. The ΔralA strain formed significantly fewer microcolonies and mBFs than strain OE1-1. Supplementation of ralfuranones A, B, J and K, but not L, significantly enhanced the development of mBF formation by ΔralA. Furthermore, a phcB- and ralA-deleted mutant (ΔphcB/ralA) exhibited less formation of mBFs than OE1-1, although a QS-deficient, phcB-deleted mutant formed mBFs similar to OE1-1. Supplementation with 3-OH MAME significantly reduced the formation of mBFs by ΔphcB/ralA. The application of each ralfuranone significantly increased the formation of mBFs by ΔphcB/ralA supplied with 3-OH MAME. Together, our findings indicate that ralfuranones are implicated not only in the development of mBFs by strain OE1-1, but also in the suppression of QS-mediated negative regulation of mBF formation.


Training Requirements and Curriculum Content for Primary Care Providers Delivering Preventive Oral Health Services to Children Enrolled in Medicaid.
Despite the emphasis on delivery of preventive oral health services in non-dental settings, limited information exists about state Medicaid policies and strategies to educate practicing physicians in the delivery of these services. This study aims to determine: (1) training requirements and policies for reimbursement of oral health services, (2) teaching delivery methods used to train physicians, and (3) curricula content available to providers among states that reimburse non-dental providers for oral health services. Using Web-based Internet searches as the primary data source, and a supplemental e-mail survey of all states offering in-person training, we assessed training requirements, methods of delivery for training, and curriculum content for states with Medicaid reimbursement to primary care providers delivering preventive oral health services. RESULTS of descriptive analyses are presented for information collected and updated in 2014. Forty-two states provide training sessions or resources to providers, 34 requiring provider training before reimbursement for oral health services. Web-based training is the most common CME delivery method. Only small differences in curricular content were reported by the 11 states that use in-person didactic sessions as the delivery method. Although we found that most states require training and curricular content is similar, training was most often delivered using Web-based courses without any additional delivery methods. Research is needed to evaluate the impact of a mixture of training methods and other quality improvement methods on increased adoption and implementation of preventive oral health services in medical practices.


Ultrastructure of Skeletal Muscles in Mice Lacking Muscle-Specific VEGF Expression.
Vascular endothelial growth factor-A (VEGF) influences several physiological processes including endothelial cell function, angiogenesis and maintenance of organ/tissue capillarity. While the functional aspects of VEGF were vigorously investigated, only little detail is known on structural integrity of skeletal muscle fibers and capillaries in mice lacking VEGF expression in their muscles. Therefore, we assessed systematically the architecture of the glycolytic plantaris and the oxidative soleus muscles obtained from muscle-specific VEGF knockout (mVEGF-KO, n = 7) mice and their wild-type (WT, n = 7) littermates by morphometry after transmission electron microscopy. The capillary/fiber ratio was lower (plantaris: -63.5%; soleus: -54.8%; P ≤ 0.05) in mVEGF-KO mice than in WT mice. In plantaris, quantification of volume density (Vv) of compartments revealed higher Vv of total mitochondria (+56.5%, P ≤ 0.05) as well as higher Vv-values for both intrafibrillar (+39%; P ≤ 0.05) and subsarcolemmal (+220%; P ≤ 0.05) mitochondrial pools in mVEGF-KO mice than WT mice. The capillary phenotype also differed (P ≤ 0.05) between the two mouse-strains: Vv (-17.4%), absolute area size (-19.1%) and thickness (-19.6%) of the endothelium layer were lower and Vv of capillary lumen (+15.1%) was higher in mVEGF-KO mice than in WT littermates. In soleus, mitochondrial Vv in fibers and the structural indicators specific to the capillary phenotype exhibited the same tendency in differences between the mouse strains without reaching statistical significance. Our morphometric analysis demonstrates that the lower capillary supply in plantaris of mVEGF-KO mice is accompanied by higher mitochondrial Vv in muscle fibers as well as lumen dilation and endothelium thinning of capillaries. These structural alterations were more pronounced in a glycolytic than an oxidative muscle. Anat Rec, 300:2239-2249, 2017. © 2017 Wiley Periodicals, Inc.


Efficient whole-cell biocatalyst for 2,3-butanediol/acetoin production with NADH/NAD+ regeneration system in engineered Serratia marcescens.
Serratia marcescens is reported to possess the potential for industrial 2,3-butanediol or acetoin production by fermentation. But 2,3-butanediol or acetoin are always co-produced and this may make purification process difficult. So biocatalytic technologies may be the appropriate production methods. In this study, we developed an auto-inducing expression system based on pET system and swr quorum sensing system by using S. marcescens. By using this system, S. marcescens could be engineered as whole-cell biocatalyst to obtain 2,3-butanediol or acetoin. In order to convert diacetyl to 2,3-butanediol, formate dehydrogenase (FDH) and 2,3-butanediol dehydrogenase were co-expressed to construct a NADH regeneration system. This whole-cell biocatalyst could efficiently produced 53.6 g/L 2,3-butanediol with a productivity of 3.35 g/Lh. Next, in order to convert 2,3-butanediol to acetoin, NADH oxidase and 2,3-butanediol dehydrogenase were co-expressed to construct a NAD+ regeneration system. This whole-cell biocatalyst could efficiently produced 59 g/L acetoin with a productivity of 2.95 g/Lh. This work indicated this auto-inducing system was a powerful tool to construct whole-cell biocatalyst in S. marcescens in 2,3-butanediol and acetoin production.


Mapping, expression and regulation of the TRα gene in porcine adipose tissue.
Thyroid hormone receptors (TR) are members of the nuclear receptor superfamily. There are at least two TR isoforms, TRα and TRβ. The TRα isoform plays a critical role in mediating the action of thyroid hormone in adipose tissue. We mapped the porcine TRα gene to chromosome 12 p11-p13, by using the ImpRH panel. We examined tissue-localization of TRα and determined expression patterns of TRα in porcine adipose tissue with quantitative real-time PCR. TRα was expressed in all tissues, including heart, liver, spleen, stomach, pancreas, brain, small intestine, skeletal muscle, and subcutaneous adipose tissue. In the adipose tissue, the expression of TRα decreased postnatally. Compared to Yorkshire pigs, Jinhua pigs had significantly lower expression levels of TRα gene in the subcutaneous fat tissue. The expression levels of β2-AR, HSL and ATGL were also significantly lower in Jinhua pigs than in Yorkshire pigs. However, no significant differences in PPARγ and SREBP-1C expression levels were found between Jinhua and Yorkshire pigs. Incubation of porcine adipose tissue explants with high doses of isoproterenol (100 and 1000 nM) significantly increased the expression levels of TRα. We conclude that there is considerable evidence that TRα plays an important role in fat deposition in porcine adipose tissue.


Characterization of proteins encoded by the short unique region of herpesvirus of turkeys by in vitro expression.
Nine open reading frames mapping in the short unique (US) region of the genome of herpesvirus of turkeys (HVT) were expressed by in vitro transcription and translation. The observed M(r)s of US10, SORF3 and US2 were as predicted from the sequence but there were discrepancies between the observed and predicted M(r)s of US1, protein kinase, gI, gD and gE. These could be accounted for in most cases by post-translational and co-translational processing. Analysis of the synthesized products at different time points provided evidence for post-translational modification of HVT protein kinase. Translation in the presence of microsomal membranes resulted in co-translational processing of HVT gD, gI and gE by glycosylation and signal peptide cleavage.


[Non-celiac wheat sensitivity - growing evidence for a wheat-dependent immune-mediated disease].
These past years, double-blinded placebo controlled food challenges in subjects with irritable bowel syndrome (IBS) reporting sensitivity to gluten have identified a group of individuals without celiac disease (CD) in whom symptoms were clearly aggravated by wheat. Not only did the exposure to wheat trigger intestinal symptoms, but also frequently fatigue and a sensation of foggy mind. Recent studies in mice and sensitive subjects suggest an immune activation by various wheat proteins, with a rapid increase of intestinal mucosal permeability and recruitment of intraepithelial lymphocytes. Moreover, markers of epithelial damage and immune activation are increased in the peripheral blood of wheat-sensitive subjects upon challenge, and decrease under gluten-free diet. Larger studies are needed to better characterize this entity and to distinguish it from food-aggravated IBS and a « forme fruste » of CD.


A new species of Symplocos (Symplocaceae) from southern Ecuador.
A new species from Ecuador, Symplocos limonensis, is here described and illustrated. It resembles Symplocos clethrifolia but differs by having larger leaves with evident (i.e., not concealed) areoles on lower surface, sessile inflorescences, smaller white corollas, and fewer stamens. The species is only known from three collections in the Andean forests of Morona-Santiago Province in southern Ecuador.


Polycyclic aromatic hydrocarbons: bioaccumulation in dragonfly nymphs (Anisoptera), and determination of alkylated forms in sediment for an improved environmental assessment.
Road runoff carries a mixture of contaminants that threatens the quality of natural water bodies and the health of aquatic organisms. The use of sedimentation ponds is a nature-based solution for the treatment of road runoff. This study assessed the concentration of polycyclic aromatic hydrocarbons (PAHs) and their alkylated homologues in sediment from seven highway sedimentation ponds and three natural urban ponds. In addition, the study explored the bioaccumulation of PAHs in dragonfly nymphs (Anisoptera). Finally, biota-sediment accumulation factors (BSAFs) were estimated. The results revealed a significant difference in the concentrations of 16 priority PAHs in sediment, with overall higher levels in sedimentation ponds (2,911 µg/kg on average) compared to natural urban ponds (606 µg/kg on average). PAH levels increased substantially once alkylated homologues were considered, with alkylated comprising between 42 and 87% of the total PAH in sediment samples. These results demonstrate the importance of alkylated forms in the environmental assessment of PAHs. The bioaccumulation assessment indicates that dragonfly nymphs bioaccumulate PAHs to a certain degree. It is not clear, however, whether they metabolize PAHs. BSAF results ranged from approx. 0.006 to 10 and indicate that BSAFs can be a powerful tool to determine the functionality of sedimentation ponds.


Histological detection of oestrogen receptor in human breast carcinomas.
Histological (immunocytochemical and cytochemical) methods for demonstrating oestrogen receptor within breast-cancer cells gave a positive reaction in 29 (83%) of 35 breast carcinomas. Oestrogen receptor could be demonstrated in cytoplasm and nucleus in 15, cytoplasm only in 10, and nucleus only in 4. 24 (68.5%) of the carcinomas had detectable oestrogen receptor by the dextran-coated charcoal method, and all of these were positive by histological methods. The cytochemical method gave much better results than the immunocytochemical method and showed that carcinomas contain variable proportions of oestrogen-receptor-positive and oestrogen-receptor-negative cells.


Isolation and characterization of Streptomyces spp. strains F-6 and F-7 capable of decomposing alkali lignin.
Biodegradation and bioconversion of lignin are the result of the combined action of fungi, bacteria and actinomycetes. Through screening from forest soil, two novel isolated actinomycete strains were identified as Streptomyces spp. strains F-6 and F-7 by their morphology, cultural characteristics and high homology to the 16S rRNA gene. Both strains possessed laccase and manganese peroxidase activities. Laccase activity produced by strain F-6 was up to 935.4 U g(-1) dry cell weight. More than 50% of alkali lignin was removed by strains F-6 and F-7 in 12 days of incubation. GC-MS analysis of the biodegraded products showed strain F-6 converted lignin into phenol and broken phenol compounds. The two strains could co-culture with white-rot fungus, and the combined actinonycete-fungus system decomposed alkali lignin effectively.


Mechanisms of inhibition of CaV3.1 T-type calcium current by aliphatic alcohols.
Many aliphatic alcohols modulate activity of various ion channels involved in sensory processing and also exhibit anesthetic capacity in vivo. Although the interaction of one such compound, 1-octanol (octanol) with different T-type calcium channels (T-channels) has been described, the mechanisms of current modulation and its functional significance are not well studied. Using patch-clamp technique, we investigated the mechanisms of inhibition of T-currents by a series of aliphatic alcohols in recombinant human Ca(V)3.1 (alpha1G) T-channel isoform expressed in human embryonic kidney (HEK) 293 cells and thalamocortical (TC) relay neurons in brain slices of young rats. Octanol, 1-heptanol (heptanol) and 1-hexanol (hexanol) inhibited the recombinant Ca(V)3.1 currents in concentration-dependent manner yielding IC(50) values of 362 microM, 1063 microM and 3167 microM, respectively. Octanol similarly inhibited native thalamic Ca(V)3.1 T-currents with an IC(50) of 287 microM and diminished burst firing without significant effect on passive membrane properties of these neurons. Inhibitory effect of octanol on T-currents in both native and recombinant cells was accompanied with accelerated macroscopic inactivation kinetics and hyperpolarizing shift in the steady-state inactivation curve. Additionally, octanol induced a depolarizing shift in steady-state activation curves of T-current in TC neurons. Surprisingly, the recovery from fast inactivation at hyperpolarized membrane potentials was accelerated by octanol up 3-fold in native but not recombinant channels. Given the importance of thalamocortical pathways in providing sleep, arousal, and anesthetic states, modulation of thalamic T-currents may at least contribute to the pharmacological effects of aliphatic alcohols.


From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinson's Disease Models.
Parkinson's disease (PD) is a progressive neurodegenerative disease that affects ∼5 million people around the world. PD etiopathogenesis is poorly understood and curative or disease modifying treatments are not available. Mechanistic studies have identified numerous pathogenic pathways that overlap with many other neurodegenerative diseases. Mutations in the protein optineurin (OPTN) have recently been identified as causative factors for glaucoma and amyotrophic lateral sclerosis. OPTN has multiple recognized roles in neurons, notably in mediating autophagic flux, which has been found to be disrupted in most neurodegenerative diseases. OPTN(+ )aggregates have preliminarily been identified in cytoplasmic inclusions in numerous neurodegenerative diseases, however, whether OPTN has a role in PD pathogenesis has yet to be tested. Thus, we chose to test the hypothesis that OPTN expression and localization would be modulated in pre-clinical PD models. To test our hypothesis, we characterized midbrain OPTN expression in normal rats and in a rat rotenone PD model. For the first time, we show that OPTN is enriched in dopamine neurons in the midbrain, and its expression is modulated by rotenone treatment in vivo Here, animals were sampled at time-points both prior to overt neurodegeneration and after severe behavioral deficits, where a lesion to the nigrostriatal dopamine system is present. The effect and magnitude of OPTN expression changes are dependent on duration of treatment. Furthermore, OPTN colocalizes with LC3 (autophagic vesicle marker) and alpha-synuclein positive puncta in rotenone-treated animals, potentially indicating an important role in autophagy and PD pathogenesis.


Antibacterial Activity Affected by the Conformational Flexibility in Glycine-Lysine Based α-Helical Antimicrobial Peptides.
Antimicrobial peptides often show broad-spectrum activity due to a mechanism based on bacterial membrane disruption, which also reduces development of permanent resistance, a desirable characteristic in view of the escalating multidrug resistance problem. Host cell toxicity however requires design of artificial variants of natural AMPs to increase selectivity and reduce side effects. Kiadins were designed using rules obtained from natural peptides active against E. coli and a validated computational algorithm based on a training set of such peptides, followed by rational conformational alterations. In vitro activity, tested against ESKAPE strains (ATCC and clinical isolates), revealed a varied activity spectrum and cytotoxicity that only in part correlated with conformational flexibility. Peptides with a higher proportion of Gly were generally less potent and caused less bacterial membrane alteration, as observed by flow cytometry and AFM, which correlate to structural characteristics as observed by circular dichroism spectroscopy and predicted by molecular dynamics calculations.


Encapsulation of clay within polymer particles in a high-solids content aqueous dispersion.
By using a two-step polymerization process, it was possible to encapsulate clay platelets within polymer particles dispersed in water. First, seed polymer particles with chemically bonded clay were obtained by batch miniemulsion polymerization. Then, the clay was buried within the particles by the addition of neat monomer in a second step. The final stable dispersions can have a solids content of up to 50 wt %. Transmission electron microscopy images clearly show the presence of clay platelets inside the polymer colloids, although they are not totally exfoliated. The obtained nanocomposites showed an increase in both the storage modulus in the rubbery state and the water resistance as the clay content increases. The approach presented here might be useful for encapsulating other high-aspect ratio nanofillers.


Synovial hemangioma: a rare benign synovial lesion.
We report an unusual case of a 10-year-old female with complaints of pain and swelling of the right knee for the last 4 years along with the limitation of movement for last 1 year. Repeated fine needle aspirations yielded blood and a provisional diagnosis of hemarthrosis was suggested. Coagulation profile subsequently carried out was found to be within normal limits. Arthroscopic biopsy was performed and tissue was sent for histopathological examination. A diagnosis of synovial hemangioma was made. Subtotal synovectomy was performed and the lesion was completely excised. The patient is completely asymptomatic and shows no signs of recurrence at 1 year.


A truncated PACT protein resulting from a frameshift mutation reported in movement disorder DYT16 triggers caspase activation and apoptosis.
Protein Activator (PACT) activates the interferon (IFN)-induced double-stranded (ds) RNA-activated protein kinase (PKR) in response to stress signals. Oxidative stress and endoplasmic reticulum (ER) stress causes PACT-mediated PKR activation, which leads to phosphorylation of translation initiation factor eIF2α, inhibition of protein synthesis, and apoptosis. A dominantly inherited form of early-onset dystonia 16 (DYT16) has been identified to arise due to a frameshift (FS) mutation in PACT. To examine the effect of the resulting truncated mutant PACT protein on the PKR pathway, we examined the biochemical properties of the mutant protein and its effect on mammalian cells. Our results indicate that the FS mutant protein loses its ability to bind dsRNA as well as its ability to interact with PKR while surprisingly retaining the ability to interact with PACT and PKR-inhibitory protein TRBP. The truncated FS mutant protein, when expressed as a fusion protein with a N-terminal fluorescent mCherry tag aggregates in mammalian cells to induce apoptosis via activation of caspases both in a PKR- and PACT-dependent as well as independent manner. Our results indicate that interaction of FS mutant protein with PKR inhibitor TRBP can dissociate PACT from the TRBP-PACT complex resulting in PKR activation and consequent apoptosis. These findings are relevant to diseases resulting from protein aggregation especially since the PKR activation is a characteristic of several neurodegenerative conditions.


Replicative cis-advantage of polyomavirus regulatory region mutants in different murine cell lines.
To determine the relative growth advantages of polyomavirus regulatory region mutants selected from Friend leukemic and neuroblastoma cells persistently infected with polyomavirus A2 wild type, different murine cell lines, some of which are capable of further differentiation in vitro, were used as hosts in mixed infection and transfection. The tests allowed the determination, through the measurement of cis-advantage in replication, of the most effective polyomavirus regulatory region constitutions for a given cell line and, in some cases, for specific stages of cell differentiation. Furthermore, different domains of the viral regulatory region were shown to have different effects--positive, neutral, or negative--depending on the host analyzed.


Phospholipid Topography of Whole-Body Sections of the Anopheles stephensi Mosquito, Characterized by High-Resolution Atmospheric-Pressure Scanning Microprobe Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging.
High-resolution atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) has been employed to study the molecular anatomical structure of rodent malaria vector Anopheles stephensi mosquitoes. A dedicated sample preparation method was developed which suits both, the special tissue properties of the sample and the requirements of high-resolution MALDI imaging. Embedding in 5% carboxymethylcellulose (CMC) was used to maintain the tissue integrity of the whole mosquitoes, being very soft, fragile, and difficult to handle. Individual lipid compounds, specifically representing certain cell types, tissue areas, or organs, were detected and imaged in 20 μm-thick whole-body tissue sections at a spatial resolution of 12 μm per image pixel. Mass spectrometric data and information quality were based on a mass resolution of 70,000 (at m/z 200) and a mass accuracy of better than 2 ppm in positive-ion mode on an orbital trapping mass spectrometer. A total of 67 imaged lipids were assigned by database search and, in a number of cases, identified via additional MS/MS fragmentation studies directly from tissue. This is the first MSI study at 12 μm spatial resolution of the malaria vector Anopheles. The study provides insights into the molecular anatomy of Anopheles stephensi and the distribution and localization of major classes of glycerophospholipids and sphingolipids. These data can be a basis for future experiments, investigating, e.g., the metabolism of Plasmodium-infected and -uninfected Anopheles mosquitoes.


Compound heterozygosity for two beta chain variants: the mildly unstable Hb Tyne (codon 5 Pro→Ser) and HbS (codon 6 Glu→Val).
Compound heterozygosity for Hb Tyne and HbS, that is very rare, was identified by direct DNA sequencing of the beta-globin gene in a Turkish patient. Hematological investigation of a girl at the age of 9 due to the presence of HbS (40.7%) led to the identification of a compound heterozygosity at codons 5-6. This was found to be the result of substitution of cytosine (C) for thymidine (T) at the fifth position and a substitution of adenine (A) for thymidine (T) at the sixth position of the beta globin gene. As a result of these mutations, the order of amino acids at codons 5-6 was changed from Pro-Glu to Ser-Val, respectively. Since the co-inheritance of Hb Tyne and HbS had not been reported in literature before, our case set an example for identification of coinheritance of Hb Tyne and HbS for the first time. Therefore, such cases may be considered as an important example for understanding the structural variants of hemoglobin and may provide important clues for critical amino acids responsible for stabilization of hemoglobin tetrameric structure and genetic counseling.


Causal attributions and perceived stigma for myalgic encephalomyelitis/chronic fatigue syndrome.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease with the hallmark symptom of post-exertional malaise. Evidence for physiological causes is converging, however, currently no diagnostic test or biomarker is available. People with ME/CFS experience stigmatization, including the perception that the disease is psychosomatic. In a sample of 499 participants with self-diagnosed ME/CFS, we investigated perceived stigma as a pathway through which perceived others' causal attributions relate to lower satisfaction with social roles and activities and functional status. Higher perceived attributions by others to controllable and unstable causes predicted lower health-related and social outcomes via higher perceived stigma.


A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening.
Embryonic stem cells (ESCs) can self-renew or differentiate into all cell types, a phenomenon known as pluripotency. Distinct pluripotent states have been described, termed "naïve" and "primed" pluripotency. The mechanisms that control naïve-primed transition are poorly understood. In particular, we remain poorly informed about protein kinases that specify naïve and primed pluripotent states, despite increasing availability of high-quality tool compounds to probe kinase function. Here, we describe a scalable platform to perform targeted small molecule screens for kinase regulators of the naïve-primed pluripotent transition in mouse ESCs. This approach utilizes simple cell culture conditions and standard reagents, materials and equipment to uncover and validate kinase inhibitors with hitherto unappreciated effects on pluripotency. We discuss potential applications for this technology, including screening of other small molecule collections such as increasingly sophisticated kinase inhibitors and emerging libraries of epigenetic tool compounds.


First zoeal stage of ?Cataleptodius parvulus (Fabricius, 1793) and Xanthodius denticulatus (White, 1848) (Decapoda: Brachyura): larval evidences and systematic position.
The first zoeal stages of ?Cataleptodius parvulus and Xanthodius denticulatus are described and compared with zoeae of other members of the subfamily Xanthinae. The larvae of ?C. parvulus and X. denticulatus differ mainly in: 1) spinulation of rostral and dorsal spines; 2) type of antenna; 3) setation of the basis of first maxilliped; and 4) type of telson. Features common to both species include a carapace provided with well-developed spines on the dorsal (1), rostral (1), and lateral (2) portions; and the antennal protopod and rostrum similar in length. The morphological differences between the zoea I of X. denticulatus and ?C. parvulus are nevertheless consistent enough to suggest that these species do not belong to the same genus Xanthodius Stimpson, 1859 as previously supposed. Also we presume that ?C. parvulus does not belong to the genus Cataleptodius.


Responses to vocalizations and auditory controls in the human newborn brain.
In the adult brain, speech can recruit a brain network that is overlapping with, but not identical to, that involved in perceiving non-linguistic vocalizations. Using the same stimuli that had been presented to human 4-month-olds and adults, as well as adult macaques, we sought to shed light on the cortical networks engaged when human newborns process diverse vocalization types. Near infrared spectroscopy was used to register the response of 40 newborns' perisylvian regions when stimulated with speech, human and macaque emotional vocalizations, as well as auditory controls where the formant structure was destroyed but the long-term spectrum was retained. Left fronto-temporal and parietal regions were significantly activated in the comparison of stimulation versus rest, with unclear selectivity in cortical activation. These results for the newborn brain are qualitatively and quantitatively compared with previous work on newborns, older human infants, adult humans, and adult macaques reported in previous work.


Congenital cyst of the orbit: A case report.
Dermoid cyst is an example of choristoma (i.e., tumors that originate from aberrant primordial tissue which result in normal appearing tissue in an abnormal location). This particular type of cyst is formed at the site where 2 suture lines of the skull close during embryonic development, and during this time, dermal or epidermal elements are pinched off which later convert to form cysts. Approximately, 50% of these tumors that involve the head are found in or adjacent to the orbit. This article presents a similar case of the orbital dermoid cyst with its management and also a review on other varieties of dermoid cysts of the head and neck region.


[Karyotypic and IPSS grouping of primary myelodysplastic syndromes patients: a comparison between FAB- and WHO-classification].
To compare the results of cytogenetic and IPSS grouping of primary myelodysplastic syndromes (pMDS) patients classified by FAB- or WHO classification. Two hundred and thirty seven cases of pMDS who were previously classified according to FAB criteria were reclassified with WHO classification. A comparison was made between the results of the two classifications. For the detection rates of cytogenetic abnormality and its risks group, there was no difference among the FAB subgroups but the detection rate was different between the WHO refractory cytopenia with multilineage dysplasia (RCMD) and RA subgroups (74.4% and 42.5%, respectively) (P < 0.001). The percentage of good karyotype abnormalities in RA (65.0%) was higher than that in RCMD (24.4%) (P < 0.001), and the percentages of intermediate and poor karyotype abnormalities in RCMD (48.9% and 26.7%, respectively) were higher than that in RA (27.5% and 7.5%, respectively) (P < 0.05). There was a good correlation between the subgroups and IPSS risk groups for both the WHO classification and the FAB classification, but the WHO classification further reflected the differences between RCMD and RA and RAEB-I and RAEB-II subgroups. The percentage of low-risk group in RCMD (1.1%) was lower than that in RA (10.0%) (P < 0.05), and the percentage of high-risk group in RAEB-II (30.5%) was higher than that in RAEB-I(0) (P < 0.001). For the correlation between subgroups and cytogenetic abnormalities and IPSS risk groups, the WHO-classification is better than the FAB-classification.


Determination of pesticide residues in high oil vegetal commodities by using various multi-residue methods and clean-ups followed by liquid chromatography tandem mass spectrometry.
Several extraction methods were evaluated in terms of recoveries and extraction precision for 113 pesticides in avocado: QuEChERS with various d-SPE clean-ups (Z-Sep, Z-Sep+, PSA+C18 and silica), miniLuke and ethyl acetate. Extracts were analysed using liquid chromatography coupled with triple quadrupole mass spectrometer working in multi-reaction monitoring mode. Z-Sep and Z-Sep+ are new types of material for high lipid matrices - these two sorbents contain ZrO2, which improves fat removal from the extracts. The QuEChERS protocol with Z-Sep provided the highest number of pesticides with recoveries in the 70-120% range along with the lowest amount of coextracted matrix compounds. Subsequently, this method was validated in two matrices - avocado and almonds. In the validation recoveries at two levels - 10 and 50μg/kg - limit of quantitation, linearity, matrix effects, as well as the inter- and intraday precision were studied. In the avocado samples, 107 analytes had LOQs equal to 10μg/kg (signal to noise of quantitative transition was equal 20 or more). In the almond samples, 92 pesticides had LOQs equal to 10μg/kg (S/N≥20) and 2 pesticides at 50μg/kg. The validated method was employed in the analysis of real avocado and almond samples.


Involving expert patients in antiretroviral treatment provision in a tertiary referral hospital HIV clinic in Malawi.
Current antiretroviral treatment (ART) models in Africa are labour intensive and require a high number of skilled staff. In the context of constraints in human resources for health, task shifting is considered a feasible alternative for ART service delivery. In 2006, Dignitas International in partnership with the Malawi Ministry of Health trained a cadre of expert patients at the HIV Clinic at a tertiary referral hospital in Zomba, Malawi. Expert patients were trained to assist with clinic tasks including measurement of vital signs, anthropometry and counseling. A descriptive observational study using mixed methods was conducted two years after the start of program implementation. Semi-structured interviews were conducted with 20 patients, seven expert patients and six formal health care providers to explore perceptions towards the expert patients' contributions in the clinic. Structured exit interviews with 81 patients, assessed whether essential ART information was conveyed during counseling sessions. Vital signs and anthropometry measurements performed by expert patients were repeated by a nurse to assess accuracy of measurements. Direct observations quantified the time spent with each patient. There were minor differences in measurement of patients' weight, height and temperature between the expert patients and the nurse. The majority of patients exiting a counseling session reported, without prompting, at least three side effects of ART, correct actions to be taken on observing a side-effect, and correct consequences of non-adherence to ART. Expert patients carried out 368 hours of nurse tasks each month, saving two and a half full-time nurse equivalents per month. Formal health care workers and patients accept and value expert patients' involvement in ART provision and care. Expert patients felt valued by patients for being a 'role model', or a 'model of hope', promoting positive living and adherence to ART. Expert patients add value to the ART services at a tertiary referral HIV clinic in Malawi. Expert patients carry out shifted tasks acceptably, saving formal health staff time, and also act as 'living testimonies' of the benefits of ART and can be a means of achieving greater involvement of People Living with HIV in HIV treatment programs.


Outbreak of Neisseria meningitidis, Edmonton, Alberta, Canada.
From December 1999 to April 2001, the greater Edmonton region had 61 cases of invasive meningococcal infection, two fatal. The outbreak was due to Neisseria meningitidis serogroup C, electrophoretic type 15, serotype 2a. Analysis of the strains showed that 50 of 56 culture-confirmed cases were due to a single clone and close relatives of this clone. This strain had not been previously identified in the province of Alberta dating back to January 1997.


Synthesis and Anticancer Evaluation of Thiazacridine Derivatives Reveals New Selective Molecules to Hematopoietic Neoplastic Cells.
Cancer has become one of the leading causes of morbidity and mortality worldwide. Limitations associated with existing agents increase the need to develop more effective anticancer drugs to improve the therapeutic arsenal available. The aim of this study was to synthesize and evaluate the antiproliferative effects of three new thiazacridine derivatives. Using a three steps synthesis reaction, three novel thiazacridine derivatives were obtained and characterized: (Z)-5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-4-thioxo-thiazolidin- 2-one (LPSF/AC-99), (Z)-5-acridin-9-ylmethylene-3-(4-chloro-benzyl)-4-thioxo-thiazolidin-2- one (LPSF/AC-119) and (Z)-5-acridin-9-ylmethylene-3-(3-chloro-benzyl)-4-thioxo-thiazolidin-2- one (LPSF/AC-129). Toxicity and selectivity assays were performed by colorimetric assay. Then, changes in cell cycle and cell death induction mechanisms were assessed by flow cytometry. All compounds exhibited cytotoxicity to Raji (Burkitt's lymphoma) and Jurkat (acute T cell leukemia) cells, where LPSF/AC-119 showed best IC50 values (0.6 and 1.53 µ M, respectively). LPSF/AC-129 was the only cytotoxic compound in glioblastoma cell line NG97 (IC50 = 55.77 µ M). None of the compounds were toxic to normal human cells and induced neoplastic cell death primarily by apoptosis. All derivatives were more cytotoxic to hematopoietic neoplastic cells when compared to solid tumor derived cells. All three compounds are promising for in vivo and combination therapy studies against cancer.


Postoperative changes on brain SPECT imaging after aneurysmal subarachnoid hemorrhage. A potential pitfall in the evaluation of vasospasm.
Serial brain SPECT imaging was performed on patients after subarachnoid hemorrhage and surgical clipping of intracranial aneurysms. A total of 20 HMPAO scans were performed on 9 patients in whom clinical vasospasm did not develop. Areas of diminished regional cerebral blood flow (rCBF) were found near the operative site in 17 of 20 studies, which did not correlate with the patients' neurologic condition and were suggestive of postoperative edema. Brain SPECT imaging has a potentially valuable role to play in the evaluation of postoperative patients susceptible to vasospasm; however, it is important to be aware of postoperative changes in rCBF that are not related to vasospasm.


Bifunctional CD4-DC-SIGN fusion proteins demonstrate enhanced avidity to gp120 and inhibit HIV-1 infection and dissemination.
Early stages of mucosal infection are potential targets for HIV-1 prevention. CD4 is the primary receptor in HIV-1 infection whereas DC-SIGN likely plays an important role in HIV-1 dissemination, particularly during sexual transmission. To test the hypothesis that an inhibitor simultaneously targeting both CD4 and DC-SIGN binding sites on gp120 may provide a potent anti-HIV strategy, we designed constructs by fusing the extracellular CD4 and DC-SIGN domains together with varied arrangements of the lengths of CD4, DC-SIGN and the linker. We expressed, purified and characterized a series of soluble CD4-linker-DC-SIGN (CLD) fusion proteins. Several CLDs, composed of a longer linker and an extra neck domain of DC-SIGN, had enhanced affinity for gp120 as evidenced by molecular-interaction analysis. Furthermore, such CLDs exhibited significantly enhanced neutralization activity against both laboratory-adapted and primary HIV-1 isolates. Moreover, CLDs efficiently inhibited HIV-1 infection in trans via a DC-SIGN-expressing cell line and primary human dendritic cells. This was further strengthened by the results from the human cervical explant model, showing that CLDs potently prevented both localized and disseminated infections. This is the first time that soluble DC-SIGN-based bifunctional proteins have demonstrated anti-HIV potency. Our study provides proof of the concept that targeting both CD4 and DC-SIGN binding sites on gp120 represents a novel antiviral strategy. Given that DC-SIGN binding to gp120 increases exposure of the CD4 binding site and that the soluble forms of CD4 and DC-SIGN occur in vivo, further improvement of CLDs may render them potentially useful in prophylaxis or therapeutics.


Effect of unilateral adrenalectomy on acute immobilization stress response in rats.
The aim of the present study was to investigate the differential effect of unilateral adrenalectomy, right vs. left, in response to acute immobilization stress (IS) in rats. Adult male rats were subjected to unilateral right or left adrenalectomy or sham operation (control). Two weeks later, the rats were sacrificed either immediately or 3 hours after IS exposure. Plasma samples were used for determination of catecholamines (CAs), adrenocorticotrophic hormone (ACTH), corticosterone (CORT), sodium, potassium, and glucose levels. After terminating the experiment, both or remaining adrenals were removed, weighed, and used for estimation of CAs and nitric oxide (NO) levels. Under basal conditions, either right or left adrenal kept all the tested parameters near to the control levels, except the adrenal weight and CAs content. These were significantly higher in the remaining right than left adrenal. However, the remaining right adrenal responded better to IS exposure than the remaining left one in the term of compensatory adrenal growth and plasma parameters which were all kept insignificantly different from those of IS intact group. Our data indicate that the adrenal glands may substitute each other under basal conditions. However, the right adrenal seems to be dominant during exposure to acute immobilization stress.


The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism.
Glucose homeostasis is regulated systemically by hormones such as insulin and glucagon, and at the cellular level by energy status. Glucagon enhances glucose output from the liver during fasting by stimulating the transcription of gluconeogenic genes via the cyclic AMP-inducible factor CREB (CRE binding protein). When cellular ATP levels are low, however, the energy-sensing kinase AMPK inhibits hepatic gluconeogenesis through an unknown mechanism. Here we show that hormonal and energy-sensing pathways converge on the coactivator TORC2 (transducer of regulated CREB activity 2) to modulate glucose output. Sequestered in the cytoplasm under feeding conditions, TORC2 is dephosphorylated and transported to the nucleus where it enhances CREB-dependent transcription in response to fasting stimuli. Conversely, signals that activate AMPK attenuate the gluconeogenic programme by promoting TORC2 phosphorylation and blocking its nuclear accumulation. Individuals with type 2 diabetes often exhibit fasting hyperglycaemia due to elevated gluconeogenesis; compounds that enhance TORC2 phosphorylation may offer therapeutic benefits in this setting.


Early experience with pay-for-performance: from concept to practice.
The adoption of pay-for-performance mechanisms for quality improvement is growing rapidly. Although there is intense interest in and optimism about pay-for-performance programs, there is little published research on pay-for-performance in health care. To evaluate the impact of a prototypical physician pay-for-performance program on quality of care. We evaluated a natural experiment with pay-for-performance using administrative reports of physician group quality from a large health plan for an intervention group (California physician groups) and a contemporaneous comparison group (Pacific Northwest physician groups). Quality improvement reports were included from October 2001 through April 2004 issued to approximately 300 large physician organizations. Three process measures of clinical quality: cervical cancer screening, mammography, and hemoglobin A1c testing. Improvements in clinical quality scores were as follows: for cervical cancer screening, 5.3% for California vs 1.7% for Pacific Northwest; for mammography, 1.9% vs 0.2%; and for hemoglobin A1c, 2.1% vs 2.1%. Compared with physician groups in the Pacific Northwest, the California network demonstrated greater quality improvement after the pay-for-performance intervention only in cervical cancer screening (a 3.6% difference in improvement [P = .02]). In total, the plan awarded 3.4 million dollars (27% of the amount set aside) in bonus payments between July 2003 and April 2004, the first year of the program. For all 3 measures, physician groups with baseline performance at or above the performance threshold for receipt of a bonus improved the least but garnered the largest share of the bonus payments. Paying clinicians to reach a common, fixed performance target may produce little gain in quality for the money spent and will largely reward those with higher performance at baseline.


Hydrogen peroxide protects tobacco from oxidative stress by inducing a set of antioxidant enzymes.
Tolerance against oxidative stress generated by high light intensities or the catalase inhibitor aminotriazole (AT) was induced in intact tobacco plants by spraying them with hydrogen peroxide (H2O2). Stress tolerance was concomitant with an enhanced antioxidant status as reflected by higher activity and/or protein levels of catalase, ascorbate peroxidase, guaiacol peroxidases, and glutathione peroxidase, as well as an increased glutathione pool. The induced stress tolerance was dependent on the dose of H2O2 applied. Moderate doses of H2O2 enhanced the antioxidant status and induced stress tolerance, while higher concentrations caused oxidative stress and symptoms resembling a hypersensitive response. In stress-tolerant plants, induction of catalase was 1.5-fold, that of ascorbate peroxidase and glutathione peroxidase was 2-fold, and that of guaiacol peroxidases was approximately 3-fold. Stress resistance was monitored by measuring levels of malondialdehyde, an indicator of lipid peroxidation. The levels of malondialdehyde in all H2O2-treated plants exposed to subsequent high light or AT stress were similar to those of unstressed plants, whereas lipid peroxidation in H2O2-untreated plants stressed with either high light or AT was 1.5- or 2-fold higher, respectively. Although all stress factors caused increases in the levels of reduced glutathione, its levels were much higher in all H2O2-pretreated plants. Moreover, significant accumulation of oxidized glutathione was observed only in plants that were not pretreated with H2O2. Extending the AT stress period from 1 to 7 days resulted in death of tobacco plants that were not pretreated with H2O2, while all H2O2-pretreated plants remained little affected by the prolonged treatment. Thus, activation of the plant antioxidant system by H2O2 plays an important role in the induced tolerance against oxidative stress.


Experience with bioresorbable splints for treatment of airway collapse in a pediatric population.
To report our experience with novel external tracheal and bronchial placed bioresorbable splints in children with severe symptomatic airway collapse. Retrospective review of patients undergoing bioresorbable splint placement. Between July 2018 and February 2020, 14 patients received 16 external splints (trachea, n = 8; left bronchus, n = 7; and right bronchus, n = 1). Preoperatively, 7 patients had a tracheostomy; 6 of them were receiving mechanical ventilation with ventilator settings so high that they required an inpatient setting, often in an intensive care unit. Median age at implant was 14.5 months (range, 2 months-14 years). Splints were formed from moldable bioresorbable plates (RapidSorb; Synthes, Oberdorf, Switzerland) and were customized intraoperatively around a Hegar dilator. A series of Prolene sutures were placed through into the airway cartilage under simultaneous bronchoscopic and direct visualization and then tied securing the airway within the splint. Concomitant procedures were also performed in the region of the airway splints, consisting of airway reconstruction, cardiovascular procedures, and/or esophageal rotation (related to posterior tracheopexy). Median follow-up was 20 months (interquartile range, 12-21 months). Four patients required no further intervention. Although not necessarily in the splinted region, 7 patients required additional procedures, including posterior tracheobronchopexy (n = 2), temporary tracheal stent placement (n = 1), tracheal resection with end-to-end anastomosis (n = 1), closure tracheostomy (n = 1), and tracheostomy placement (n = 2). One patient required splint replacement and in 1 patient, the splint was removed later. All patients (except 2 deaths from unrelated causes) were discharged home. Three patients required mechanical ventilation at lower settings that allowed home ventilation (1 of those only at night), and 4 patients required tracheostomy collar. Indications for tracheostomy included subglottic stenosis, vocal cord paralysis, pulmonary insufficiency, small airway malacia, and laryngomalacia. An external bioresorbable splint can provide temporary external support while allowing the age-proportional growth of the airway. We applied readily available bioresorbable plates that were custom-molded based on the location, shape, and length of the collapsing airway in selected patients presenting with severe tracheobronchomalacia from loss of structural support and/or cartilage deformation. Further study that includes long-term outcomes are necessary to define the best role for these external splints as part of comprehensive airway management.


Chiroptical Activity Enhancement via Structural Control: The Chiral Synthesis and Reversible Interconversion of Two Intrinsically Chiral Gold Nanoclusters.
We report the synthesis and crystal structure determination of two novel chiral gold nanoclusters. By utilizing BINAP, we isolate atomically precise intrinsically chiral Au nanoclusters [Au9( R-/ S-BINAP)4](CF3COO)3 and [Au10( R-/ S-BINAP)4( p-CF3C6H4C≡C)](CF3COO)3 in high yield with one-pot synthesis. Au9 has C2 geometry, while Au10 is C1 symmetric. Interestingly, reversible interconversion between Au9 and Au10 can be realized by the addition or removal of a RC≡CAu component. The transformation from Au9 to Au10 leads to significant enhancement of CD signals. The maximum anisotropy factor in the visible region of [Au10(BINAP)4( p-CF3C6H4C≡C)]3+ is the hitherto largest (up to 6.6 × 10-3) among gold nanoclusters, which is approximately twice of that of [Au9(BINAP)4]3+. This work demonstrates that the chiroptical activity of gold nanoclusters can be modulated by structural control through the introduction of second ligands.


In Vitro Activity of Benzimidazole (SPR719) Against Clinical Isolates of Nontuberculous Mycobacteria With and Without Clarithromycin or Amikacin Resistance.
Limited data are available regarding the in vitro activity of SPR719, a derivative of benzimidazole, against diverse nontuberculous mycobacteria (NTM) species. We investigated the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of SPR719 against clinical NTM isolates, including clarithromycin- and amikacin-resistant strains. NTM isolates were obtained from patients with NTM-pulmonary disease caused by various NTM species, including Mycobacterium avium complex, M. abscessus (subspecies abscessus and massiliense), M. kansasii, and M. fortuitum. Regardless of clarithromycin or amikacin resistance, the MIC and MBC values of SPR719 were comparable among these major pathogenic NTM species. In over 70% of the isolates, the MIC values were ≤2 μg/mL with MBC values of ≤4 μg/mL. The MIC and MBC values of M. kansasii were relatively lower than those of the other species with little difference between them, demonstrating the bactericidal properties of SPR719. The in vitro activity of SPR719 against major clinical NTM species suggests that SPR719 can serve as a novel treatment option for NTM-pulmonary disease.


Early-onset cataracts, spastic paraparesis, and ataxia caused by a novel mitochondrial tRNAGlu (MT-TE) gene mutation causing severe complex I deficiency: a clinical, molecular, and neuropathologic study.
Mitochondrial respiratory chain disease is associated with a spectrum of clinical presentations and considerable genetic heterogeneity. Here we report molecular genetic and neuropathologic findings from an adult with an unusual manifestation of mitochondrial DNA disease. Clinical features included early-onset cataracts, ataxia, and progressive paraparesis, with sequencing revealing the presence of a novel de novo m.14685G>A mitochondrial tRNA(Glu) (MT-TE) gene mutation. Muscle biopsy showed that 13% and 34% of muscle fibers lacked cytochrome c oxidase activity and complex I subunit expression, respectively. Biochemical studies confirmed a marked decrease in complex I activity. Neuropathologic investigation revealed a large cystic lesion affecting the left putamen, caudate nucleus, and internal capsule, with evidence of marked microvacuolation, neuron loss, perivascular lacunae, and blood vessel mineralization. The internal capsule showed focal axonal loss, whereas brainstem and spinal cord showed descending anterograde degeneration in medullary pyramids and corticospinal tracts. In agreement with muscle biopsy findings, reduced complex I immunoreactivity was detected in the remaining neuronal populations, particularly in the basal ganglia and cerebellum, correlating with the neurologic dysfunction exhibited by the patient. This study emphasizes the importance of molecular genetic and postmortem neuropathologic analyses for furthering our understanding of underlying mechanisms of mitochondrial disorders.


Cancer communication science funding trends, 2000-2012.
Since 2000, the field of health communication has grown tremendously, owing largely to research funding by the National Cancer Institute (NCI). This study provides an overview of cancer communication science funding trends in the past decade. We conducted an analysis of communication-related grant applications submitted to the NCI in fiscal years 2000-2012. Using 103 keywords related to health communication, data were extracted from the Portfolio Management Application, a grants management application used at NCI. Automated coding described key grant characteristics such as mechanism and review study section. Manual coding determined funding across the cancer control continuum, by cancer site, and by cancer risk factors. A total of 3307 unique grant applications met initial inclusion criteria; 1013 of these were funded over the 12-year period. The top funded grant mechanisms were the R01, R21, and R03. Applications were largely investigator-initiated proposals as opposed to responses to particular funding opportunity announcements. Among funded communication research, the top risk factor being studied was tobacco, and across the cancer control continuum, cancer prevention was the most common stage investigated. NCI support of cancer communication research has been an important source of growth for health communication science over the last 12 years. The analysis' findings describe NCI's priorities in cancer communication science and suggest areas for future investments.


Comparative and evolutionary studies of mammalian arylsulfatase and sterylsulfatase genes and proteins encoded on the X-chromosome.
At least 19 sulfatase genes have been reported on the human genome, including four arylsulfatase (ARS) genes (ARSD; ARSE; ARSF; ARSH) and a sterylsulfatase (STS) gene located together on the X-chromosome. Bioinformatic analyses of mammalian genomes were undertaken using known human STS and ARS amino acid sequences to study the evolution of these genes and proteins encoded on eutherian and marsupial genomes. Several domain regions and key residues were conserved including signal peptides, active site residues, metal (Ca2+) and substrate binding sequences, transmembranes and N-glycosylation sites. Phylogenetic analyses describe the relationships and potential origins of these genes during mammalian evolution. Primate ARSH enzymes lacked signal peptide sequences which may influence their biological functions. CpG117 and CpG92 were detected within the 5' region of the human STS and ARSD genes, respectively, and miR-205 within the 3'-UTR for the human STS gene, using bioinformatic methods A proposal is described for a primordial invertebrate STS-like gene serving as an ancestor for unequal cross over events generating the gene complex on the eutherian mammalian X-chromosome.