Catecholamine metabolism and body weight in anorexia nervosa.
Urinary MHPG (3-methoxy-4-hydroxyphenyl-ethylene glycol) was measured in seven anorexia nervosa patients during a bed rest and refeeding programme. MHPG levels were positively related to increase in body weight.


Effects of synthetic sphingosine-1-phosphate analogs on cytosolic phospholipase A2alpha-independent release of arachidonic acid and cell toxicity in L929 fibrosarcoma cells: the structure-activity relationship.
Sphingolipid metabolites including ceramide, sphingosine, and their phosphorylated products [sphingosine-1-phosphate (S1P) and ceramide-1-phosphate] regulate cell functions including arachidonic acid (AA) metabolism and cell death. The development of analogs of S1P may be useful for regulating these mediator-induced cellular responses. We synthesized new analogs of S1P and examined their effects on the release of AA and cell death in L929 mouse fibrosarcoma cells. Among the analogs tested, several compounds including DMB-mC11S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMB-mC9S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-nonyl)phenylpropyl phosphate] released AA within 1 h and caused cell death 6 h after treatment. The release of AA was observed in C12 cells [a L929 variant lacking a type alpha cytosolic phospholipase A(2) (cPLA(2)alpha)] and L929-cPLAalpha-siRNA cells (L929 cells treated with small interference RNA for cPLA(2)alpha). Treatment with pharmacological inhibitors of secretory and Ca(2+)-independent PLA(2)s decreased the DMB-mC11S-induced release of AA. The effect of the S1P analogs tested on the release of AA was comparable to that on cell death in L929 cells, and a high correlation coefficient was observed. Two analogs lacking a butoxycarbonyl moiety [DMAc-mC11S (dimethyl (2S,3R)-2-acetamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMAm-mC11S [dimethyl (2S,3R)-2-amino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate)] had inhibitory effects on the release of AA and cell toxicity induced by DMB-mC11S. Synthetic phosphorylated lipid analogs may be useful for studying PLA(2) activity and its toxicity in cells. [Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08284FP].


The Ran-binding protein RanBPM can depress the NF-κB pathway by interacting with TRAF6.
Ran-binding protein in microtubule-organizing center (RanBPM) has been reported to interact with the neurotrophin receptors p75NTR and TrkA, meanwhile p75NTR and TrkA can also interact with TRAF6. Whether RanBPM interacts directly with TRAF6 has not yet been established. In this study, using a yeast two-hybrid system and glutathione-S: -transferase pull-down assays, we determined that RanBPM binds to the TRAF6 C-terminus through its SPRY motif. Complex formation between overexpressed RanBPM and TRAF6 was also confirmed with a co-immunoprecipitation assay, laser scanning confocal and fluorescence resonance energy transfer. Additional co-immunoprecipitation experiments verified that endogenous RanBPM and TRAF6 interact in several mammalian cell lines. A series of experiments revealed that RanBPM influences TRAF6 ubiquitination and the TRAF6-triggered NF-κB signaling pathway through RanBPM's interaction with TRAF6. These data suggest that RanBPM participates in gene transcription by binding to TRAF6.


Valve-sparing aortic root replacement: a primer for cardiologists.
The purpose of this article is to review the contemporary evidence supporting valve-sparing aortic root replacement as the best option for patients with aortic root aneurysms and preservable aortic valves as well as to review the technical variations and modern adjuncts of these operations that impact both short and long-term durability. In patients with an aortic root aneurysm, with or without aortic valve regurgitation, valve-sparing aortic root replacement provide excellent clinical outcomes and stable valve function over several decades. Successful execution of this operation depends on careful patient selection and a thorough understanding of the anatomical and physiological relationships between the various components of the aortic root. Echocardiography remains the mainstay of imaging to determine the feasibility of valve-sparing root replacement. Valve-sparing aortic root replacement is an excellent alternative to composite valve graft replacement in nonelderly patients with aortic root aneurysms. Dedicated aortic root surgeons perform several technical variations of valve-sparing procedures aimed at matching the specific aortic root disorder with the optimal operation.


Anthropometric Measurements of Knee Joints in the Hispanic Population.
Total knee arthroplasty (TKA) systems provide a set of incrementally sized tibial and femoral components intended to accommodate most knee parameters. However, the most commonly used systems in the United States were developed using data from Caucasian patients which might not lead to the best fit in non-Caucasians. Therefore, we wanted to evaluate whether these TKA systems proportionally match femoral and tibial measurements in Hispanics. All lower extremity magnetic resonance imaging performed at our institution between January 2007 and October 2015 were screened. A total of 500 nonarthritic knees from the same number of Hispanic patients were included in this retrospective descriptive radiographic study. Intraoperative osseous TKA resections were simulated on magnetic resonance imaging. Linear regression analyses were used to contrast the mediolateral (ML) width/anteroposterior (AP) length of simulated resected femoral condyle and tibia with the ML/AP dimensions of components offered by 4 current TKA systems. Simulated resected male femurs tended to be wider than most TKA system components for a given AP size, probably leading to component ML underhang. Altogether, systems studied accommodated most AP and ML measurements of female condyles. However, we identified subsets of Hispanic female patients with certain AP lengths and/or ML widths that particular knee systems could not accommodate. Resected male and female tibias tended to be slightly narrower than all TKA systems for a given AP size. The results of our study provide valuable data concerning the unique morphology of the Hispanic knee. These data can assist surgeons in the selection of the most suitable TKA systems for these patients.


APOA5 gene expression in the human intestinal tissue and its response to in vitro exposure to fatty acid and fibrate.
APOA5, a key gene regulating triglyceride (TG) levels, is reported to be expressed exclusively in the liver where it may regulate TG-rich particle synthesis and secretion. Since the same lipoprotein processing occurs in the intestine, we have postulated that this organ would also express APOA5. We have detected the APOA5 gene expression in C57BL/6J mouse and in human small intestine samples. In humans, it is expressed mainly in the duodenum and colon, with messenger RNA (mRNA) levels four orders of magnitude lower than in the liver, and the protein product being one-sixth of the liver equivalent. Subsequently, we carried out in vitro experiments in TC-7/CaCo(2) human intestinal cells to analyse the expression of APOA5, APOC3, APOB and MTP genes after the incubation with long- and short-chain fatty acids, and a peroxisome proliferator-activated receptor alpha (PPARα) agonist (Wy 14643, a fibrate therapeutic agent). In the TC-7 cell line, APOA5 expression was significantly upregulated by saturated fatty acids. The short-chain fatty acid butyrate increased APOA5 expression almost fourfold while APOB was downregulated by increasing butyrate concentrations. When TC-7 cells were incubated with PPARα agonist, the APOA5 expression was increased by 60%, while the expression of APOB, MTP and APOC3 was decreased by 50%, 30% and 45%, respectively. Our results demonstrate that APOA5 is expressed in the intestine, albeit at a much lower concentration than in the liver. While it remains to be determined whether intestinal apo A-V is functional, our in vitro experiments show that its expression is modifiable by dietary and pharmacological stimuli.


Salient Beliefs Associated with Unsanctioned Adult Cannabis Use in an Evolving Socio-Political Environment.
Background: The changing cannabis legal climate in the United States has been associated with increased prevalence of use, more favorable general attitudes, and cultural norms toward its use among young adults. The purpose of this study was to conceptualize salient beliefs governing illicit cannabis use within a state where medical use is legal and adult use remains illegal. Methods: Following an initial qualitative pilot, a prospective study (baseline and a 30-day follow-up) that utilized an electronic survey design was conducted. Students at a large US university (N = 514) completed a baseline assessment of cannabis use and Theory of Planned Behavior (TPB) constructs, and 169 completed the follow-up assessing actual behavior. Results: Roughly 60% reported illicit cannabis use. Attitude and subjective norms accounted for 57% of the variation in intention for cannabis use in the next 30 days, while intention and perceived behavioral control (PBC) explained 51% of the variation in prospective use. The majority of salient beliefs identified exhibited moderate to strong correlations with intention and behavior among the larger sample. Close friends and partners were identified as important referents, outcome expectations of relaxation, improved social functioning, and more enjoyment, as well as environmental factors, such as proximity to use, safe utilization location, and continued illegality of adult use exhibited strong associations to intention and behavior. Conclusions: The practical utility of the salient belief measures identified herein presents a useful foundation for interventions aimed at reducing illicit cannabis utilization among young adults.


Chemical modification of erythromycins. II. Synthesis and antibacterial activity of O-alkyl derivatives of erythromycin A.
A series of O-alkyl erythromycin A derivatives have been synthesized and their antibacterial activities compared with those of erythromycin A (1) and 6-O-methylerythromycin A (3). Methylation of the hydroxyl groups of erythromycin A analogue proceeded stepwise by the two main pathways beginning at the C-6 and C-11 positions, individually. O-Alkylation, other than methylation, took place at the C-11 hydroxyl group exclusively. Among O-alkyl derivatives, 6,12-di-O-methylerythromycin A (5) showed comparable in vitro antibacterial activity to those of 1 and 3. 11-O-Methylerythromycin A (8) was slightly less active than 1. O-Methylation at the C-4" position resulted in a decrease of antibacterial activity.


Standing with electrical stimulation and splinting is no better than standing alone for management of ankle plantarflexion contractures in people with traumatic brain injury: a randomised trial.
Is a combination of standing, electrical stimulation and splinting more effective than standing alone for the management of ankle contractures after severe brain injury? A multi-centre randomised trial with concealed allocation, assessor blinding and intention-to-treat analysis. Thirty-six adults with severe traumatic brain injury and ankle plantarflexion contractures. All participants underwent a 6-week program. The experimental group received tilt table standing, electrical stimulation and ankle splinting. The control group received tilt table standing alone. The primary outcome was passive ankle dorsiflexion with a 12Nm torque. Secondary outcomes included: passive dorsiflexion with lower torques (3, 5, 7 and 9Nm); spasticity; the walking item of the Functional Independence Measure; walking speed; global perceived effect of treatment; and perceived treatment credibility. OUTCOME MEASURES were taken at baseline (Week 0), end of intervention (Week 6), and follow-up (Week 10). The mean between-group differences (95% CI) for passive ankle dorsiflexion at Week 6 and Week 10 were -3 degrees (-8 to 2) and -1 degrees (-6 to 4), respectively, in favour of the control group. There was a small mean reduction of 1 point in spasticity at Week 6 (95% CI 0.1 to 1.8) in favour of the experimental group, but this effect disappeared at Week 10. There were no differences for other secondary outcome measures except the physiotherapists' perceived treatment credibility. Tilt table standing with electrical stimulation and splinting is not better than tilt table standing alone for the management of ankle contractures after severe brain injury. ACTRN12608000637347. [Leung J, Harvey LA, Moseley AM, Whiteside B, Simpson M, Stroud K (2014) Standing with electrical stimulation and splinting is no better than standing alone for management of ankle plantarflexion contractures in people with traumatic brain injury: a randomised trial.Journal of Physiotherapy60: 201-208].


Objective quantification and spatial mapping of cataract with a Shack-Hartmann wavefront sensor.
Based on wavefront sensor images an objective and quantitative method is presented for characterising cataract. By separating direct and scattered light in the focal plane of the microlenses, the new procedure is able to make two-dimensional maps of the spatial variation of scattering properties in the crystalline lens, and also provides a single figure descriptive for the whole eye. The developed evaluation algorithm successfully quantifies cataract, especially that of nuclear type. To demonstrate its operation, a custom-built measurement setup was constructed using a Shack-Hartmann wavefront sensor with [Formula: see text] microlenses to capture 12-bit images of the pupil plane, and a superluminescent diode of 830 nm wavelength as a light source. Slit-lamp clinical measurements served as reference for calibration and to estimate the accuracy of the new method. The tests were carried out on 78 eyes with cataract in different progression state ranging from healthy to above 5 on the LOCS III scale. The residual error of the calibration (i.e. the standard deviation of difference between clinical reference and our algorithmic characterisation) turned out to be [Formula: see text] category on the LOCS III N scale, which approximates the [Formula: see text] precision of classic cataract measurements carried out with the greatest care.


Para-aortic lymph node dissection in left-sided colorectal cancer: Risk factors, prognostic impact, and therapeutic value.
This study aimed to clarify risk factors, prognostic impact, and the therapeutic value of para-aortic lymph node (PALN) dissection in left-sided colorectal cancer. One hundred and fifty-four patients who underwent primary tumor resection and PALN dissection for left-sided colorectal cancer were included. Logistic regression analysis was used to identify risk factors for PALN metastasis. Cox regression analysis was performed to identify risk factors for overall survival (OS). PALN metastasis was pathologically confirmed in 47 patients (30.5%). Postoperative complications occurred in 42 patients (27.3%). Pathological N stage (OR = 4.661, p = 0.034) and inferior mesenteric artery LNs metastasis (OR = 6.048, p = 0.003) remained to be independently associated with PALN metastasis, the 5-year OS rate and median survival in patients with PALN metastasis was 37.7% and 24 months. Elevated preoperative serum CA19-9 level (HR = 1.006, p = 0.007), number of positive LNs > 7 (HR = 7.263, p = 0.001), and mucinous adenocarcinoma or signet ring cell carcinoma (HR = 6.511, p = 0.001) were independently associated with OS in patients with PALN metastasis. PALN dissection in addition to primary tumor resection have acceptable postoperative complications and may be oncologically beneficial in selected left-sided colorectal cancer patients with clinically suspicious PALN metastasis.


Essential oil yield and quality of methyl eugenol rich Ocimum tenuiflorum L.f. (syn. O. sanctum L.) grown in south India as influenced by method of harvest.
A field experiment carried out during 2001--2002 under semi-arid conditions of Hyderabad, India investigated the effect of three different methods of harvesting at full bloom stage, on essential oil yield and quality of methyl eugenol rich sacred/holy basil (Ocimum tenuiflorum L.f.; Lamiaceae). The harvest methods were: harvesting of primary branches, secondary branches and shoot biomass cut at 30 cm above ground level. Four harvests at 102, 192, 287 and 360 days after transplanting of the crop were taken in 1 year in each method of harvest. Harvesting of secondary branches led to maximum plant height and number of secondary branches per plant compared to harvesting of primary branches or shoot biomass cut at 30 cm above ground during second, third and fourth harvests. On the contrary, secondary branch harvest gave least biomass yield in all the four harvests. But due to higher essential oil content, secondary branch harvest gave 25.2 and 15.4% higher total (sum total of all four harvests) essential oil yield (kg/ha per year) over primary branches and shoot biomass cut at 30 cm above ground methods of harvesting, respectively. A similar treatment difference was observed in respect of oil composition studied in the first harvest. Harvesting shoot biomass at 30 cm above ground produced oil containing highest amount of methyl eugenol. The content of methyl eugenol decreased in the order of shoot biomass cut at 30 cm above ground > primary branch > secondary branch treatments. A reverse trend was observed, however, in respect of (E)-cinnamyl acetate, eugenol and beta-elemene constituents of the oil. Little variability was, however, observed among the treatments in respect of 24 other constituents of the oils.


Effect of amino acid infusion on potassium serum levels in neuroendocrine tumour patients treated with targeted radiopeptide therapy.
Administration of positively charged amino acids has been introduced to reduce the nephrotoxicity of targeted radiopeptide therapy (TRT). However, the amino acid solution may have side effects, including hyperkalaemia. The aim of this study was to evaluate the frequency and the magnitude of hyperkalaemia in neuroendocrine tumour (NET) patients undergoing TRT. Enrolled in the study were 31 patients with NET eligible for TRT with [(90)Y-DOTA(0),Tyr(3)]octreotide ((90)Y-DOTATOC). Their mean age was 54 ± 14 years. Of these 31 patients, 21 (67%) were referred for the first treatment cycle, while 10 (33%) were referred for a subsequent therapy cycle. Patients were treated with therapeutic doses of (90)Y-DOTATOC ranging from 7,030 to 35,520 MBq. To inhibit tubular reabsorption of (90)Y-DOTATOC, 1 l of physiological saline solution containing 25 g of arginine hydrochloride and 25 g of lysine hydrochloride was given over 4 h starting 1 h before (90)Y-DOTATOC injection. All patients underwent a standard biochemical blood analysis at baseline, and 4 h and 24 h after the beginning of the amino acid infusion. ANOVA repeated measures showed a significant overall effect on K(+) levels over time (F = 118.2, df = 2, P < 0.0001). Mean serum levels of K(+) were 4.00 ± 0.33 mmol/l at baseline, 5.47 ± 0.57 mmol/l at 4 h, and 4.38 ± 0.63 mmol/l at 24 h after the beginning of the infusion. Post-hoc analysis showed that K(+) levels at 4 h were significantly (P < 0.05) higher than at baseline. K(+) levels at 24 h were significantly (P < 0.05) lower than at 4 h but they were still significantly (P < 0.05) higher than K(+) levels at baseline. On a subject-by-subject basis, none of the 31 patients had increased K(+) levels at baseline. At 4 h, 24 of the 31 patients (77%) had K(+) levels above the normal range, and 6 patients (19%) experienced severe hyperkalaemia (K(+) ≥ 6 mmol/l). All patients with increased K(+) levels were clinically asymptomatic. At 24 h, only 4 patients (13%) had increased K(+) serum levels. The magnitude of the increase in K(+) levels between baseline and 4 h was relatively homogeneous over the whole group (1.41 ± 0.50 mmol/l) and it was not related (linear regression, P>0.05) to baseline K(+) levels. Intravenous administration of 40 mg furosemide 1 h after the beginning of the amino acid infusion did not have a significant effect on K(+) levels (P>0.05). No clinical characteristic was predictive for the increase in K(+) levels (chi-squared test, P > 0.05). Hyperkalaemia is a frequent, potentially life-threatening side effect of basic amino acid infusion during TRT. K(+) levels 4 h after the beginning of the infusion should be monitored in patients at risk of complications, such as those with heart disease and those with risk factors for nephrotoxicity.


Intraoperative radiotherapy in resected pancreatic cancer: feasibility and results.
To evaluate the impact of intraoperative radiotherapy (IORT) combined with postoperative external beam irradiation in patients with pancreatic cancer treated with curative surgical resection. From January 1986 to April 1995 25 patients (11 male and 14 female, median age 61 years) underwent a curative resection with IORT for pancreatic adenocarcinoma. The tumour was located in the head of the pancreatic gland in 22 patients, in the body in two patients and in the tail in one patient. The pathological stage was pT1 in nine patients, pT2 in nine patients, pT3 in seven patients, pN0 in 14 patients and pN1 in 11 patients. All the patients were pM0. A pancreaticoduodenectomy was performed in 22 patients, a distal pancreatectomy was performed in two patients and a total pancreatectomy was performed in one patient. The resection was considered to be complete in 20 patients. One patient had microscopic residual disease and gross residual disease was present in four patients. IORT using electrons with a median energy of 12 MeV was performed in all the patients with doses ranging from 12 to 25 Gy. Postoperative EBRT was delivered to 20 patients (median dose 44 Gy). Concurrent chemotherapy with 5-fluorouracil was given to seven patients. The overall survival was 56% at 1 year, 20% at 2 years and 10% at 5 years. Nine local failures were observed. Twelve patients developed metastases without local recurrence. Twenty patients died from tumour progression and two patients died from early postoperative complications. Three patients are still alive; two patients in complete response at 17 and 94 months and one patient with hepatic metastases at 13 months. IORT after complete resection combined with postoperative external beam irradiation is feasible and well tolerated in patients with pancreatic adenocarcinoma.


Birth Weight and Preterm Delivery Outcomes of Perinatally vs Nonperinatally Human Immunodeficiency Virus-Infected Pregnant Women in the United States: Results From the PHACS SMARTT Study and IMPAACT P1025 Protocol.
Pregnancy outcomes of perinatally human immunodeficiency virus-infected women (PHIV) are poorly defined. We compared preterm delivery and birth weight (BW) outcomes (low BW [LBW], <2500 g), small-for-gestational-age [SGA], and BW z scores [BWZ]) in HIV-exposed uninfected infants of PHIV vs nonperinatally HIV-infected (NPHIV) pregnant women in the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities or International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 studies. Mixed effects models and log binomial models were used to assess the association of maternal PHIV status with infant outcomes. Age-stratified analyses were performed. From 1998 to 2013, 2270 HIV-infected pregnant women delivered 2692 newborns (270 born to PHIV and 2422 to NPHIV women). PHIV women were younger, (mean age 21 vs 25 years, P < .01) and more likely to have a pregnancy CD4 count <200 cells/mm3 (19% vs 11%, P = .01). No associations between maternal PHIV status and preterm delivery, SGA, or LBW were observed. After adjustment, BWZ was 0.12 lower in infants of PHIV vs NPHIV women (adjusted mean, -0.45 vs -0.33; P = .04). Among women aged 23-30 years (n = 1770), maternal PHIV was associated with LBW (aRR = 1.74; 95% confidence interval, 1.18, 2.58; P < .01). The overall lack of association between maternal PHIV status and preterm delivery or infant BW outcomes is reassuring. The higher rates of LBW observed in PHIV women aged 23-30 years warrants further mechanism-based investigations as this is a rapidly growing and aging population worldwide. PHACS SMARTT study, NCT01310023. IMPAACT 1025, NCT00028145.


Hepatic angiosarcoma: mimicking of angioma on three-phase technetium-99m red blood cell scintigraphy.
A [99mTc]RBC study in a 63-yr-old man showed intrahepatic lesions which initially had less activity than surrounding liver tissue. When viewed 3 hr later, these had "reversed" and the lesions revealed increased uptake of the radiolabeled red cells. Some extrahepatic areas showed the same pattern (these were in the mesentery of the small bowel). The lesions proved to be angiosarcomas. Hence, the behavior of labeled red cells in these angiosarcomas mimicked that in benign hemangiomas.


Winter wheat yield prediction using convolutional neural networks from environmental and phenological data.
Crop yield forecasting depends on many interactive factors, including crop genotype, weather, soil, and management practices. This study analyzes the performance of machine learning and deep learning methods for winter wheat yield prediction using an extensive dataset of weather, soil, and crop phenology variables in 271 counties across Germany from 1999 to 2019. We proposed a Convolutional Neural Network (CNN) model, which uses a 1-dimensional convolution operation to capture the time dependencies of environmental variables. We used eight supervised machine learning models as baselines and evaluated their predictive performance using RMSE, MAE, and correlation coefficient metrics to benchmark the yield prediction results. Our findings suggested that nonlinear models such as the proposed CNN, Deep Neural Network (DNN), and XGBoost were more effective in understanding the relationship between the crop yield and input data compared to the linear models. Our proposed CNN model outperformed all other baseline models used for winter wheat yield prediction (7 to 14% lower RMSE, 3 to 15% lower MAE, and 4 to 50% higher correlation coefficient than the best performing baseline across test data). We aggregated soil moisture and meteorological features at the weekly resolution to address the seasonality of the data. We also moved beyond prediction and interpreted the outputs of our proposed CNN model using SHAP and force plots which provided key insights in explaining the yield prediction results (importance of variables by time). We found DUL, wind speed at week ten, and radiation amount at week seven as the most critical features in winter wheat yield prediction.


Why are Drosophila larvae more sensitive to avermectin than adults?
The insects have different physiological and morphological characteristics in various developmental stages. The difference in the characteristics may be related to the different sensitivity of insects to insecticides. In avermectin resistant strain screening assay, we found that the Drosophila larvae displayed a higher sensitivity to the insecticidal effect of avermectin, compared with adults. In this study, we found that the Drosophila larvae have relatively thicker chitin layer, faster avermectin metabolism and lower P-glycoprotein (P-gp) level, when compared with the adults. Besides, the expression levels of the molecular targets of avermectin, glutamate-gated chloride channel and γ-aminobutyric acid (GABA)-gated chloride channel, are lower in the larval stage than the adult. These results suggested that lower P-gp level in the body especially in brain may be the major reason for the higher sensitivity of Drosophila larvae to the insecticide. In summary, these results shed new light on the concept that different developmental stages of insects display different sensitivity to the same insecticide, which also provided a physiological explanation of the relevant mechanism of the difference of sensitivity of insect at its larval and adult stages to insecticide.


Best Practice Guideline - DEGUM Recommendations on Breast Ultrasound.
Alongside mammography, breast ultrasound is an important and well-established method in assessment of breast lesions. With the "Best Practice Guideline", the DEGUM Breast Ultrasound (in German, "Mammasonografie") working group, intends to describe the additional and optional application modalities for the diagnostic confirmation of breast findings and to express DEGUM recommendations in this Part II, in addition to the current dignity criteria and assessment categories published in Part I, in order to facilitate the differential diagnosis of ambiguous lesions.The present "Best Practice Guideline" has set itself the goal of meeting the requirements for quality assurance and ensuring quality-controlled performance of breast ultrasound. The most important aspects of quality assurance are explained in this Part II of the Best Practice Guideline.


Discrete Choice Experiments in Health State Valuation: A Systematic Review of Progress and New Trends.
Discrete choice experiments (DCEs) are increasingly used in health state valuation studies. This systematic review updates the progress and new findings of DCE studies in the health state valuation, covering the period since the review of June 2018 to November 2022. The review reports the methods that are currently being used in DCE studies to value health and study design characteristics, and, for the first time, reviews DCE health state valuation studies published in the Chinese language. English language databases PubMed and Cochrane, and Chinese language databases Wanfang and CNKI were searched using the self-developed search terms. Health state valuation or methodology study papers were included if the study used DCE data to generate a value set for a preference-based measure. Key information extracted included DCE study design strategies applied, methods for anchoring the latent coefficient on to a 0-1 QALY scale and data analysis methods. Sixty-five studies were included; one Chinese language publication and 64 English language publications. The number of health state valuation studies using DCE has rapidly increased in recent years and these have been conducted in more countries than prior to 2018. Wide usage of DCE with duration attributes, D-efficient design and models accounting for heterogeneity has continued in recent years. Although more methodological consensus has been found than in studies conducted prior to 2018, this consensus may be driven by valuation studies for common measures with an international protocol (the 'model' valuation research). Valuing long measures with well-being attributes attracted attention and more realistic design strategies (e.g., inconstant time preference, efficient design and implausible states design) were identified. However, more qualitative and quantitative methodology study is still necessary to evaluate the effect of those new methods. The use of DCEs in health state valuation continues to grow dramatically and the methodology progress makes the method more reliable and pragmatic. However, study design is driven by international protocols and method selection is not always justified. There is no gold standard for DCE design, presentation format or anchoring method. More qualitative and quantitative methodology study is recommended to evaluate the effect of new methods before researchers make methodology decisions.


Influence of Online Social Support on the Public's Belief in Overcoming COVID-19.
The sudden outbreak of coronavirus disease 2019 (COVID-19) in early 2020 has dramatically changed people's lives. Some countries have taken mass home quarantine to control the virus. However, the side effects of quarantine have rarely been interrogated by current COVID-19 research. This study thus investigates the effects of online social support on the public's beliefs in overcoming COVID-19 by embracing their cognition and emotion during the epidemic. First, by crawling and content analysis of the messages posted on "Baidu COVID-19 bar", this study identified 5 types of online social support given or received by the public during COVID-19. On this basis, a model explaining the public's beliefs was developed from the perspectives of online social support, cognition and emotion. 334 valid online questionnaires were collected to examine the proposed model and hypotheses. The results show that cognition has a direct effect on the belief, while emotion affects the belief via a full mediating effect of cognition. Tangible support and esteem support can directly affect the public's beliefs, and educational level significantly moderates these effects. In addition, the public's cognition is influenced by informational support, however, emotion is not influenced by social support but by other factors (e.g., information disclosure, material supplies and frustration caused by the epidemic). These research results provide a deep insight into how to reduce the negative effects of quarantine, consolidate the theoretical basis of the public's beliefs, and have important practical implications for individuals and the government in dealing with such emergencies.


Parental Vaccine Hesitancy and Association With Childhood Diphtheria, Tetanus Toxoid, and Acellular Pertussis; Measles, Mumps, and Rubella; Rotavirus; and Combined 7-Series Vaccination.
Parental vaccine hesitancy can be a barrier to routine childhood immunization and contribute to greater risk for vaccine-preventable diseases. This study examines the impact of parental vaccine hesitancy on childhood vaccination rates. This study assessed the association of parental vaccine hesitancy on child vaccination coverage with ≥4 doses of diphtheria, tetanus toxoid, and acellular pertussis vaccine; ≥1 dose of measles, mumps, and rubella vaccine; up-to-date rotavirus vaccine; and combined 7-vaccine series coverage for a sample of children aged 19-35 months using data from the 2018 and 2019 National Immunization Survey-Child (N=7,645). Adjusted differences in multivariable analyses of vaccination coverage were estimated among vaccine hesitant and nonhesitant parents and population attributable risk fraction of hesitancy on undervaccination, defined as not being up to date for each vaccine. Almost a quarter of parents reported being vaccine hesitant, with the highest proportion of vaccine hesitancy among parents of children who are non-Hispanic Black (37.0%) or Hispanic (30.1%), mothers with a high school education or less (31.9%), and households living below the poverty level (35.6%). Childhood vaccination coverage for all vaccines was lower for children of hesitant than nonhesitant parents, and the population attributable fraction of hesitancy on undervaccination ranged from 15% to 25%, with the highest percentage for ≥1 dose of measles, mumps, and rubella vaccine. Parental vaccine hesitancy may contribute up to 25% of undervaccination among children aged 19-35 months. Implementation of strategies to address parental vaccine hesitancy is needed to improve vaccination coverage for children and minimize their risk of vaccine-preventable diseases.


Dipyridamole-aspirin as thromboembolic prophylaxis in patients with aortic valve prosthesis. Prospective study with the Model 2320 Starr-Edwards prosthesis.
In a prospective study, the efficacy of a dipyridamole-aspirin regimen in prevention of thromboembolism was evaluated in 50 patients having isolated aortic valve replacement with the Model 2320 Starr-Edwards prosthesis. These operations were performed between February, 1972, and October, 1974. In 1,380 patient-months of follow-up, there was a 20% incidence of thromboembolism with a rate of 8.7/100 patient-years and a 19% probability of an embolic episode occurring by 3 years. Seven patients had transient episodes, two had permanent neurologic residua, and one patient died. Comparison is made to a similar group of patients having solitary aortic valve replacement but receiving no medication, studied by Starr and associates. There was no statistical difference in the incidence of thromboembolism between the two groups. In November, 1975, all patients were converted to a regimen of warfarin therapy. Since conversion to anticoagulation, there have been two thromboembolic episodes in 2,132 patient-months of follow-up for a rate of 1.1/100 patient-years. We conclude that the use of antiplatelet therapy in the form of dipyridamole-aspirin is inadequate for routine thromboembolic prophylaxis following SE 2320 aortic valve replacement.


Exploring the Mechanistic Link Between Obesity and Heart Failure.
Among subtypes of cardiovascular disease, obesity has a potent and unique association with heart failure (HF) that is unexplained by traditional cardiovascular risk mediators. The concomitant rise in the prevalence of obesity and HF necessitates better understanding of their relationship to develop effective prevention and treatment strategies. The purpose of this review is to provide mechanistic insight regarding the link between obesity and HF by elucidating the direct and indirect pathways linking the two conditions. Several direct pathophysiologic mechanisms contribute to HF risk in individuals with excess weight, including hemodynamic alterations, neurohormonal activation, hormonal effects of dysfunctional adipose tissue, ectopic fat deposition with resulting lipotoxicity and microvascular dysfunction. Obesity further predisposes to HF indirectly through causal associations with hypertension, dyslipidemia, and most importantly, diabetes via insulin resistance. Low levels of physical activity and fitness further influence HF risk in the context of obesity. These various processes lead to myocardial injury and cardiac remodeling that are reflected by abnormalities in cardiac biomarkers and cardiac function on myocardial imaging. Understanding and addressing obesity-associated HF is a pressing clinical and public health challenge which can be informed by a deeper understanding of the complex pathways linking these two conditions together.


Stereospecificity of diacylglycerol for stimulus-response coupling in platelets.
In intact platelets, a permeable diacylglycerol having a 1,2-sn- but not 2,3-sn- configuration activated protein kinase C directly. In the presence of Ca2+-ionophore this diacylglycerol caused full activation of platelet release reaction. 1,3-Isomer was inactive. Among these isomers only 1,2-sn-diacylglycerol was converted rapidly to the corresponding phosphatidic acid in both intact and broken cell preparations. Thus, the diacylglycerol which functions in stimulus-response coupling possesses a 1,2-sn-glycerol backbone, and other isomers are not involved in the signal transduction through the protein kinase C pathway.


Bioprotective and Functional Effect of Carnosine on Sepsis Induced Renal Damage in Male Albino Rat Model through Targeting IL-1β and TNF-α Production.
Acute kidney injury (AKI), one of the frequently diagnosed and serious sepsis induced complication has high morbidity and mortality. The present study investigated the bioprotective and functional effect of carnosine on AKI induced pathological damage in Male Albino rat model in vivo. AKI in Albino rats was induced by cecal ligation and puncture surgery where as TNF-α and IL-1β levels were detected using ELISA assay. Protein expression was examined by western blotting and pathological damage using hematoxylin and eosin (H&E). Treatment with carnosine suppressed AKI induced urea nitrogen and creatinine in Male Albino rat serum in dose-dependent manner. Development of sepsis mediated renal injury in Albino rats was also effectively prevented on treatment with carnosine. Secretion of AKI-induced IL-1β, IL-18, and TNF-α in renal tissues was alleviated significantly in Albino rats by carnosine treatment. Additionally, in carnosine-treated Albino rats renal tissues AKI induced Bax expression was alleviated while as Bcl-2 was promoted compared to AKI Albino rats. Carnosine treatment improved the survival rate of the Albino rats with AKI. Carnosine inhibits renal tissue damage and increases survival rate in AKI Albino rat model. The mechanism involves alleviation of inflammatory cytokine secretion and promotion of Bcl-2 expression. Thus, carnosine may be used as a therapeutic agent for treatment of AKI.


Baroreceptor stimulation for resistant hypertension: first implantation in France and literature review.
Despite a wide choice of effective antihypertensive treatments, blood pressure (BP) in roughly half of hypertensive subjects is not controlled. Resistant hypertension is defined as an uncontrolled BP despite optimal doses of three antihypertensive treatments, including a diuretic. After confirmation of resistant BP using home BP measurement or 24-hour ambulatory BP monitoring (ABPM), patients usually go through a work-up to rule out secondary hypertension. If secondary hypertension is ruled out, the recent European guidelines on hypertension consider baroreceptor stimulation or renal denervation to be possible options. The prevalence of resistant primary hypertension may reach up to 10% in specialized centres. The two proposed non-pharmacological therapeutic strategies have been developed recently to inhibit sympathetic overactivity in resistant hypertension. Among them, baroreceptor activation therapy (BAT) is an innovative approach that interferes with baroreflex function. The first-generation BAT device (Rheos(®); CVRx, Inc., Minneapolis, MN, USA) demonstrated good efficacy in lowering office BP and ABPM, but had an insufficient safety profile due to complex surgery. The second-generation BAT device (Barostim neo™ system; CVRx, Inc.) seems to share the same BP-lowering efficacy but has a better safety profile. We report the first French case of baroreceptor stimulation for hypertension using the Barostim neo™ system. We also discuss the pathophysiological features of and current levels of evidence for this technique.


Large Chaperone Complexes Through the Lens of Nuclear Magnetic Resonance Spectroscopy.
Molecular chaperones are the guardians of the proteome inside the cell. Chaperones recognize and bind unfolded or misfolded substrates, thereby preventing further aggregation; promoting correct protein folding; and, in some instances, even disaggregating already formed aggregates. Chaperones perform their function by means of an array of weak protein-protein interactions that take place over a wide range of timescales and are therefore invisible to structural techniques dependent upon the availability of highly homogeneous samples. Nuclear magnetic resonance (NMR) spectroscopy, however, is ideally suited to study dynamic, rapidly interconverting conformational states and protein-protein interactions in solution, even if these involve a high-molecular-weight component. In this review, we give a brief overview of the principles used by chaperones to bind their client proteins and describe NMR methods that have emerged as valuable tools to probe chaperone-substrate and chaperone-chaperone interactions. We then focus on a few systems for which the application of these methods has greatly increased our understanding of the mechanisms underlying chaperone functions.


Chemical-resistant ammonia sensor based on polyaniline/CuO nanoparticles supported on three-dimensional nitrogen-doped graphene-based framework nanocomposites.
A novel ammonia (NH3) chemical sensor is presented with ultra-high response, good selectivity, fast response, and long-term stability using detecting layer of polyaniline/cupric oxide nanoparticles supported on three-dimensional nitrogen-doped graphene-based frameworks (PANI/CuO@3D-NGF) nanocomposite. The NH3 gas sensing response of the PANI/CuO@3D-NGF nanocomposite was studied by resistivity method in low concentration range of 50 ppb-100 ppm at room temperature. The PANI/CuO@3D-NGF nanocomposite was prepared through in situ polymerization of PANI on the CuO@3D-NGF with a high surface area. Morphological and structural analysis revealed that the ultrathin 3D interconnected graphene substrate maximizes the surface area. It is also shown that the CuO nanoparticles offer active adsorption sites for free NH3 molecule. The PANI/CuO@3D-NGF nanocomposite gas sensor shows the response of 930% to 100 ppm NH3 with an outstanding low detection limit of 50 ppb and an average response time of 30 s at room temperature. The excellent sensing performance of the PANI/CuO@3D-NGF nanocomposite was attributed to 3D interconnected porous structure, remarkable enhancement of charge carriers as a result of CuO@3D-NGF, and modified π-interactions between molecules. Graphical abstract.


Changes in retinal circulation and choroidal thickness in patients with acute myeloid leukemia detected by optical coherence tomography angiography.
To investigate changes in retinal circulation and the choroid in patients with acute myeloid leukemia (AML) in the acute and remission stages, to analyze the correlation between retinal circulation and laboratory parameters, and to assess risk factors associated with leukemic retinopathy. Forty-eight patients (93 eyes) with AML were enrolled and divided into two groups according to fundus examination findings: the retinopathy and no retinopathy groups. Patients underwent eye measurements before treatment and after remission. Macular vessel density (VD), perfusion density (PD), foveal avascular zone (FAZ), and choroidal thickness (ChT) were measured using optical coherence tomography angiography. Patients with healthy eyes were recruited as control participants. Patients with leukemic retinopathy had higher measurements of white blood cells (WBCs), circulating blasts, fibrin degradation products, and cross-linked fibrin degradation products (D-dimer) and a lower hemoglobin (HB) count (p < 0.05). In the acute phase of the disease, the VD and PD were lower and the ChT was thicker in patients with AML than in controls (p < 0.05), irrespective of the presence of leukemic retinopathy; however, the patients were partially recovered in the remission stage. The VD was lower in patients with higher WBC (r = -0.217, p = 0.036), D-dimer (r = -0.279, p = 0.001), fasting blood glucose (FBG) (r = -0.298, p = 0.004) and triglyceride (r = -0.336, p = 0.001) levels. The FAZ area was negatively correlated with HB (r = -0.258, p = 0.012). Patients with AML appear to have subclinical retinal perfusion loss and choroidal thickening in the acute phase of the disease, but this is reversible. Injury to bone marrow function may cause a decrease in retinal perfusion. Leukemic retinopathy is associated with abnormal hematologic parameters and coagulopathy.


Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer.
Serine and one-carbon unit metabolisms are essential biochemical pathways implicated in fundamental cellular functions such as proliferation, biosynthesis of important anabolic precursors and in general for the availability of methyl groups. These two distinct but interacting pathways are now becoming crucial in cancer, the de novo cytosolic serine pathway and the mitochondrial one-carbon metabolism. Apart from their role in physiological conditions, such as epithelial proliferation, the serine metabolism alterations are associated to several highly neoplastic proliferative pathologies. Accordingly, prostate cancer shows a deep rearrangement of its metabolism, driven by the dependency from the androgenic stimulus. Several new experimental evidence describes the role of a few of the enzymes involved in the serine metabolism in prostate cancer pathogenesis. The aim of this study is to analyze gene and protein expression data publicly available from large cancer specimens dataset, in order to further dissect the potential role of the abovementioned metabolism in the complex reshaping of the anabolic environment in this kind of neoplasm. The data suggest a potential role as biomarkers as well as in cancer therapy for the genes (and enzymes) belonging to the one-carbon metabolism in the context of prostatic cancer.


MicroRNA-197-3p mediates damage to human coronary artery endothelial cells via targeting TIMP3 in Kawasaki disease.
Kawasaki disease (KD) causes cardiovascular system injury in children. However, the pathogenic mechanisms of KD have not been well defined. Recently, strong correlation between aberrant microRNAs and KD nosogenesis has been revealed. A role of microRNA-197-3p (miR-197-3p) in the pathogenesis of KD is identified in the present study. Cell proliferation assay showed human coronary artery endothelial cells (HCAECs) were suppressed by serum from KD patients, which was correlated with high levels of miR-197-3p in both KD serum and HCAECs cultured with KD serum. The inhibition of HCAECs by miR-197-3p was confirmed by cells expressing miR-197-3p mimic and miR-197-3p inhibitor. Comparative proteomics analysis and Ingenuity Pathway Analysis (IPA) revealed TIMP3 as a potential target of miR-197-3p, which was demonstrated by western blot and dual-luciferase reporter assays. Subsequently, by detecting the endothelium damage markers THBS1, VWF, and HSPG2, the role of miR-197-3p/TIMP3 in KD-induced damage to HCAECs was confirmed, which was further validated by a KD mouse model in vivo. The expressions of miR-197-3p and its target, TIMP3, are dramatically variational in KD serum and HCAECs cultured with KD serum. Increased miR-197-3p induces HCAECs abnormal by restraining TIMP3 expression directly. Hence, dysregulation of miR-197-3p/TIMP3 expression in HCAECs may be an important mechanism in cardiovascular endothelium injury in KD patients, which offers a feasible therapeutic target for KD treatment.


(RS)-alpha-Methyl-4-carboxyphenylglycine inhibits long-term potentiation only following the application of low frequency stimulation in the rat dentate gyrus in vitro.
The effect of the metabotropic glutamate receptor (mGluR) antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) was investigated on the induction of long-term potentiation (LTP) of alpha-amino-3-hydroxy-5- methyl-4-isoxazoleproprionate receptor-mediated excitatory postsynaptic currents (epscs) recorded from dentate granule cells in response to presynaptic stimulation of the associational/commissural pathway of the rat dentate gyrus in vitro. MCPG (500 microM, 60 min) did not inhibit the induction of LTP of epscs induced by high frequency stimulation (HFS) at sites which had received only test stimulation (0.05/s) preceding the HFS. MCPG did, however, block the induction of LTP of epscs elicited by HFS if the HFS was preceded by the induction of long-term depression elicited by low frequency stimulation (5 Hz for 3 min). After such low frequency stimulation, HFS induced only a short-term potentiation lasting up to a maximum of 10 min in the presence of MCPG.


Recurrence of radial bowing after soft tissue distraction and subsequent radialization for radial longitudinal deficiency.
Centralization and radialization are the most widely reported surgical treatments for Bayne and Klug Type III and IV radial longitudinal deficiency. Prior soft tissue distraction has been introduced to improve reducibility of the deformity without skeletal resection. Satisfying long-term effects have been reported with centralization but are still unclear with radialization. This is a retrospective study of 8 consecutive children with Bayne and Klug Type III or IV radial longitudinal deficiency treated with preliminary soft tissue distraction followed by radialization between 2003 and 2008. All children underwent the same surgical protocol. End points of the study were clinical appearance, the hand-forearm angle, and mean angular correction at last follow-up. The mean preoperative hand-forearm angle was 61° (26°-91°). The average duration of distraction was 1.9 month (1-3 mo). The initial postoperative angle averaged 12° (-14°-40°). There were 3 postoperative complications: 2 cases of pin loosening and 1 case of fracture of the base of the small finger metacarpal. Mean follow-up duration was 2.6 years (1-4 y). At last follow-up, 7 of the 8 patients had visible recurrence of the deformity, the hand-forearm angle had deteriorated to 44° (20°-69°), and the mean angular correction was 18° (-43°-59°). Preoperative distraction allows a gradual realignment of the hand on the forearm without skeletal resection, but the recurrence rate after radialization is high. Tendon transfers and soft tissue tensioning were unable to maintain hand-forearm alignment following soft tissue distraction. Therapeutic IV.


Evaluation of the efficacy of drug treatment based on measurement of the oxidative stress, using reactive oxygen metabolites and biological antioxidant potential, in children with autism spectrum disorder and attention deficit hyperactivity disorder.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, mainly characterized by impairment of social communication and restricted interests. ASD is frequently accompanied by attention deficit hyperactivity disorder (ADHD), which is characterized by carelessness, hyperactivity and impulsivity (ASD/ADHD). It has been suggested that ASD and ADHD are associated with oxidative stress, that is, that patients with ASD/ADHD are in a state of increased oxidative stress. There are currenr tly no objective or biological test criteria for evaluating the efficacy of drug therapy in these patients. The purpose of this study was to evaluate whether oxidative stress markers [serum reactive oxygen metabolites (d-ROMs) levels and biological antioxidant potential (BAP)] can be used as objective indicators for evaluating the efficacy of drug treatment in ASD/ADHD patients. The subjects of this study subjects were 50 Japanese patients with ASD/ADHD aged 4 to 14 years old. Serum samples were obtained from the patients to measure the serum levels of d-ROMs and the serum BAP. The study subjects were divided into two age groups: preschool children (4 to 6 years old) and school-age children (7 to 14 years old), and the serum levels of d-ROMs, serum BAP, serum BAP/d-ROMs ratio (hereinafter, the prefix serum will be dropped), and scores on the Parent-interview ASD Rating Scales-Text Revision (PARS-TR) and ADHD Rating Scale (ADHD-RS) were determined before and after drug therapy and compared between the two groups. In addition, changes in the d-ROMs, BAP and BAP/d-ROMs ratio and changes in the scores on the PARS-TR and ADHD-RS after treatment were also analyzed. Significant decrease of the d-ROMs, BAP, and scores on the PARS-TR and ADHD-RS, with a significant increase of the BAP/d-ROMs ratio, was observed after treatment. In addition, a significant correlation was observed between the changes in the d-ROMs and changes in the scores on the PARS-TR and ADHD-RS after treatment in the school-age ASD/ADHD children. Our results suggest the possibility that the serum level of d-ROMs may be useful as an objective assessment marker to supplement the subjective assessment of the effects of drug treatment in school-age children with ASD/ADHD.


Decoding the function of nuclear long non-coding RNAs.
Long non-coding RNAs (lncRNAs) are mRNA-like, non-protein-coding RNAs that are pervasively transcribed throughout eukaryotic genomes. Rather than silently accumulating in the nucleus, many of these are now known or suspected to play important roles in nuclear architecture or in the regulation of gene expression. In this review, we highlight some recent progress in how lncRNAs regulate these important nuclear processes at the molecular level.


A randomized, triple masked, placebo-controlled clinical trial for controlling childhood obesity.
The efficacy of pharmacological treatment in controlling childhood obesity is controversial. We aimed to compare the effects of three types of drug regimens and placebo on generalized and abdominal obesity among obese children and adolescents who did not succeed to lose weight 3 months after lifestyle modification (diet and exercise). This triple-masked randomized clinical trial was conducted among 180 participants aged 10-16 years. They were assigned randomly to 4 groups of equal number to receive metformin, fluoxetine, a combination of the two drugs, or placebo. The trial lasted for 12 weeks and participants were followed up for an additional 12-week period. Overall, 91.1% (n=164) of the enrolled participants completed the trial. After the 12-week trial, the body mass index decreased significantly in all groups receiving medications [approximately -1.2 (0.2) kg/m², P<0.05]. This decrease was not significant in the placebo group. Waist circumference decreased significantly in the groups receiving metformin [-2.1 (0.4) cm, P=0.03)] as well as in the group receiving a combination therapy of metformin and fluoxetine [-2.5 (0.4) cm, P=0.01)]. In the 24-week follow-up study, these anthropometric indexes were lower than the baseline in the group that had received a combination therapy of metformin and fluoxetine. No serious drug side-effects were reported. A limited period of such treatment may help weight control, and might be used to encourage those children who have been refractory to weight loss for continuing the non-pharmacological programs. Our findings should be confirmed in future studies with a longer follow-up period.


In vitro studies of intestinal permeability and hepatic and intestinal metabolism of 8-prenylnaringenin, a potent phytoestrogen from hops (Humulus lupulus L.).
The absorption potential and metabolism of 8-prenylnaringenin (8-PN) from hops (Humulus lupulus L.) were investigated. 8-PN is a potent estrogen with the potential to be used for the relief of menopausal symptoms in women. Monolayers of the human intestinal epithelial cancer cell line Caco-2 and human hepatocytes were incubated with 8-PN to model its intestinal absorption and hepatic metabolism, respectively. The apparent permeability coefficients for 8-PN in the apical-to-basolateral and basolateral-to-apical directions of a Caco-2 monolayer were 5.2 +/- 0.7 x 10(-5) and 4.9 +/- 0.5 x 10(-5) cm/s, respectively, indicating good intestinal absorption via passive diffusion. Both glucuronide and sulfate conjugates of 8-PN were detected in the Caco-2 cell incubations. The 4'-O-glucuronide was the predominant Caco-2 cell metabolite, followed by 7-O-sulfate and 4'-O-sulfate. Both phase I and phase II metabolites of 8-PN were formed by human hepatocytes. The 7-O-glucuronide was the most abundant hepatocyte metabolite, and no sulfate conjugates were detected. Incubations with various cDNA-expressed UDP-glucuronosyltransferases indicated that the isozymes UGT1A1, UGT1A6, UGT1A8, and UGT1A9 were responsible for glucuronidation of 8-PN. Although orally administered 8-PN should be readily absorbed from the intestine, its bioavailability should be reduced significantly by intestinal and hepatic metabolism.


Individual improvements and selective mortality shape lifelong migratory performance.
Billions of organisms, from bacteria to humans, migrate each year and research on their migration biology is expanding rapidly through ever more sophisticated remote sensing technologies. However, little is known about how migratory performance develops through life for any organism. To date, age variation has been almost systematically simplified into a dichotomous comparison between recently born juveniles at their first migration versus adults of unknown age. These comparisons have regularly highlighted better migratory performance by adults compared with juveniles, but it is unknown whether such variation is gradual or abrupt and whether it is driven by improvements within the individual, by selective mortality of poor performers, or both. Here we exploit the opportunity offered by long-term monitoring of individuals through Global Positioning System (GPS) satellite tracking to combine within-individual and cross-sectional data on 364 migration episodes from 92 individuals of a raptorial bird, aged 1-27 years old. We show that the development of migratory behaviour follows a consistent trajectory, more gradual and prolonged than previously appreciated, and that this is promoted by both individual improvements and selective mortality, mainly operating in early life and during the pre-breeding migration. Individuals of different age used different travelling tactics and varied in their ability to exploit tailwinds or to cope with wind drift. All individuals seemed aligned along a race with their contemporary peers, whose outcome was largely determined by the ability to depart early, affecting their subsequent recruitment, reproduction and survival. Understanding how climate change and human action can affect the migration of younger animals may be the key to managing and forecasting the declines of many threatened migrants.


Research progress on ANXA5 in recurrent pregnancy loss.
The incidence of recurrent pregnancy loss (RPL) in fertile women ranges from 1% to 5%, of which about 50% of them are due to unknown causes. The possible pathogenesis of RPL is an urgent problem to be solved in the clinical. Mutations or polymorphisms of certain genes in the coagulation mechanism are associated with susceptibility to thrombotic diseases and are one of the main reasons for the occurrence of RPL. Among them, the ANXA5 gene was newly studied and some single nucleotide polymorphisms (SNPs) in the promoter region of ANXA5 have been reported to be associated with RPL in multiple races. In this review, we summarized the research progress on the correlation between the SNPs in ANXA5 and RPL, hoping to provide some valuable guidance for the future studies.


New Perspective on the Nanoplastics Disrupting the Reproduction of an Endangered Fern in Artificial Freshwater.
The potential risks of micro/nanoplastics on the ecological environment, particularly aquatic fauna, have been realized in recent years. However, information about its potential effects on aquatic plants is scarce. In this study, a four-week exposure experiment was conducted to investigate the effects of varying polystyrene nanoplastics concentration (PS-NPs, 0-100 μg/mL) on the early development of an endangered aquatic plant, Ceratopteris pteridoides. Fluorescent observations demonstrated that PS-NPs were adsorbed and accumulated on the spore surface of C. pteridoides rapidly and massively with increasing exposure concentration and time. The adsorption and accumulation of PS-NPs on the spore surface posed a negative effect on spore imbibition, causing 2.3-22.4% reduction in final spore size. Spore germination and gametophyte sex differentiation were both negatively affected by PS-NP exposure, resulting in 10.4-88.0% inhibition in germination ratio and 2.9-53.4% reduction in hermaphroditic gametophyte ratio. Additionally, PS-NPs were observed to penetrate into the roots of gametophytes. Higher concentration of PS-NPs (100 μg/mL) can even induce pathological changes on gametophytes, although with a low incidence (4.9%). The results above indicated that exposure to PS-NPs caused a series of disruptions from the spore imbibition to germination and gametophyte stages, and are likely to pose an eco-physiological risk on the reproductive success of endangered ferns.


Heterochromatic DNA in Triturus (Amphibia, Urodela). I. A satellite DNA component of the pericentric C-bands.
We have studied the structure, genome organization, chromosomal location, conservation across species and transcription on lampbrush chromosomes, of an AT-rich satellite DNA component of the newt, Triturus vulgaris meridionalis. The satellite (Sat G), originally isolated by gradient centrifugation, represents about 2% of the vulgaris genome and comprises a highly repetitive sequence family (HindIII family), whose monomers have been cloned. The repeat units are about 330 bp long, as measured on gels, and a cloned unit (pTvm1) is 310 bp long, as shown by sequencing. Abundant clusters of the HindIII family sequences are located within the pericentric heterochromatin (i.e. the C-bands placed at both sides of, and at a certain distance from, the centromeres) in most chromosomes. Both the sequence family and its overall pattern of chromosomal distribution are conserved within the genus Triturus, despite a few species-specific differences. The great majority of the HindIII family sequences are unexpressed on lampbrush chromosomes; they reside within pericentric, condensed segments of the chromosome axis ("loopless bars"). Only a few sequences are transcribed on some loops, suggesting that transcription promotion does not depend on the satellite sequences themselves.


Structure and dynamics of a designed helix-loop-helix dimer in dilute aqueous trifluoroethanol solution. A strategy for NMR spectroscopic structure determination of molten globules in the rational design of native-like proteins.
The overwhelming majority of engineered amino acid sequences designed to fold into well defined tertiary structures show the hallmarks of molten globules. Although imperfectly folded, the structures of these polypeptides are of considerable interest in assessing the predictive power of design strategies and in understanding the structural basis for the formation of proteins with native-like properties. This paper describes a strategy for the structural characterization of molten globules by NMR spectroscopy applied to the study of SA-42, a polypeptide with 42 amino acids that folds into a hairpin helix-loop-helix dimer. The 1H NMR spectrum of SA-42 was assigned in several mixtures of water and trifluoroethanol (TFE) (0-30 vol%) and small amounts of TFE were shown to have a significant effect on the spectrum. The secondary and supersecondary structures of SA-42 were determined. In aqueous solution a helix-loop-helix dimer is formed, but in 30 vol% of TFE the population of hairpin dimers are negligible and SA-42 is monomeric, folding into two non-interacting helical segments. In solutions containing less than 3 vol% of TFE the structure is very similar to that in water and the structural information may be used to develop the motif in aqueous solution. Less well ordered amino acid residue sidechains in the hydrophobic core were identified. Helix distortion in the tetrahelix bundle was found to be small. Detailed information about molten globule structures in aqueous solution can be obtained from NMR spectroscopy if the spectra are assigned in dilute TFE solution. On the basis of the NMR spectroscopic analysis, the solution structure of SA-42 was found to be close to the designed one. A route for developing native-like properties in SA-42 is suggested based on the identification by NMR spectroscopy of some less well ordered amino acid sidechains in the hydrophobic core and on the observed structural rigidity of the two helices.


Nature of the superconductor-insulator transition in disordered superconductors.
The interplay of superconductivity and disorder has intrigued scientists for several decades. Disorder is expected to enhance the electrical resistance of a system, whereas superconductivity is associated with a zero-resistance state. Although superconductivity has been predicted to persist even in the presence of disorder, experiments performed on thin films have demonstrated a transition from a superconducting to an insulating state with increasing disorder or magnetic field. The nature of this transition is still under debate, and the subject has become even more relevant with the realization that high-transition-temperature (high-T(c)) superconductors are intrinsically disordered. Here we present numerical simulations of the superconductor-insulator transition in two-dimensional disordered superconductors, starting from a microscopic description that includes thermal phase fluctuations. We demonstrate explicitly that disorder leads to the formation of islands where the superconducting order is high. For weak disorder, or high electron density, increasing the magnetic field results in the eventual vanishing of the amplitude of the superconducting order parameter, thereby forming an insulating state. On the other hand, at lower electron densities or higher disorder, increasing the magnetic field suppresses the correlations between the phases of the superconducting order parameter in different islands, giving rise to a different type of superconductor-insulator transition. One of the important predictions of this work is that in the regime of high disorder, there are still superconducting islands in the sample, even on the insulating side of the transition. This result, which is consistent with experiments, explains the recently observed huge magneto-resistance peak in disordered thin films and may be relevant to the observation of 'the pseudogap phenomenon' in underdoped high-T(c) superconductors.


Bilateral variations of the vertebral arteries: the left originating from the aortic arch and the left and right entering the C5 transverse foramina.
During the dissection course for second year medical students at the University of Toyama in 2005, we encountered variations of the bilateral vertebral arteries: the left directly came off from the aortic arch as the third branch between the left common carotid artery and the left subclavian artery and entered the transverse foramen of C5, instead of C6, whereas the right originated from the right subclavian artery and entered the transverse foramen of C5. The present vertebral artery of each side was possibly formed by the 6th cervical intersegmental artery linked with the longitudinal anastomoses between the cervical intersegmental arteries. Detailed knowledge of vertebral artery variations is crucially important for surgical treatment of blood vessels in the brain, neck and chest.


The effects of co-cultivation with the acetogen Acetitomaculum ruminis on the fermentative metabolism of the rumen fungi Neocallimastix patriciarum and Neocallimastix sp. strain L2.
The effects of co-cultivation with the hydrogen-utilizing acetogenic bacterium Acetitomaculum ruminis on the fermentative activities of the rumen fungi Neocallimastix patriciarum or Neocallimastix sp. L2 were investigated. In both co-cultures acetate production increased, making it the predominant fermentation product, as the accumulation of lactate, formate, ethanol, H2 and (in the case of Neocallimastix sp. L2) succinate all decreased. The effects of co-cultivation with Methanobrevibacter smithii were more pronounced. Decreased activities of lactate dehydrogenase, alcohol dehydrogenase and (in the case of Neocallimastix sp. L2) fumarate reductase accompanied the shift in fermentation product formation. The rate of glucose utilization and the fungal biomass yield were also increased in the co-culture.


Bioluminescence: pH activity profiles of related luciferase fractions.
The 27, 000g supernatant from crude extracts of the dinoflagellate Gonyaulax can be fractionated into two components having luciferase activity that differ both in molecular weight (35, 000 and 150, 000) and in pH activity profile. The smaller component has activity over a broad range from pH 5 to 9, while the larger one is active only in the acid region. This clarifies the previous ambiguity in the literature regarding the optimum pH for the assay of luciferase.


One-step construction of lentiviral reporter using Red-mediated recombination.
Current approaches to generate lentiviral vectors, which have been used extensively for gene therapy, are time consuming and require a large expenditure. Here, we directly clone the full length myosin light chain kinase cDNA into enhanced green fluorescence protein (EGFP)-fused pLenti6/V5 expression vector in just one step with the use of Red-mediated recombination system, allowing for rapid and effective cloning of lentiviral expression vectors. In addition, the simultaneous expression of EGFP reporter provides a convenient monitoring mean for host cell infection and for localization of the target proteins.


Alterations in insulin receptor signalling in the rat epitrochlearis muscle upon cessation of voluntary exercise.
The major purpose of this study was to elucidate mechanisms by which decreasing enhanced physical activity induces decreased insulin sensitivity in skeletal muscle. Rats with access to voluntary running wheels for 3 weeks had their wheels locked for 5 h (WL5), 29 h (WL29), or 53 h (WL53); a separate group of rats never had wheel access (sedentary, SED). Relative to WL5, submaximal insulin-stimulated 2-deoxyglucose uptake into the epitrochlearis muscle was lower in WL53 and SED. Insulin binding, insulin receptor beta-subunit (IRbeta) protein level, submaximal insulin-stimulated IRbeta tyrosine phosphorylation, and glucose transporter-4 protein level were each lower in both WL53 and SED than in WL5 and WL29. Akt/protein kinase B Ser(473) phosphorylation was lower in WL53 and SED than in WL5. Protein levels of protein tyrosine phosphatase-1B, Src homology phosphatase-2, and protein kinase C- did not vary among groups. The amount of protein tyrosine phosphatase-1B, Src homology phosphatase-2, and protein kinase C- associated with IRbeta in insulin-stimulated muscle also did not differ among the four groups. The mean of SED and WL53 had a significantly higher IRbeta-associated protein tyrosine phosphatase-1B than the mean of WL5 and WL29. The enclosure of multiple changes (decreases in insulin binding, IRbeta protein, IRbeta tyrosine phosphorylation, and glucose transporter-4 protein) in the epitrochlearis muscle within the 29th to 53rd hour after cessation of voluntary wheel running raises the possibility that a single regulatory event could be responsible for the coordinated decrease.


Applying fingerprint FTIR spectroscopy and chemometrics to assess soil ecosystem disturbance and recovery.
The assessment and monitoring of soil disturbance and its effect on soil quality (i.e., ability to support a range of ecosystem services) has been hindered due to the shortcomings of many traditional analytical techniques (e.g., soil enzyme activities, microbial incubations), including: high cost, long-term time investment and difficulties with data interpretation. Consequently, there is a critical need to develop a rapid and repeatable approach for quantifying changes in soil quality that will provide an assessment of the current status, condition and trend of natural and managed ecosystems. Here we report on a rapid, high-throughput approach to develop an ecological 'fingerprint' of a soil using Fourier transformed infrared (FTIR) spectroscopy and chemometric modeling, and its application to assess soil ecosystem status and trend. This methodology was applied in a highly disturbed forest ecosystem over a 19-year sampling period to detect changes in soil quality (detected via changes in spectral properties), resulting from changes in dynamic soil properties (e.g., soil organic matter, reactive mineralogy). Two chemometric statistical techniques (i.e., hierarchical clustering analysis and discriminate analysis of principal components) were evaluated for interpreting and quantifying similarities/dissimilarities between samples utilizing the entire FTIR spectra (i.e., fingerprint) from each sample. We found that this approach provided a means for clearly discriminating between degraded soils, soils in recovery and reference soils. Results from fingerprint FTIR analysis illustrate its power and potential for the monitoring and assessment of soil quality and soil landscape change.


Optimal Pore Chemistry in an Ultramicroporous Metal-Organic Framework for Benchmark Inverse CO2 /C2 H2 Separation.
Isolation of CO2 from acetylene (C2 H2 ) via CO2 -selective sorbents is an energy-efficient technology for C2 H2 purification, but a strategic challenge due to their similar physicochemical properties. There is still no specific methodology for constructing sorbents that preferentially trap CO2 over C2 H2 . We report an effective strategy to construct optimal pore chemistry in a CeIV -based ultramicroporous metal-organic framework CeIV -MIL-140-4F, based on charge-transfer effects, for efficient inverse CO2 /C2 H2 separation. The ligand-to-metal cluster charge transfer is facilitated by CeIV with low-lying unoccupied 4f orbitals and electron-withdrawing F atoms functionalized tetrafluoroterephthalate, affording a perfect pore environment to match CO2 . The exceptional CO2 uptake (151.7 cm3 cm-3 ) along with remarkable separation selectivities (above 40) set a new benchmark for inverse CO2 /C2 H2 separation, which is verified via simulated and experimental breakthrough experiments. The unique CO2 recognition mechanism is further unveiled by in situ powder X-ray diffraction experiments, Fourier-transform infrared spectroscopy measurements, and molecular calculations.


Immunoaffinity Mass Spectrometry Diagnostic Tests for Multi-Biomarker Assays.
Immunoaffinity mass spectrometry as an approach for diagnostic biomarker assays combines the advantages of antibody selectivity with the multiplexing and analytical performance of mass spectrometry. A method has been developed to detect and quantify three protein biomarkers for a diabetic kidney disease prognostic assay, PromarkerD. The methodology reflects an immunoaffinity approach compatible with higher throughput and robust clinical application. After preparation and purification of antibody-bead conjugates for the three target proteins, an immunoaffinity capture step provides a solution for reduction, alkylation, and digestion on-bead. Targeted mass spectrometry provides a quantitative measure of each biomarker in a rapid 8 min run using a microflow LCMS workflow.


Gut microbiota-microRNA interactions in ankylosing spondylitis.
Ankylosing spondylitis (AS) is a chronic autoimmune inflammatory disability that is part of the rheumatic disease group of spondyloarthropathies. AS commonly influences the joints of the axial skeleton. The contributions to AS pathogenesis of genetic susceptibility (particularly HLA-B27 and ERAP-1) and epigenetic modifications, like non-coding RNAs, as well as environmental factors, have been investigated over the last few years. But the fundamental etiology of AS remains elusive to date. The evidence summarized here indicates that in the immunopathogenesis of AS, microRNAs and the gut microbiome perform critical functions. We discuss significant advances in the immunological mechanisms underlying AS and address potential cross-talk between the gut microbiome and host microRNAs. This critical interaction implicates a co-evolutionary symbiotic link between host immunity and the gut microbiome.


2-Fluoro-N'-(2-hy-droxy-benzyl-idene)benzohydrazide.
In the title compound, C(14)H(11)FN(2)O(2), an intra-molecular O-H⋯N hydrogen bond influences the mol-ecular conformation; the two benzene rings form a dihedral angle of 18.4 (3)°. The F atom is disordered over two positions in a 0.717 (5):0.283 (5) ratio. In the crystal, inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into chains extending along the c axis.


Regional variation in primary care improvement strategies and policy: case studies that consider qualitative contextual data for performance measurement in three Canadian provinces.
To explore regional primary care improvement strategies that are potentially determinants of primary care performance. Multiple comparative embedded case study. Three regions in Canada: Fraser East, British Columbia; Eastern Ontario Health Unit, Ontario; Central Zone, Nova Scotia. (1) In-depth interviews with purposively selected key informants (eg, primary care decision-makers, physician leads, regulatory agencies) and focus groups with patients and clinicians (n=68 participants) and (2) published and grey literature (n=205 documents). Variations in spread and uptake of primary care improvement strategies across the three study regions. NVivo (V.11) was used to manage data and perform content analysis to identify categories within and across cases. The coding structure was developed by researchers through iterative collaboration, using inductive and deductive processes. Six overarching primary care improvement strategies, differing in focus and spread, were implemented across the three study regions: interprofessional team-based approaches, provider skill mix expansion, physician groups and networks, information systems, remuneration and performance measurement and reporting infrastructure. The addition of information on regional improvement strategies to primary care performance reports could add important contextual insights into primary care performance results. This could help identify possible drivers of reported performance outcomes and levers for change in practice, regional and system-level settings.


Pulmonary circulation after biventricular repair in patients with major systemic-to-pulmonary collateral arteries.
To determine factors affecting postoperative pulmonary circulation in patients with major systemic-to-pulmonary collateral arteries. A total of 48 patients underwent biventricular repair subsequent to unifocalization at ages in the range 1-34 years. The preparative procedures consisted of ligation of the collateral arteries in 6, plasty to the pulmonary arteries using no artificial materials in 12 and extensive reconstruction using heterologous pericardial tubes in 30. The number of the pulmonary vascular segments unifocalized was 9-18 (16 +/- 3). The amount of flow draining via residual minute systemic-to-pulmonary collaterals measured at the time of repair was 4-58% (24 +/- 16%) of the total perfusion by the cardiopulmonary bypass machine. This value was 40 +/- 16% in 5 patients dying in the short term after repair. The number of segments was nine or ten after unifocalization in 2 of these. Another 4 patients died in the longer term, 3 of these with CATCH 22 syndrome dying because of pulmonary hypertension. Postoperative catheterization demonstrated mean pulmonary arterial pressures in the range 8-40 (21 +/- 9) mmHg and pulmonary resistance in the range 1.7-10 (5.0 +/- 2.1) units/m2. Pulmonary resistance was correlated statistically to age at repair (r = 0.77), the number of pulmonary vascular segments (r = -0.41) and to percent collateral flow (r = 0.48). The use of a heterologous pericardial tube for unifocalization was also related probably to higher pulmonary resistance. It is essential to accomplish effective unifocalizations followed by earlier definitive repair so as to establish better pulmonary circulation.


PET imaging of maze processing.
Covered maze traversal models nonverbal planning, involving sequential execution of moves using learned spatial maps. To determine the neural substrate involved in maze processing, eleven adults underwent [H(2)15O]-PET while performing motor control, following the computer; visual control, choosing the wall with more dead-ends; uncovered maze, traversing fully visible mazes; covered maze, traversing mazes only locally visible. Maze processing lateralizes to the right hemisphere: uncovered maze versus controls revealed area 23 and 29 activation; covered maze versus controls activated areas 8, 10 and 19. The extrastriate region may store path information, evoked by prefrontal areas for spatial planning and navigation.


The reality of scientific research in Latin America; an insider's perspective.
There is tremendous disparity in scientific productivity among nations, particularly in Latin America. At first sight, this could be linked to the relative economic health of the different countries of the region, but even large and relatively rich Latin American countries do not produce a good level of science. Although Latin America has increased the number of its scientists and research institutions in recent years, the gap between developed countries and Latin American countries is startling. The prime importance of science and technology to the development of a nation remains unacknowledged. The major factors contributing to low scientific productivity are the limited access to grant opportunities, inadequate budgets, substandard levels of laboratory infrastructure and equipment, the high cost and limited supply of reagents, and inadequate salaries and personal insecurity of scientists. The political and economic instability in several Latin America countries results in a lack of long-term goals that are essential to the development of science. In Latin America, science is not an engine of the economy. Most equipment and supplies are imported, and national industries are not given the incentives to produce these goods at home. It is a pity that Latin American society has become accustomed to expect new science and technological developments to come from developed countries rather than from their own scientists. In this article, we present a critical view of the Latin American investigator's daily life, particularly in the area of biomedicine. Too many bright young minds continue to leave Latin America for developed countries, where they are very successful. However, we still have many enthusiastic young graduates who want to make a career in science and contribute to society. Governments need to improve the status of science for the sake of these young graduates who represent the intellectual and economic future of their countries.


Integration of ζ-deficient CARs into the CD3-zeta gene conveys potent cytotoxicity in T and NK cells.
Chimeric antigen receptor (CAR)-reprogrammed immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in non-physiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T cells and natural killer (NK) cells with CARs. By transferring shorter, truncated CAR-transgenes lacking a main activation domain into the human CD3 ζ (CD247) gene, functional CAR fusion-genes are generated that exploit the endogenous CD3 ζ gene as the CAR's activation domain. Repurposing this T/NK-cell lineage gene facilitated physiological regulation of CAR-expression and reprogramming of various immune cell types, including conventional T cells, TCRγ/δ T cells, regulatory T cells, and NK cells. In T cells, CD3 ζ in-frame fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the-shelf settings. CD3 ζ-CD19-CAR-T cells exhibited comparable leukemia control to T cell receptor alpha constant ( TRAC )-replaced and lentivirus-transduced CAR-T cells in vivo . Tuning of CD3 ζ-CAR-expression levels significantly improved the in vivo efficacy. Compared to TRAC -edited CAR-T cells, integration of a Her2-CAR into CD3 ζ conveyed similar in vitro tumor lysis but reduced susceptibility to activation-induced cell death and differentiation, presumably due to lower CAR-expression levels. Notably, CD3 ζ gene editing enabled reprogramming of NK cells without impairing their canonical functions. Thus, CD3 ζ gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes. Integration of ζ-deficient CARs into CD3 ζ gene allows generation of functional TCR-ablated CAR-T cells for allogeneic off-the-shelf use CD3 ζ-editing platform allows CAR reprogramming of NK cells without affecting their canonical functions.


Capillary electrophoretic approach to screen for enzyme inhibitors in natural extracts.
This paper demonstrates development of electrophoretically mediated micro analysis (EMMA), for screening protein tyrosine phosphatase (PTP) inhibitors in natural extracts. It is demonstrated that capillary electrophoresis (CE) separation of the substrate and the product allows for using the assay in an on-column format to monitor the reaction without typically used fluorogenic substrates. Michaelis-Menten kinetics parameters calculated based on the EMMA results (Km = 1.2-1.5 microM) were in a good agreement (Km = 1.0-1.5 microM) obtained using an off-line CE functional assay (CE FA). EMMA of PTP titrated with different concentrations of ligand demonstrated the peak-shift phenomenon normally seen in affinity capillary electrophoresis. This feature of EMMA gives an indication of the binding affinity of the ligand in addition to its functional activity, providing another dimension in characterization of the protein-inhibitor interaction. It was demonstrated that simultaneous screening of the primary PTP target and a secondary, counter target (PTP-C) using the EMMA format can be used to prioritize hits based on their specificity.


Decrease in patient radiation exposure by a tantalum filter during electrophysiological procedures.
Minimization of X-ray exposure remains a primary issue in cardiac electrophysiology. The effectiveness of X-ray beam filtration during cardiac electrophysiological procedures was therefore studied, using a 0.05-mm-thick tantalum (Ta) foil, as a filter on the primary X-ray beam, to reduce the patient dose without degradation of image quality. Preliminary tests were made on a phantom developed with polymethylmethacrylate, catheters, and guide wires. The filter was then used in patients during cardiac procedures. Identical patient images were obtained with and without the Ta filter insertion and the ratio between image quality and patient dose was evaluated. Changes in patient dose and signal-to-noise ratio, as image quality index were measured on the phantom and in patients. When the Ta filter was used, the mean effective individual patient dose decreased by 3 to 40% (mean reduction = 27%), with no perceivable difference in image quality estimated by electrophysiologists. This Ta filter may be useful to limit the radiation exposure of patients and operators during cardiac procedures.


Artemin activates axonal growth via SFK and ERK-dependent signalling pathways in mature dorsal root ganglia neurons.
Artemin, one of the glial cell line-derived neurotrophic factor (GDNF) family, enhances the generation and survival of early sympathetic neurons and superior cervical ganglion (SCG) neurons. Src-family kinases (SFK) are involved in the growth and differentiation of cells, which are composed of unique Src homology 2 (SH2), Src homology 3 (SH3) and kinase domains. Various extra-cellular molecules containing growth factors and G-protein coupled receptors stimulate SFK. In this report, artemin is shown to have a significant effect on the neurite growth of dorsal root ganglia (DRG) neurons. Also, artemin triggers Src-family kinase activation and the phosphorylation of extra-cellular signal-regulated kinases (ERK) mitogen-activated protein kinase (MAPK). Artemin also regulated actin polymerization. There are several indications that another SH3-containing protein, Hck, and an SH3-containing adaptor protein, Nck1, play an important role in the organization of the actin cytoskeleton by cellular signalling. These findings suggest that the exploration of binding partners for the SH3 domain could provide an insight into regulation between the microtubule and actin networks. The binding partners for the SH3 domains of Nck, Src and Hck that we identified were Smc chromosome segregation ATPases, FOG Zn-finger protein and the FYVE zinc-binding domain, respectively.


Three-dimensional analysis of flow disturbances caused by clots in inferior vena cava filters.
To assess the hemodynamics associated with clot captured within two different types of inferior vena cava (IVC) filters. Computational flow models were constructed for different clot sizes and shapes captured within the Greenfield (GF) (Medi-tech/Boston Scientific, Watertown, Massachusetts) and TrapEase (Cordis, Miami Lakes, Florida) IVC filters. Two models were employed; one was a straight tube (ST), and the other was a realistic model (RM) that included iliac and renal veins and lumbar curvature, with filter deployment between these inflows. Calculations were based on the Lattice Boltzmann method (LBM), allowing for accurate modeling of flows that are in transition from laminar to turbulent. Flow disturbances were noted downstream of captured clots, with turbulence intensities reaching 41%. Disturbances were strongest with large clot volumes and in ST models. The RM vessel geometry greatly reduced the level of flow disturbance (majority of <2%; maximum turbulence intensity of 11%). Implementing flow rate representative of the infrarenal vena cava (rather than suprarenal) was also shown to reduce the amount of flow disturbance in ST models. Although there is a mild amount of flow disturbance caused by captured clots, these flow patterns are not of the variety that have been shown to trigger platelet activation in other studies. Turbulence intensities were lower in the RMs, indicating the need to perform such flow studies under physiologic conditions.


A portable, low-resistance puff topography instrument for pulsating, high-flow smoking devices.
A smoking topography instrument appropriate for pulsating high flow rate smoking devices, such as the narghile water pipe, has been developed and tested. Instrument precision and repeatability was determined using a digitally controlled smoking machine, and the added draw resistance due to the topography instrument was measured over the range of expected puff flow rates. The maximum error in any topography variable was found to be less than 5%. The instrument was successfully demonstrated in a pilot field study of 30 volunteer narghile smokers. The pilot study yielded an average smoker puff volume, duration, and interpuff interval of 0.531, 2.47 sec, 16.28 sec, respectively.


Endocrine studies in a male patient with choriocarcinoma and gynecomastia.
Sex hormone profiles were studied in serum and tumor extracts of a man with pulmonary choriocarcinoma and gynecomastia. Although levels of serum estrogens were elevated as expected, serum androgen levels were uncharacteristically quite high. Tumor extract contained increased quantities of both androgens and estrogens when compared with surrounding normal lung tissue, but lacked the enzymes necessary for androgen biosynthesis while retaining aromatase activity. It is concluded that unlike the usual male patient with choriocarcinoma, the tumor-derived beta-human chorionic gonadotropin stimulated testicular androgen production. These androgens were in turn concentrated by the tumor and converted in part to estrogens. Furthermore, gynecomastia can occur even in the face of high serum androgen concentrations provided total estrogen levels are also disproportionately elevated.


Improving oxygen reduction reaction by cobalt iron-layered double hydroxide layer on nickel-metal organic framework as cathode catalyst in microbial fuel cell.
Cobalt Iron -layered double hydroxide (CoFe-LDH) nano sheets were attached to Nickel-metal organic frameworks (Ni-MOF) by utilizing hydrothermal reaction method, and CoFe-LDH@Ni-MOF was synthesized and worked as the cathode catalyst in microbial fuel cell. The surface of this composite material provided generous electrochemical active sites, consisting of wrinkled strips of CoFe-LDH adhering to a lamellar structure of Ni-MOF. In terms of the maximum output power density, CoFe-LDH@Ni-MOF as the catalyst was 211 mW/m2, 2.54 times higher than that of Ni-MOF (83 mW/m2), and it was stable at about 225 mV for 150 h. CoFe-LDH@Ni-MOF showed high oxygen reduction reaction capability and high specific surface area, and the electron transfer rate was accelerated. This work might set the stage for the development and utilization of fuel cell cathode catalysts.


Synergistic antidepressant effects of citalopram and SB-334867 in the REM sleep-deprived mice: Possible role of BDNF.
This study was done to evaluate the effect of co-treatment of orexin agents along with citalopram on the modulation of depression-like behavior and the expression of BDNF in the prefrontal cortex (PFC) of sleep-deprived male mice. A sleep deprivation model was performed in which rapid eye movement (REM) sleep was completely prohibited, and non-REM sleep was intensely reduced for 24 h. For drug microinjection, the guide cannula was surgically fixed in the left lateral ventricle of mice. Furthermore, we used the open-field test (OFT), forced swim test (FST), tail suspension test (TST), and splash test for recording depression-like behavior as well as Real-Time PCR amplification for assessing the expression of BDNF in the PFC of REM sleep-deprived mice. Our results revealed that REM sleep deprivation did not change locomotor activity while increased depressive-like behavior in FST, TST, and splash tests. However, the expression of BDNF was decreased in the PFC. Intraperitoneally (i.p.) administration of citalopram induced antidepressant effect in the normal and REM sleep-deprived mice. Moreover, intracerebroventricular (i.c.v.) microinjection of a non-effective dose of SB-334867, an orexin antagonist, potentiated the antidepressant-like effect of citalopram. On the other hand, a non-significant dosage of orexin-1 reversed the antidepressant effect of citalopram in the normal and REM sleep-deprived animals. Furthermore, our results showed that injection of citalopram alone or with SB-334867 increased the mRNA expression level of BDNF in the PFC of REM sleep-deprived mice. These data suggest that REM sleep deprivation interferes with the neural systems underlying the depression-like process and supports a likely interaction of the orexin system with citalopram on the modulation of depression-like behavior in REM sleep-deprived mice.


The tissue-specificity associated region and motif of an emx2 downstream enhancer CNE2.04 in zebrafish.
Expression level of EMX2 plays an important role in the development of nervous system and cancers. CNE2.04, a conserved enhancer downstream of emx2, drives fluorescent protein expression in the similar pattern of emx2. CNE2.04 truncated or motif-mutated transgenic reporter plasmids were constructed and injected into the zebrafish fertilized egg with Tol2 mRNA at the unicellular stage of zebrafish eggs. The green fluorescence expression patterns were observed at 24, 48, and 72 hpf, and the fluorescence rates of different tissues were counted at 48 hpf. Compared to CNE2.04, CNE2.04-R400 had comparable enhancer activity, while the tissue specificity of CNE2.04-L400 was obviously changed. Motif CCCCTC mutation obviously changed the enhancer activity, while motif CCGCTC mutations also changed it. Due to their correlation with tissue specificity, CNE2.04-R400 is associated with the tissue-specificity of CNE2.04, and motif CCCCTC plays an important role in the enhancer activity of CNE2.04.