Complications and outcomes after early surgical treatment for poor-grade ruptured intracranial aneurysms: A multicenter retrospective cohort.
Early surgical treatment has been proposed to improve outcomes of selected patients with poor-grade ruptured intracranial aneurysms. We performed a multicenter retrospective analysis to identify complications and outcomes after early surgery. We analyzed data from the two cohorts of patients with poor-grade ruptured aneurysms. Poor-grade aneurysm was defined as a World Federation of Neurosurgical Society (WFNS) grade of IV or V after resuscitation. Early surgery was defined as surgery performed within 72 h after poor-grade condition. Of the 144 patients who underwent surgical treatment for poor-grade aneurysm, 80 underwent early surgery and were included in this report. Forty-one (51%) patients presented with a WFNS grade of IV and 39 (49%) presented with a WFNS grade of V. Cerebral infarction occurred in 17 (21%) patients and was the most common complication except for pneumonia. No patients had a good outcome after postoperative aneurysm rebleeding. At follow-up (mean 12.6 months), 37 (46%) patients had a good outcome after early surgery. Multivariate analysis showed that a WFNS grade of V, presence of intraventricular hemorrhage, brain herniation were independent predictors of poor outcome after early surgery. Patients with WFNS grade V more often had a poor outcome after postoperative cerebral infarction, rebleeding or symptomatic vasospasm. Patients with a WFNS grade of V, intraventricular hemorrhage, brain herniation were more likely to have a poor outcome after early surgery. Postoperative complications, including rebleeding and cerebral infraction, should be prevented and treated aggressively to maximize the chance of good outcome in poor-grade patients.


Angioedema responding to antiprotease treatment but without abnormalities of the complement system.
Four patients suffered from chronic or recurrent angioedema, of sudden onset in adult life, associated with visceral pain and impossible to control by dietary means. In spite of normal complement function they respond very well to tranexamic acid therapy. Antiprotease drugs need not be restricted to cases of ClsINH deficiency.


[Update on the efficacy of triple therapy for Helicobacter pylori infection and clarithromycin resistance rates in Spain (2007-2012)].
Triple therapy, which remains the standard treatment for Helicobacter pylori infection, should be discouraged when its efficacy is lower than 80% or when clarithromycin resistance rates are above 15-20%. To update the available evidence on the effectiveness of triple therapy and clarithromycin resistance rates in adults in Spain over the last 6 years. A literature search (2007-2012) was conducted in Medline and the abstracts books of the annual meetings of several Spanish gastroenterological and microbiological congresses. The search terms were « Helicobacter pylori », « Spain » and « clarithromycin ». Studies were selected if they included triple therapy consisting of a proton pump inhibitor with clarithromycin and amoxicillin or if they analyzed H. pylori clarithromycin susceptibility in treatment-naïve patients. There were five articles and nine abstracts (3147 patients) on triple therapy, which showed a mean cure rate of 70.8% (95% CI = 66-76%). When stratified by the duration of therapy, the mean cure rates were 68.8% (60-76%) for 7-day regimens and 71.76% (68-78%) for 10-day regimens. For clarithromycin resistance rates, four articles and five abstracts (1709 patients) revealed a mean resistance rate of 18.3% (13-22%). The efficacy of triple therapy seems to be unacceptable in recent studies conducted in Spain, possibly associated with clarithromcyin resistance rates higher than previously reported.


Associations of the serotonin transporter promoter polymorphism (5-HTTLPR) with bipolar disorder and treatment response: A systematic review and meta-analysis.
Associations of the serotonin transporter promoter polymorphism (5-HTTLPR) with bipolar disorder (BPD) and treatment response in bipolar patients were not conclusive. This study not only assessed the association between the 5-HTTLPR and BPD with accumulating relevant studies, but also in the first time evaluated the effect of the 5-HTTLPR on both anti-depressive and anti-manic treatment responses in bipolar patients. PubMed, Embase, PsycINFO, Cochrane Library and Cochrane Control Trials databases were systematically searched before February 2017. This meta-analysis followed the PRISMA guidelines. A total of 32 population-based studies (5567 cases and 6993 controls) and 9 family-based studies (837 trios) were finally screened out and statistically joined into a single meta-analysis that revealed an association between S allele and an increased risk of BPD (OR = 1.06, p = .038). Pooled analysis of the 32 population-based studies indicated an association of S-carrier genotypes with an increased risk of BPD (OR = 1.10, p = .029). Meanwhile, the association remained significant in Caucasians (OR = 1.15, p = .004), which could provide an enough power (88%) to detect a significant association. Regarding the treatment response studies, 6 studies reporting the relationship of the 5-HTTLPR in anti-depressive remission rate (1034 patients) and 7 studies reporting in response rate (1098 patients) were included for pooled analyses. We observed a significant association of S-carrier genotypes with a reduced anti-depressive remission rate (OR = 0.64, p = .006) but not with anti-depressive response rate. The association between the 5-HTTLPR with anti-manic response rate was not observed in the included 6 studies (676 patients). The present study supported the presence of a marginal but detectable effect of the 5-HTTLPR on susceptibility to BPD. Moreover, the detected association in Caucasian was statistically reliable. Besides, the 5-HTTLPR was identified as a useful predictor for anti-depressive remission but not for anti-depressive or anti-manic response.


Development of engineered Escherichia coli whole-cell biocatalysts for high-level conversion of L-lysine into cadaverine.
A whole-cell biocatalytic system for the production of cadaverine from L-lysine has been developed. Among the investigated lysine decarboxylases from different microorganisms, Escherichia coli LdcC showed the best performance on cadaverine synthesis when E. coli XL1-Blue was used as the host strain. Six different strains of E. coli expressing E. coli LdcC were investigated and recombinant E. coli XL1-Blue, BL21(DE3) and W were chosen for further investigation since they showed higher conversion yield of lysine into cadaverine. The effects of substrate pH, substrate concentrations, buffering conditions, and biocatalyst concentrations have been investigated. Finally, recombinant E. coli XL1-Blue concentrated to an OD(600) of 50, converted 192.6 g/L (1317 mM) of crude lysine solution, obtained from an actual lysine manufacturing process, to 133.7 g/L (1308 mM) of cadaverine with a molar yield of 99.90 %. The whole-cell biocatalytic system described herein is expected to be applicable to the development of industrial bionylon production process.


Expression of microRNAs, CYP1A1 and CYP2B1 in the livers and ovaries of female rats treated with DDT and PAHs.
In this study, we determined the expression level of miRNAs and the induction of CYP1A1 and CYP2B1 in the livers and ovaries of female Wistar rats treated with DDT, benzo[a]pyrene (BP), and 3-methylcholanthrene (MC). This study compared CYP1A/2B induction and miRNA expression levels to cast light on a possible role of miRNA in the tissue-specific induction of CYPs. The induction of CYP1A1/2B1 enzymes was detected by ethoxy-, pentoxyresorufin O-dealkylation and Western blot analysis. The CYP1A1/2B1 gene expression was determined by RT-real time PCR. Relative levels of expression for selected in silico miR species were determined by real time PCR with small nuclear U6 RNA employed as a reference gene. After bioinformatic analysis, miR-21, 221, 222, and 429 were chosen as potential post-transcriptional regulators of rat CYP1A and CYP2B. It was shown that miR-21, 221, 222, and 429 expression levels decreased in the liver of DDT-, BP-, and MC-treated rats, whereas increases were observed in CYP1A1 and CYP2B1 mRNA expression levels and protein content, and EROD and PROD activities. Conversely, a tendency for elevated levels of miRNAs in the ovaries of inducer-treated female rats was observed. In the ovaries, a high level of CYP1A1 and CYP2B1 mRNA expression was observed, although protein content and enzyme activity were not visible. These data suggest a potential involvement of miRNA in the post-transcriptional regulation of CYP1A and CYP2B in the livers and ovaries of chemically induced rats.


Child Opportunity Index Disparities in Pediatric Surgical Encounters During the Coronavirus 2019 Pandemic.
Surgical encounters decreased during the coronavirus disease (COVID-19) pandemic and may have been deferred more in children with impeded health care access related to social/community risk factors. We compared surgery trends before and during the pandemic by Child Opportunity Index (COI). Retrospective analysis of 321,998 elective surgical encounters of children ages 0-to-18 years in 44 US children's hospitals from January 1, 2017 to December 31, 2021. We used auto-regression to compare observed versus predicted encounters by month in 2020-21, modeled from 2017 to 2019 trends. Encounters were compared by COI score (very low, low, moderate, high, very high) based on education, health/environment, and social/economic attributes of the zip code from the children's home residence. Most surgeries were on the musculoskeletal (28.1%), ear/nose/pharynx (17.1%), cardiovascular (15.1%), and digestive (9.1%) systems; 20.6% of encounters were for children with very low COI, 20.8% low COI, 19.8% moderate COI, 18.6% high COI, and 20.1% very high COI. Reductions in observed volume of 2020-21 surgeries compared with predicted varied significantly by COI, ranging from -11.3% (95% confidence interval [CI] -14.1%, -8.7%) for very low COI to -2.6% (95%CI -3.9%, 0.7%) for high COI. Variation by COI emerged in June 2020, as the volume of elective surgery encounters neared baseline. For 12 of the next 18 months, the reduction in volume of elective surgery encounters was the greatest in children with very low COI. Children from very low COI zip codes experienced the greatest reduction in elective surgery encounters during early COVID-19 without a subsequent increase in encounters over time to counterbalance the reduction.


Supporting newly qualified dental therapists into practice: a longitudinal evaluation of a foundation training scheme for dental therapists (TFT).
Focused on the dental therapists foundation training (TFT) scheme run by the Postgraduate Dental Deaneries of Oxford and Wessex (NHS Education South Central - NESC) the objectives were (1) to evaluate the TFT 2010/11 scheme, identifying strengths, areas for development and drawing comparisons with the 2009 evaluation; and (2) to follow-up previous cohorts, reporting current work and retrospective reflections on the scheme. Data were collected from 2010/11 ('current') trainees (n = 10) through group discussion, questionnaire and portfolio extracts. Eleven past-trainees from 2008/09 and 2009/10 took part in a structured telephone interview or responded to questions via e-mail. Data from 2011 consolidated that collected earlier. The scheme was highly valued. Current participants thought the scheme should be mandatory and all past-participants would recommend it to others. Trainees attributed an increase in confidence and ability in their clinical skills to participation in TFT. Current trainees' concerns about finding therapy work were echoed in past-participants' post-scheme employment. At the point of qualification, trainees do not feel well-prepared for starting work as dental therapists. Opportunity to develop confidence and skills in a supportive environment is a key benefit of the scheme. Maintaining ability in the full range of duties requires continued use of skills and the opportunity to do this remains an ongoing challenge.


Fetal response to maternal methadone administration.
The purpose of this study was to investigate the effect of methadone on fetal neurobehavioral functions and maternal physiologic indicators. Forty women attending a substance abuse treatment facility with otherwise uncomplicated pregnancies were evaluated at peak and trough methadone levels. Fetal measures included heart rate, variability, periodic accelerations/decelerations, motor activity, and fetal movement-heart rate coupling. Maternal measures included maternal heart period, variability, electrodermal skin conductance, respiration, and respiratory sinus arrhythmia (RSA). Repeated measure analysis of variance was used to evaluate within-subject changes. At peak methadone, fetal heart rate was slower, less variable, and displayed fewer accelerations. Fetuses displayed less motor activity, and the integration between heart rate and motor activity was attenuated. Maternal heart rate and skin conductance were unchanged, but methadone administration was associated with lower respiratory rate and RSA, an indicator of parasympathetic tone. Maternal methadone administration has significant effects on fetal behavioral functions that are independent of maternal effects.


Systems engineering of Escherichia coli for high-level shikimate production.
To further increase the production efficiency of microbial shikimate, a valuable compound widely used in the pharmaceutical and chemical industries, ten key target genes contributing to shikimate production were identified by exploiting the enzyme constraint model ec_iML1515, and subsequently used for promoting metabolic flux towards shikimate biosynthesis in the tryptophan-overproducing strain Escherichia coli TRP0. The engineered E. coli SA05 produced 78.4 g/L shikimate via fed-batch fermentation. Deletion of quinate dehydrogenase and introduction of the hydroaromatic equilibration-alleviating shikimate dehydrogenase mutant AroET61W/L241I reduced the contents of byproducts quinate (7.5 g/L) and 3-dehydroshikimic acid (21.4 g/L) by 89.1% and 52.1%, respectively. Furthermore, a high concentration shikimate responsive promoter PrpoS was recruited to dynamically regulate the expression of the tolerance target ProV to enhance shikimate productivity by 23.2% (to 2 g/L/h). Finally, the shikimate titer was increased to 126.4 g/L, with a yield of 0.50 g/g glucose and productivity of 2.63 g/L/h, using a 30-L fermenter and the engineered strain E. coli SA09. This is, to the best of our knowledge, the highest reported shikimate titer and productivity in E. coli.


Evaluation of overnight storage conditions for autologous peripheral blood stem cell products: comparison of three different conditions.
Overnight (ON) storage of peripheral blood stem cell (PBSC) occurs frequently in clinical settings. However, there are no standard guidelines for optimal storage conditions of freshly harvested PBSC. The aim of this study was to investigate the influence of storage temperatures on the quality of autologous PBSC and establish optimal storage conditions before cryopreservation. A retrospective analysis was performed on 260 PBSC harvests according to pre-cryopreservation conditions: immediate processing or ON storage at room temperature (RT). For direct comparison, 30 autologous PBSC products were collected prospectively and prepared under three different pre-cryopreservation conditions: immediate processing, ON storage at 4°C and ON storage at RT. The recovery of CD34(+) cells, post-thaw CFU-GM count and viability were analysed. Retrospective analysis revealed that post-thaw CFU-GM count was significantly lower when PBSC were stored ON at RT compared to when immediately processed (136·4 vs. 409·6/μl). Prospective analysis showed a mean recovery of CD34(+) cells of 65·5 ± 25·1%, 70·5 ± 27·4% and 35·9 ± 25·1% for immediate processing, ON storage at 4°C and ON storage at RT, respectively. Similarly, mean viability and CFU-GM counts were significantly reduced when stored ON at RT compared to when immediately processed or stored ON at 4°C (60·4 ± 25·6 vs. 84·1 ± 12·9 vs. 82·7 ± 12·6%, 15·7 ± 25·7 vs. 398·5 ± 906·2 vs. 350·0 ± 847·9/μl, respectively). ON storage of autologous PBSC at RT significantly decreased the quality of HPCs. These data indicate that ON storage of autologous PBSC at 4°C would be the most reasonable approach for maintaining the quality of HPCs when immediate processing is not possible.


Promoter vectors with restriction-site banks.
New vectors harboring the promoter for the chloramphenicol acetyl transferase gene (cat promoter) have been constructed. These vectors are all derived from pJRD184 [Heusterspreute et al., Gene 39 (1985) 299-304], which contains a restriction-site bank. The cat promoter has been inserted at various positions and in reverse orientations so that almost all the restriction sites originally present on JRD184 can be used in cloning experiments. The expression of the aceK gene of Escherichia coli cloned under the control of the cat promoter has been tested. A large increase in the synthesis of the isocitrate dehydrogenase kinase, the aceK gene product, has demonstrated the efficiency of the newly constructed vectors.


Developmental aspects of renal beta-amino acid transport. VI. The role of membrane fluidity and phospholipid composition in the renal adaptive response in nursing animals.
Accumulation of the beta-amino acid taurine is higher in adult rat renal brush border membrane vesicles than in nursing animals, which relates to a higher initial rate Vmax. A low sulfur amino acid diet increases and a 3% taurine diet reduces the Vmax of Na+-taurine cotransport in brush border membrane vesicles at all ages after 7 days as compared to values on a normal diet. To determine if changes in membrane fluidity account for these developmental and adaptive events, the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene was used to measure fluorescence anisotropy. A two-component, single break curve fit the data over the range 4 to 56 degrees C. Values for the break temperature centered around 23 degrees C, not different than a break temperature determined in adult membranes. The values for membrane polarization range from 0.311 to 0.329 in membranes from 7-, 14-, and 21-day-old pups exposed to each of the three diets, significantly lower than the value in adult membranes (p less than 0.02). The slopes of each component, equivalent to the apparent energy of activation, did not differ in relation to diet. The ontogenic changes in taurine uptake by brush border membrane vesicles related to the exposure to different dietary sulfur amino acid levels are not related to changes in membrane fluidity using 1,6-diphenyl-1,3,5-hexatriene as a probe. However, there is a decrease in fluidity with age. Total phospholipid content falls postweaning, and the percent of total content of phosphatidyl choline and glycerol phosphate fall, and phosphatidyl serine and ethanolamine rise as the rat ages.(ABSTRACT TRUNCATED AT 250 WORDS)


A new amplified π-shape electrochemical aptasensor for ultrasensitive detection of aflatoxin B1.
There is a prompt need for determination of aflatoxin B1 (AFB1) in food products to avoid distribution and consumption of contaminated food products. In this study, an accurate electrochemical sensing strategy was presented for detection of AFB1 based on aptamer (Apt)-complementary strands of aptamer (CSs) complex which forms a π-shape structure on the surface of electrode and exonuclease I (Exo I). The presence of π-shape structure as a double-layer physical barrier allowed detection of AFB1 with high sensitivity. In the absence of AFB1, the π-shape structure remained intact, so only a weak peak current was recorded. Upon the addition of AFB1, the π-shape structure was disassembled and a strong current was recorded following the addition of Exo I. Under optimal conditions, the electrochemical signals enhanced as AFB1 concentrations increased with a dynamic range of 7-500pg/mL and a limit of detection (LOD) of 2pg/mL. The developed aptasensor was also used to analyze AFB1 spiked human serum and grape juice samples and the recoveries were 95.4-108.1%.


Relevance of the ventricular remodeling pattern in the model of myocardial infarction in rats.
The relevance of the remodeling pattern in the model of infarcted rats is not known. To analyze the presence of different patterns of remodeling in this model and its functional implications. Infarcted rats (n=47) have been divided according to the geometry pattern, analyzed by echocardiogram: normal (normal mass index and normal relative thickness), concentric remodeling (normal mass index and increased relative thickness), concentric hypertrophy (increased mass index and increased relative thickness) and eccentric hypertrophy (increased mass index and normal relative thickness). Data are median and interquartile range. Infarcted rats showed only two of the four geometric patterns: normal pattern (15%) and eccentric hypertrophy - EH (85%). Groups of normal pattern and EH showed no differences in the values of fractional area change (Normal = 32.1 - 28.8 to 50.7; EH = 31.3 - 26.5 to 36.7; p = 0.343). Out of the infarcted animals, 34 (74%) had systolic dysfunction, detected by fractional area change. Considering these two geometry patterns, 77% of animals with eccentric hypertrophy and 57% with normal geometry presented systolic dysfunction (p=0.355). The relative wall thickness, the geometric patterns and the body mass index were not predictors of ventricular dysfunction (p> 0.05). On the other hand, infarct size was a predictive factor for ventricular dysfunction in univariate analysis (p<0.001) and multivariate analysis (p = 0.004). Rats that underwent coronary occlusion showed two different patterns of remodeling, which do not constitute a predictor of ventricular dysfunction.


Evaluation of short food-frequency questionnaires to assess the dietary pattern associated with atherosclerotic cardiovascular diseases.
Cardiovascular diseases are strongly related to dietary habits. Diet can be assessed using dedicated questionnaires that can be self-completed by subjects but with the risk of errors. To compare the completion error rate of two questionnaires designed to assess dietary pattern linked to cardiovascular diseases and to study the correlation between the two questionnaires. Two questionnaires were used to assess dietary patterns of students: the 14-item Food-Frequency-Questionnaire (FFQ) that was validated against biomarkers, and the Cardiovascular-Dietary-Questionnaire 2 (CDQ2), which is a 19-item-FFQ derived from the previous 14-item FFQ. Both questionnaires assessed the intake of various food groups associated with either favourable or unfavourable effects on cardiovascular risk. A global dietary score was calculated for each questionnaire. FFQ and CDQ2 were completed by 150 sport degree students. In the case of FFQ, 111 questionnaires out of 150 (74.0%) were incomplete compared to only 1 CDQ2 out of 150 (0.7%) (P<0.001). The correlation coefficient between the overall CDQ2 score and the FFQ dietary score was 0.53 (P<0.01). The self-completion of CDQ2 compared to FFQ was associated with far less errors. There was a significant correlation between CDQ2 and FFQ. Preference should be given to CDQ2 in clinical practice and in studies where dietary pattern are evaluated without any interviewer.


Lymphopenia and abnormal balance of T-lymphocyte subpopulations in toxic epidermal necrolysis.
A lymphopenia (peripheral-blood-lymphocyte count less than 1,000/mm3) was observed in seven out of ten patients with toxic epidermal necrolysis (TEN). The enumeration of T-lymphocyte subsets with monoclonal antibodies showed a decreased number of pan T-lymphocytes (OKT3-positive), which was related to a profound depletion of OKT4-positive cells. In contrast, OKT8-positive cell counts were not significantly changed. This abnormal balance of T-lymphocytes was linked to the acute phase of the disease and was not found after recovery. The pathogenetic mechanisms of such T-lymphocyte abnormalities in TEN remain unclear.


The role of antibiotics in upper gastrointestinal bleeding among cirrhotic patients without major complications after endoscopic hemostasis.
Antibiotic prophylaxis should be instituted for cirrhotic patients with upper gastrointestinal bleeding (UGIB), but the benefit on compensated patients remains undetermined. We aimed to compare the clinical outcomes between cirrhotic patients without major complications with UGIB with and without antibiotic prophylaxis. We conducted this population-based cohort study by using Taiwanese Longitudinal Health Insurance Database 2000 (LHID2000, between 1997 to 2013), aged 18 years or older with a hospital discharge diagnosis of cirrhosis (n = 64,506), UGIB (n = 7,784), and endoscopic therapy (n = 2,292). After strict exclusions, 1205 patients were enrolled and were divided into antibiotic exposure (n = 558) and non-exposure (n = 647) groups. The outcomes were rebleeding and mortality. After completing the analysis adjusted by death, the rebleeding rates within 4 weeks were significantly lower in patients with antibiotic prophylaxis (3.05% versus 6.03%, P = 0.0142) and those with endoscopic therapy (0.72% vs 3.09%, P = 0.0033) but not significant after 3 months and onwards. Male patients aged > 55, high CCI score ≧ 4, and UGIB of variceal etiologies were benefited from rebleeding. The use of antibiotics did not significantly impact 6-week mortality (adjusted hazard ratio: 1.07, 95%CI: 0.41~2.75; P = 0.8943). Old age, multiple comorbidities, and UGIB of variceal etiologies were risk factors of all-cause mortality. The current study suggested that cirrhotic patients without major complications who suffered from UGIB were benefited by the use of antibiotics to prevent rebleeding within 4 weeks after endoscopic treatment of UGIB especially for those with age > 55, high CCI score ≧ 4, and UGIB of variceal etiologies.


[The effects of cold and deep freezing of the liver on its dielectric loss factor].
The dielectric loss factor d was measured on 130 porcine liver samples which were subjected to different cooling conditions. Immediately after slaughtering, all livers showed d less than or equal to 3. Subsequent cool storage caused continuous increases of d, which however does not provide reliable information about the storage time, since similar increases may result from mechanical treatment. On the other hand, samples thawed after long-term deep freezing showed extremely high values of d. d greater than or equal to 40 resulted after freezing for some weeks. Here, a distinction from fresh liver can be obtained within a few seconds and without sample taking. However, livers deep frozen for short periods cannot be detected in all cases. The observed effects are attributable to membrane defects due to four different mechanisms.


A novel spectrophotometric method for batch and flow injection determination of sulfite in beverages.
A novel spectrophotometric assay method for batch and flow injection determination of sulfite in beverages is described. The method involves a reaction with diaquacobyrinic acid heptamethyl ester (diaquacobester, DACbs) in acetate buffer of pH 3 to form a highly stable sulfite cobester complex (SO3Cbs). In the absence of sulfite, the reagent displays three absorption maxima at 349, 409 and 525 nm. Addition of sulfite is associated with the development of a new absorption band at 313 nm, an increase in the intensity of the band at 425 nm and a decrease in the absorbance of the bands at 349 and 525 nm. Variations of the absorptions at 313, 349, 425 and 525 nm are linearly proportional to sulfite concentrations over the range of 0.05-25 microg ml(-1)with a detection limit of 0.01-0.2 microg ml(-1). Negligible interferences are caused by most common ions. Validation of the method according to the quality assurance standards shows suitability for quality control assessment of sulfite in complex matrices without prior treatment. The method has the advantages of high selectivity, good sensitivity, fast reaction, high stability of the reagent and reaction product and absorbance measurements at four different wavelengths in the same run. The method is successfully applied to determine the sulfite contents of some beverages. The results compare fairly well with data obtained using the standard method.


Evidence for the presence of Legionella bacteriophages in environmental water samples.
The existence and preliminary characterization of bacteriophages active against the Gram-negative human pathogen Legionella pneumophila, the causative agent of a very severe form of pneumonia, are reported. Four phages belonging to the family of the Myoviridae were isolated from various fresh water environments, and preliminary characterization showed that these crude preparations infect exclusively bacteria belonging to the genus Legionella. Standard phage amplification, purification, and characterization procedures were, however, not efficiently applicable making more research into these novel phages and their mechanism of infection necessary. The existence of Legionella bacteriophages is very promising for future applications such as the development of novel molecular tools, the design of new detection and typing methods, and the bioremediation of this environmental pathogen.


Tailoring zinc porphyrin to the Ag nanostructure substrate: an effective approach for photoelectrochemical studies in the presence of mononucleotides.
The substituted porphyrin 2-cyano-3-(2'-(5',10',15',20-tetraphenyl porphyrinato zinc-(ii))yl) acrylic acid was used to modify nanostructured Ag surfaces. This porphyrin-modified surface exhibits photocurrent when exposed to a light source, which is modulated in the presence of nucleotides. The addition of the nucleotides adenosine-5'-monophosphate (AMP), guanosine-5'-monophosphate (GMP) and cytidine-5'-monophosphate (CMP) causes partial quenching of the photoelectrochemical response of the porphyrin. The quenching efficiency is 80%, 68% and 48% for AMP, CMP and GMP, respectively. This work represents a new aspect of Ag NS substrates and highlights their usefulness as transducers a for potential chemosensor systems.


Risk factors for development of severe post-traumatic elbow stiffness.
The purpose of this study was to compare different grades of elbow stiffness and investigate demographic, injury, and treatment factors potentially associated with the development of severe elbow stiffness. We performed a retrospective study involving 169 patients with post-traumatic elbow stiffness between June 2014 and June 2016. Patient demographics, injury, and treatment details were reviewed. Patients were classified into three groups according to the elbow motion. Ordinal regression analyses were performed to examine the independent factors. Patients were classified into: mild (49 patients), moderate (59 patients), and severe (61 patients) groups. Patients with severe stiffness had a significantly worse elbow functional performance. Univariate ordinal regression revealed that severe elbow stiffness was associated with high-energy injury (odds ratio [OR] 4.73), olecranon fracture (OR 1.92), fracture-dislocation (OR 2.28), and open fracture (OR 3.24). Multivariate regression showed that higher-energy injuries were associated with severe stiffness (OR 4.45, p = 0.003). Elbow stiffness after fracture surgery often results in joint stiffness. Severe stiffness often resulted in more significant functional impairment. Our study suggested that high-energy injuries were associated with the development of severe elbow stiffness.


How delayed full enteral feeding could affect extrauterine growth restriction in a neonatal intensive care unit: a retrospective, short-term, observational single-center study.
Achieving adequate growth in preterm newborns through enteral feeding is one of the most important aspects of providing medical assistance in neonatal intensive care units due to not only improved outcomes (the prevention of complications such as necrotizing enterocolitis) but also the evaluation of the well-known consequences of adequate weight gain beyond metabolism and cognitive abilities later in life. In our study, we evaluated how the impact of delayed full enteral feeding could influence the entity of extrauterine growth restriction. We retrospectively analyzed the data of preterm subjects from a neonatal intensive care unit anonymous database. We detected significant correlations between delayed full enteral feeding as well as prolonged parenteral nutrition and extrauterine growth restriction. The achievement of full enteral feeding in the shortest possible time may be reasonably considered an important aspect in preterm newborn care.


Shaping a research agenda to ensure a successful European health technology assessment: insights generated during the inaugural convention of the European access academy.
Key challenges for a joint European Health Technology Assessment (HTA) include consolidated approaches towards the choice of adequate comparator(s), selection of endpoints that are relevant to patients with a given disease, dealing with remaining uncertainties as well as transparent and consistent management of related processes. We aimed to further crystallize related core domains within these four areas that warrant further research and scrutiny. Building on the outcomes of a previously conducted questionnaire survey, four key areas, processes, uncertainty, comparator choice and endpoint selection, were identified. At the inaugural convention of the European Access Academy dedicated working groups were established defining and prioritizing core domains for each of the four areas. The working groups consisted of ~ 10 participants each, representing all relevant stakeholder groups (patients/ clinicians/ regulators/ HTA & payers/ academia/ industry). Story books identifying the work assignments were shared in advance. Two leads and one note taker per working group facilitated the process. All rankings were conducted on an ordinal Likert Response Scale scoring from 1 (low priority) to 7 (high priority). Identified key domains include for processes: i) address (resource-) challenge of multiple PICOs (Patient/ Intervention/ Comparator/ Outcomes), ii) time and capacity challenges, iii) integrating all involved stakeholders, iv) conflicts and aligning between different multi-national stakeholders, v) interaction with health technology developer; for uncertainty: i) early and inclusive collaboration, ii) agreement on feasibility of RCT and acceptance of uncertainty, iii) alignment on closing evidence gaps, iv) capacity gaps; for comparator choice: i) criteria for the choice of comparator in an increasingly fragmented treatment landscape, ii) reasonable number of comparators in PICOs, iii) shape Early Advice so that comparator fulfils both regulatory and HTA needs, iv) acceptability of Indirect Treatment Comparisons (ITC), v) ensure broad stakeholder involvement in comparator selection; for endpoint selection: i) approaching new endpoints; ii) patient preferences on endpoints; iii) position of HTA and other stakeholders; iv) long-term generation and secondary use of data; v) endpoint challenges in RCTs. The implementation of a joint European HTA assessment is a unique opportunity for a stronger European Health Union. We identified 19 domains related to the four key areas, processes, uncertainty, comparator choice and endpoint selection that urgently need to be addressed for this regulation to become a success.


Tasty but protected--first evidence of chemical defense in oribatid mites.
Oribatid mites (Acari, Oribatida) represent one of the most abundant and speciose groups of microarthropods in the decomposer food webs of soils, but little is known of their top-down regulation by predators. Oribatids are relatively long-lived and have numerous morphological defensive adaptations, and so have been proposed to live in 'enemy-free space'. Most also possess a pair of large exocrine oil glands that produce species-specific mixtures of hydrocarbons, terpenes, aromatics, and alkaloids with presumably allomonal functions, although their adaptive value has never been tested empirically. We developed a protocol that discharges the oil glands of the model oribatid species, Archegozetes longisetosus. and offered 'disarmed' individuals as prey to polyphagous Stenus beetles (Staphylinidae), using untreated mites as controls. Stenus juno fed on disarmed mites with behavioral sequences and success rates similar to those observed when they prey on springtails, a common prey. In contrast, mites from the control group with full glands were almost completely rejected; contact with the gland region elicited a strong reaction and cleaning behavior in the beetle. This is the first evidence of an adaptive value of oribatid mite oil gland secretions for chemical defense. The protocol of discharging oil glands should facilitate future studies on top-down control of oribatid mites that aim to differentiate between morphological and chemical aspects of defensive strategies.


The Chabot case: analysis and account of Dutch perspectives.
The aims of this essay are twofold: to point out the main problems of the Chabot precedent and to report the findings of a fieldwork in the Netherlands during which some experts were asked to voice an opinion regarding the psychiatrist's conduct and the legal precedent. During the summer of 1999, twenty-eight interviews with some of the leading authorities on the euthanasia policy were conducted in the Netherlands. Multiple reasons were mentioned to either condone or condemn Chabot's practice.


Effects of zinc acexamate on blood flow and prostanoid levels in the gastric mucosa of the rat.
The effects of the new antiulcer compound zinc acexamate on blood flow and prostanoid levels in the gastric mucosa have been studied. Zinc acexamate (30 and 300 mg/kg) dose-dependently prevents the reduction induced by the perfusion of noradrenaline (3.5 micrograms/kg.min, 30 min) in gastric mucosal blood flow, as measured by 3H-aniline clearance. Zinc acexamate pretreatment also increases the levels of prostaglandin E2 in the gastric mucosa of the rat, both under control conditions and after infusion with noradrenaline. The levels of thromboxane A2 and prostacyclin were not modified by zinc acexamate. These results confirm the importance of microcirculation in pathogenesis and the idea that the antiulcer activity of zinc acexamate is due in part to its action in increasing the mechanism which defend the gastric mucosa against aggression.


A simple technique for milking the venom of a small parasitic wasp, Melittobia digitata (Hymenoptera: Eulophidae).
We describe a simple method for obtaining good a quantity of pure venom from a small parasitoid wasp, Melittobia digitata. Crushing the insect's head causes venom to be extruded from the ovipositor that dries rapidly as it is collected onto an insect pin. This technique may be applicable to other parasitic Hymenoptera.


Use of ivermectin to control sarcoptic mange in goats in Indonesia.
The results of three experiments aimed at controlling sarcoptic mange in goats in Indonesia are reported. In Experiment 1 treatment with ivermectin (0.2 mg/kg body weight) or coumaphos (0.05% dip solution) resulted in a significant reduction in mite numbers and an increase in body weight while in the untreated controls all animals had to be withdrawn from the experiment due to severity of infection. In Experiment 2 three treatment levels of ivermectin were shown to be equally effective in reducing mite numbers, while again all untreated control animals were withdrawn. The third experiment demonstrated a significantly greater reduction in mite numbers following two doses of ivermectin at a seven day interval when compared to a single dose. Again the majority of untreated control animals were withdrawn. Future control strategies and reasons for failure to eliminate the presence of mites are discussed.


Advancement sleeve flaps for treatment of severe perianal Crohn's disease.
Traditionally proctectomy has been the treatment for severe, complex fistula in ano from Crohn's disease. However, based on the success of rectal advancement flaps in Crohn's disease, circumferential transanal sleeve advancement flaps (TSAFs) were proposed for this subgroup of patients with severe fistula. From 1991 to 1995, 13 patients (12 women) with severe perianal Crohn's disease and multiple fistula tracts underwent a TSAF procedure. Data were collected retrospectively using a standard data sheet. There were no postoperative deaths or major morbidity. One year after surgery, the fistula had healed in eight of 13 patients (with three requiring additional surgery before healing). Of patients in whom the procedure failed, three underwent proctectomy for progression of disease and the other two had recurrence of a rectovaginal fistula 6 and 8 months after surgery. Of six variables evaluated (previous procedure, steroid use, steroid dosage, associated Crohn's disease, associated procedures and diverting stoma), only associated procedures were significantly related to a successful outcome (P=0.008). Some patients with severe perianal Crohn's fistula and a relatively normal rectum can be offered TSAFs. Even with successful outcome in eight of 13 patients, this may still be a viable option if the only alternative would be total proctocolectomy and a permanent stoma.


Development of a degradable composite for orthopaedic use: in vivo biomechanical and histological evaluation of two bioactive degradable composites based on the polyhydroxybutyrate polymer.
As a direct method for the evaluation of tissue bonding to two polyhydroxybutyrate (PHB) based composites, a mechanical push-out test was performed on implants in the femur of mature Japanese White rabbits. Three composites were tested. The first, a hydroxyapatite/PHB (HA/PHB) composite showed an increase in interfacial shear strength (ISS) up to 8 wk, after which the ISS decreased due to degradation of the implant. The second composite was an HA/glass/PHB (HGP) composite and this gave lower values for the ISS attributed to ion release from the glass causing a soft tissue reaction at the interface. The third composite was a carbon fibre reinforced polysulfone (CFRP) and this showed high interfacial shear strength values, which continued to increase with time. These conclusions were supported by contact microradiography (CMR) and histology which showed enhanced endosteal bone growth for the HA/PHB but for the HGP, no periosteal or endosteal activity was detected. Interposed soft tissue for the HGP composite was difficult to discern, histologically, but it was proposed that this was the reason for the low ISS values. It was concluded that the high ISS values for the carbon fibre control were due to surface morphology allowing deep ingrowth of soft tissue and this was confirmed by SEM.


99mTc-gallic-gold nanoparticles as a new imaging platform for tumor targeting.
Early and accurate detection of tumor assists in identifying more effective therapies. Gold nanoparticles (GNPs) were synthesized by green synthesis method using gallic acid (GA) then characterized and labeled with technetium-99m. This new platform was biologically evaluated in both normal and solid tumor bearing mice. The in-vivo study of [99mTc]Tc-gallic-GNPs via both I.V. and I.T injecton showed a high accumulation in tumor site. As a result, [99mTc]Tc-gallic-GNPs can be afforded as a potential nano-platform for tumor imaging.


Benchmarking diagnostic laboratory performance: Survey results for Germany, Austria, and Switzerland.
The need for patient safety through consistent diagnostic performance has increasingly been brought into focus during the last two decades. Around the globe operational efficiency of diagnostic laboratories plays a key role in satisfying this need, which has impressively been shown during the recent months of the SARS-CoV‑2 pandemic. On a global level, however, there has been a lack to collate and benchmark data for diagnostic laboratories. The goals of this study were to design and pilot a questionnaire addressing key aspects of diagnostic laboratory management. The questionnaire was designed using an iterative process and taking into consideration information that could be extracted from the literature, author experience and feedback from informal focus groups of laboratory professionals. The resulting tool consisted of 50 items, either relating to general information or more specifically addressing the topics of "operational performance", "integrated clinical care performance", and "financial sustainability". A limited number of laboratories were surveyed to be able to further improve the newly developed tool and motivate the global laboratory community to participate in further benchmarking activity. Altogether, 65 laboratories participated in the survey, 42 were hospital laboratories and 23 were commercial laboratories. Potential for further improvement and standardization became apparent across the board, e.g. use of IT for order management, auto-validation, or turn-around time (TAT) monitoring. Notably, a gap was identified regarding services provided to physicians, in particular "reflexive test suggestions", "proactive consultation on complex cases", and "diagnostic pathways guidance", which were only provided by about two thirds of laboratories. Concordantly, within-laboratory TAT (Lab TAT) was monitored by about 80% of respondents, while sample-to-result TAT, which is arguably the TAT most relevant to clinicians, was only monitored by 32% of respondents. Altogether, the need for stronger integration of the laboratory into the clinical care process became apparent and should be a main trajectory of future laboratory management.


Nodular late syphilis.
We present an unusual case of nodular late syphilis in a 52-year-old black man who had grouped, violaceous, pruritic papulonodules. Overlapping features of both secondary and teritary stages of the disease were present. The clinical presentation and histopathology are discussed.


[Gestational diabetes].
Gestational diabetes is one of the most common complications during pregnancy. Its incidence has increased in recent decades. This is partly due to improved screening strategies and more stringent diagnostic criteria. Using the updated diagnostic thresholds, it is expected that 5-10% at least of all pregnant women will be diagnosed with diabetes mellitus. The rationale for the novel blood glucose criteria are data from prospective studies reporting an increase of fetal and maternal complications even when the blood glucose is only slightly increased. For the first time, solid evidence now exists for the diagnosis and treatment of gestational diabetes.


Efficacy, predictability and safety of small incision lenticule extraction (SMILE).
The purpose of this case series is to report the one-year outcomes of small incision lenticule extraction (SMILE) using the VisuMax® femtosecond laser. Two hundred and six patients were recruited for this retrospective, single center study at TRSC International LASIK Center in Bangkok, Thailand. Patients underwent SMILE, whereby an intrastromal lenticule was cut using a femtosecond laser and then manually extracted without the need for flap creation. Outcome measures included refraction, visual acuity and contrast sensitivity evaluation. Patients were treated and followed for one year. SMILE for the correction of low to high myopia was performed on 347 eyes of 206 patients. The mean preoperative spherical equivalent was -4.96 ± 1.88 diopters (D). On the first day following surgery, for eyes with a plano target refraction (99.14 % of all eyes), uncorrected distance visual acuity (UDVA) was 20/20 or better in 90 % of eyes. At the one week postoperative exam, the mean spherical equivalent was 0.01 ± 0.36 D and UDVA was 20/20 or better in 84 % of eyes. After one year follow-up, no eyes showed loss of 2 or more lines of visual acuity and 31 % of eyes gained one or more lines. The photopic contrast sensitivity of SMILE treated eyes at 12 and 18 cycles per degree (cpd) improved from 1.59 and 0.94 preoperatively to 1.6 and 0.98, respectively, after one year. In this series, SMILE using the VisuMax® femtosecond laser demonstrated that after one year it is an effective, predictable and safe minimally invasive corneal refractive procedure.


The assessment of primary varicose veins by Doppler ultrasound--the role of sapheno-popliteal incompetence and the short saphenous systems in calf varicosities.
One hundred consecutive limbs presenting with primary varicose veins to a surgical outpatient clinic were assessed clinically and by Doppler ultrasound. By this means the incidence of sapheno-femoral and sapheno-popliteal incompetence was established and the relative role of these two systems in the development of varicosities determined.


Sema4D knockdown in oligodendrocytes promotes functional recovery after spinal cord injury.
Semaphorin4D (Sema4D) belongs to Semaphorins family and is secreted and membrane-bound protein. Its function on angiogenesis and axon regeneration makes it an ideal therapeutic target for spinal cord injury (SCI). Here we examined Sema4D expression profile by real-time PCR and western blot and found Sema4D was upregulated after SCI. In vitro study showed Sema4D was not only expressed in oligodendrocytes but also in endothelial cells (ECs). Hypoxia can mimic Sema4D upregulation in both cell lines. Moreover, overexpression of Sema4D through lentivirus in ECs promoted tube formation. However, Sema4D overexpression in oligodendrocytes precursor cells (OPCs) inhibited neuron myelination in neuron-oligodendrocyte co-culture system. Therefore, Sema4D knockdown in OPCs was applied in SCI rats. The results indicated that Sema4D knockdown significantly promoted functional recovery with blood-brain barrier score. Taken together, our data suggest that specific Sema4D knockdown in oligodendrocytes without disturbing its angiogenesis effect can be a beneficial strategy for SCI treatment.


Rapid Population Growth throughout Asia's Earthquake-Prone Areas: A Multiscale Analysis.
Assessing the changes of the population living throughout the most seismically hazardous area (MSHA) constitutes an important foundation for seismic risk assessment. However, the changes of the population living in the MSHA of Asia, which exhibits the highest number of earthquake related fatalities, were poorly understood. Therefore, this study analyzed the changes of the population in the MSHA between 2000 and 2015 at the continental, subcontinental, and national scales. We found that the population, especially the vulnerable population (i.e., children under or equal to the age of 14 and elderly people over or equal to the age of 65), in Asia's MSHA increased rapidly between 2000 and 2015. The population in the MSHA increased by 185.88 million with a growth rate of 20.93%, which was 3.38% greater than that in the non-MSHA region. Meanwhile, the vulnerable population in the MSHA increased by 63.65 million with a growth rate of 19.73%. The increase of the vulnerable population in the MSHA was 19.93% greater than that in the non-MSHA region. We also found that urban population growth was a major factor impacting the increase in both the population and the vulnerable population throughout Asia's MSHA. Therefore, attention should be paid to the changes of the population in Asia's MSHA, whilst it is imperative to execute strict building codes and select the development location more carefully in the MSHA.


Opuntia (Cactaceae) plant compounds, biological activities and prospects - A comprehensive review.
Opuntia species are utilized as local medicinal interventions for chronic diseases and as food sources mainly because they possess nutritional properties and biological activities. The Opuntia plant is distributed worldwide and has great economic potential. Differences in Opuntia species phytochemical composition exist between wild and domesticated species, and within species. Opuntia aerial and underground parts exhibit beneficial properties due to their phenolic content, other antioxidants (for example ascorbate), pigments (carotenoids, betalains), and other unidentified components. This work comprehensively reviews the phytochemical composition of the different aerial and underground plant parts of Opuntia species. The applications of Opuntia compounds and their biological activities are also discussed. Other topical aspects covered include Opuntia spp. taurine composition, Opuntia side effects, Opuntia by-products valorisation and the role of Opuntia spp. in tackling antimicrobial resistance. Although biological activities have been extensively researched, much less information is available on reaction mechanisms, herbal mixtures toxicology and commercialisation prospects - aspects which should be considered for future research in this area.


An efficient isolation procedure of Ca-tolerant ventricular myocytes from ferret heart for applications in electrophysiological studies.
A simple procedure which provides a large yield of isolated ferret ventricular myocytes is described. The enzymatic dissociation was performed by perfusion of the whole heart with the "Langendorff method" at 37 degrees C, without an incubation period. Special attention was given to the period of perfusion with Ca-free or low-calcium containing solutions and to the proportion of both collagenase and elastase used. The viability and calcium tolerance of the isolated cells were tested by ultrastructural and electrophysiological studies. Photo-microscopy showed that 60 to 80% of the isolated cells had an elongated shape (18 microns in diameter, 150 microns in length) and did not beat spontaneously in normal Tyrode solution. The morphological and ultrastructural integrity of these cells was shown in SEM by their smooth surface with regularly spaced T-tubule openings and in TEM by the regular distribution of the transverse tubular system, mitochondrium and sarcomeres. Using the whole-cell patch-clamp technique, they had a resting membrane potential of -72 mV, two types ("Purkinje like" and "ventricular like") of action potentials could be elicited and they were correctly affected by well-known modulators of calcium channels. This technique was successfully applied to the rat heart and could be used for heart dissociation of small mammals. It can simultaneously provide isolated cells of different regions of the heart and can be easily and routinely used by any investigator.


Rasmussen syndrome: multifocal spread of inflammation suggested from MRI and PET findings.
A 6-year-old girl with Rasmussen syndrome (RS) showed multiple small high-signal-intensity areas independently in the right hemisphere by fluid-attenuated inversion recovery (FLAIR) imaging on magnetic resonance imaging (MRI) 1 year after the onset of epilepsy. MRI performed 4 months later demonstrated a further increase in the number of these foci and enlargement in the size of the previous FLAIR lesions. An [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) study showed a strong, spotty uptake in the right temporooccipital regions, corresponding to the sites of continuous EEG seizure discharges. In contrast, [11C]methionine PET demonstrated multifocal uptake regions, which corresponded anatomically to the FLAIR lesions, suggesting sites of underlying chronic inflammation. These neuroimaging findings suggested that the inflammatory process in RS spreads either multifocally at the same time, as seen in this case, or from one discrete area to the adjacent region, as reported previously.


Decreased expression and frequent promoter hypermethylation of RASSF2 and RASSF6 correlate with malignant progression and poor prognosis of gastric cardia adenocarcinoma.
The RAS-association domain family (RASSF) consists of 10 members, and several members act as tumor suppressor genes and epigenetically inactivated in different tumor types. The present study investigated the role and methylation status of RASSF2, RASSF3, RASSF4, and RASSF6 in the pathogenesis and prognosis of GCA. Quantitative real-time RT-PCR, Western blot, and immunohistochemistry (IHC) methods were used respectively to detect the expression of RASSF2, RASSF3, RASSF4, and RASSF6 in 135 GCA cases and BS-MSP method was used to clarify the methylation status of these four genes. Decreased mRNA and protein expression of RASSF2, RASSF3, RASSF4, and RASSF6 were detected in GCA tumor tissues. Aberrant CpG island methylation of RASSF2, RASSF4, and RASSF6 were detected in GCA tumor tissues and were inversely correlated with the expression levels of these genes. Both of RASSF2 and RASSF6 expression and methylation were associated with TNM stage, depth of invasion, LN metastasis, distant metastasis or recurrence, and UGIC family history. GCA patients with simultaneous negative protein expression of RASSF2 and RASSF6 or with simultaneous methylation of both genes demonstrated poor patient survival. These results suggest that down-regulation of RASSF2, RASSF3, RASSF4, and RASSF6 is a tumor-specific phenomenon and the inactivation of RASSF2 and RASSF6 may be associated with tumor progression. Inactivation of RASSF2, RASSF4, and RASSF6 through CpG island methylation may play important roles in GCA carcinogenesis. A combination of RASSF2 and RASSF6 expression or hypermethylation may serve as useful prognostic biomarker for GCA. © 2015 Wiley Periodicals, Inc.


Physical activity, cardiovascular health, quality of life and blood pressure control in hypertensive subjects: randomized clinical trial.
Physical activity (PA) promotes cardiovascular health and health related quality of life (HRQoL), although the effect of that on blood pressure (BP) control has rarely been studied in hypertensive subjects. Our aim was to evaluate the effectiveness of a PA intervention programme on cardiovascular disease (CVD) risk, HRQoL and BP control in hypertensive subjects. A randomized clinical trial, with a PA intervention programme of 9 months duration, comprising a walking group of 120 min/week, supervised, and with socio-cultural activities. Participants were 207 hypertensive subjects (68.2 years, 76.8% women). PA (IPAQ-s), diet, CVD risk, BP, BMI, smoking, and HRQoL (SF-36) were assessed at baseline and at the end of the intervention. Changes in CVD risk and in HRQoL during the intervention was calculated (end-baseline score). Multivariate models were applied. In multivariate models, the PA intervention programme, with no modification of the diet, decreased CVD risk (- 1.19 points) and the systolic BP (- 8.68 mmHg), and increased some areas of HRQoL (4.45 to 14.62 points). An increase in the percentage of subjects with controlled BP was observed by the PA programme itself (OR 5.395 to 5.785 according to multivariate models), and by the changes during the intervention in the decrease in CVD risk (OR 0.609) and in the increase in the HRQoL in physical component summary (OR 1.041), role physical (OR 1.010), and bodily pain (OR 1.014), independently of controlled BP at baseline. This PA intervention programme improved cardiovascular health and HRQoL, and favoured BP control in primary care users with hypertension. Clinicaltrials.gov ID NCT02767739 ; Trial registered on May 5th, 2016. Retrospectively registered.


Ab Initio Study of Vibronic and Magnetic 5f-to-5f and Dipole-Allowed 5f-to-6d and Charge-Transfer Transitions in [UX6]n- (X = Cl, Br; n = 1, 2).
The absorption spectra of the octahedral [UX6]n- (X = Cl, Br; n = 1, 2) complexes in the near-infrared (NIR) and UV-vis spectral regions were studied theoretically, using a relativistic restricted active space second-order perturbation theory (RASPT2) wavefunction framework, with the spin-orbit (SO) coupling treated by state interaction, in conjunction with Kohn-Sham density functional theory calculations for determining the vibrational normal modes. The electric-dipole-allowed ligand-to-metal charge-transfer (LMCT) and 5f-to-6d transitions, and the electric-dipole-forbidden 5f-to-5f ligand field (LF) transitions, are thereby obtained within the same theoretical framework. For the 5f-to-5f LF transitions, the observed absorption intensity is mostly due to vibronic coupling with low-energy electric-dipole-allowed transitions, but in some cases, the magnetic dipole intensity of the purely electronic transition has comparable intensity to the vibronic transitions. Experimental LF spectra of 5f2 open-shell systems have been reported decades back, but ab initio calculations of their vibronic intensity have not yet been reported in the literature. Although the LF spectra for the 5f2 systems can be assigned in detail, based on the calculations, the spectra are very complex and the underlying electronic states are strongly multiconfigurational. Therefore, the usefulness of the LF spectra beyond serving as a "fingerprint" of the LF and the metal oxidation state appears to be limited.


Reversible modulation of protocell volume via collective response of functional protein in its membrane.
Volume change plays an important role in biological cells to regulate their internal microenvironment. To adapt to the rapid variation of the surface area during the volume change, the lipid membrane is dynamically modulated via membrane folding invagination, or spontaneous uptake or release of lipid molecules under osmotic pressure. Here, we demonstrate an alternative approach to design a functional protocellular system capable of dynamically adjusting its volume and intracellular microenvironment in response to the alteration of pH. By assembling and subsequently cross-linking pH-responsive caseinate at the water-oil interface, the caseinate-based protocell with more than ten thousand caseinate units in its membrane was established and showed a reversible volume and pore size change to pH variation due to the collective response of the caseinate in the membrane, which could be used to control the spatial distribution of proto-organelle by regulating of the viscosity inside the protocell.


Pharmacokinetic study of solid-lipid-nanoparticles of altretamine complexed epichlorohydrin-β-cyclodextrin for enhanced solubility and oral bioavailability.
Altretamine is a synthetic drug approved for treatment of ovarian cancer. The only drawback with its formulation is poor aqueous solubility and low oral bioavailability. In the present work an attempt has been made to prepare inclusion complex of altretamine with epichlorohydrin beta cyclodextrin. The complexes were prepared by kneading, co-evaporation and freeze-drying method and were confirmed by FTIR, XRD, DSC, drug content and dissolution study. Kneaded complex possess maximum solubilizing efficiency of 82.63 in 25mM Epi-β-CD solution. SLNs of pure altretamine and ALT complexed with Epi-β-CD were prepared by modified emulsification-ultrasonication method. The particle size and zeta potential was found to be 151.5nm and -21.3mV. The drug release pattern of SLNs was bi-phasic in nature; with an initial burst release followed by sustained drug release. Pharmacokinetic study showed that the average Cmax was found to be 0.94μg/ml, which was 2.47 times higher as compared to the pure drug. The AUCt for SLNs was 150minμgh/ml and 54minμgh/ml for pure ALT suspension which proved that the SLNs exhibited greater absorption compared to the pure drug. Thus, smaller particle size, higher entrapment efficiency and enhanced aqueous solubility led to improvement in oral bioavailability of ALT.


Cre-lox recombination in Escherichia coli cells. Mechanistic differences from the in vitro reaction.
The mechanism of the Cre recombinase of bacteriophage P1 in Escherichia coli cells was analyzed by topological methods in order to determine the important features of the in vivo reaction. Lambda infection was used to introduce the cre gene into cells containing plasmid substrates. The products of Cre resolution on substrates with directly repeated sites were predominantly free circles, even though decatenation by DNA gyrase was blocked by the drug norfloxacin. Recombination by Cre was greatly stimulated by negative supercoiling, and inversion occurred inefficiently. These results are strikingly different from those found with purified enzyme in vitro. Our data imply that Cre recombination in vivo is much more tightly controlled than it is in vitro, and that Cre acts predominantly as a resolvase in vivo. We suggest a role for Cre-mediated recombination in P1 plasmid amplification that is consistent with the selectivity of the enzyme in vivo.


[Effects of orthokeratology lenses on the magnitude of accommodative lag and accommodativeconvergence/accommodation].
To evaluate the change in accommodative lag and accommodation convergence/accommodation (AC/A) after patients with myopia wear orthokeratology lenses. A total of 48 myopic subjects (a test group), who wore orthokeratology lenses regularly, and 48 myopic subjects (a control group), who wore spectacles regularly, were enrolled for this study from January 2011 to January 2013 in Optometric Center, the Forth Hospital of Changsha. Accommodative lag was measured by fused cross cylinder method, where the patients should gaze at the front optotypes 40 cm away. Gradient of the AC/A ratio was measured by Von Grafe method to check closer distance heterophoria. Accommodative lag and AC/A ratio were analyzed by statistics. After 1-year follow-up, accommodative lag and AC/A rate in patients with low or moderate myopia in the test group was decreased in 1, 3, 6 months or 1 year compared with that in the control group (P<0.05). Compared with spectacles, orthokeratology lenses are able to decrease accommodative lag and high AC/A rate in patients with low or moderate myopia. The relationship between accommodation and convergence is improved by orthokeratology lenses. Orthokeratology is an effective way to control myopia.


Strabismus therapy in private practice: Cure rates after three months of therapy.
In this study, a random strabismus sample of 86 strabismus therapy patients meeting certain criteria was evaluated. The roles of retinal correspondence, amblyopia, eccentric fixation, prior surgeries, type and magnitude of deviation, number of therapy sessions undertaken, age at onset of therapy, and academic difficulties were scrutinized to see how they affect prognosis for functional cures(Flom's criteria), cosmetic cures (angle less than, or equal to 15 prism diopters) and total cures; the sum of functional cures and cosmetic cures.


Effects of emotional content on social inhibition of gaze in live social and non-social situations.
In real-life interactions, it is crucial that humans adequately respond to others' emotional expressions. Emotion perception so far has mainly been studied in highly controlled laboratory tasks. However, recent research suggests that attention and gaze behaviour significantly differ between watching a person on a controlled laboratory screen compared to in real world interactions. Therefore, the current study aimed to investigate effects of emotional expression on participants' gaze in social and non-social situations. We compared looking behaviour towards a confederate showing positive, neutral or negative facial expressions between live social and non-social waiting room situations. Participants looked more often and longer to the confederate on the screen, than when physically present in the room. Expressions displayed by the confederate and individual traits (social anxiety and autistic traits) of participants did not reliably relate to gaze behaviour. Indications of covert attention also occurred more often and longer during the non-social, than during the social condition. Findings indicate that social norm is a strong factor modulating gaze behaviour in social contexts. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on September 13, 2021. The protocol, as accepted by the journal, can be found at: https://doi.org/10.6084/m9.figshare.16628290 .


[11C] acetoacetate utilization by breast and prostate tumors: a PET and biodistribution study in mice.
A significant positive correlation has been observed between ketone body availability and their uptake by tumor cells. Our objective was to evaluate [11C]acetoacetate as a potential tracer of ketone body utilization by breast and prostate tumors and to compare it with [11C]acetate. Biodistribution studies were performed with [11C]acetoacetate and [11C]acetate in mice bearing breast or prostate tumors. The percentage of the injected dose accumulated per gram of tissue was determined. These results were complemented by dynamic positron emission tomography (PET) imaging of the radiotracer uptake and dosimetry calculations. [11C]Acetoacetate uptake was optimal between 5 and 30 min, with maximal uptake of 2.72, 2.42, 2.54, and 2.19% injected dose (%ID)/g for MC7-L1, MC4-L2, PC3, and LN-CaP tumors respectively. Tumor retention for [11C]acetoacetate tended to be higher than [11C]acetate, but this did not reach statistical significance. [11C]Acetate uptake was reached within 15 min with optimal uptake of 1.25, 2.30, and 0.96%ID/g for MC7-L1, MC4-L2, and PC-3 tumors, respectively. We observed a moderate uptake of [11C]acetoacetate in breast and prostate tumors with low background activity due to rapid elimination of this tracer. Further studies are warranted to determine if this tracer can detect slow-growing breast and prostate cancers in the clinical setting.


Stool consistency and stool frequency are excellent clinical markers for adequate colon preparation after polyethylene glycol 3350 cleansing protocol: a prospective clinical study in children.
Colon preparation for a colonoscopy in children is a difficult task because of the unpalatable taste and large volume of cleansing solution that needs to be consumed to ensure a clean colon. Consequently, an unprepared colon frequently occurs in routine practices, which causes early termination and a repeated procedure. (1) To assess the effectiveness of polyethylene glycol solution (PEG 3350) in preparing the colon of children scheduled for a colonoscopy and (2) to investigate clinical markers associated with an adequate colon preparation before a colonoscopy. A total of 167 children scheduled for a colonoscopy. In a prospective study, children scheduled for a colonoscopy were given PEG 3350 solution (1.5 g/kg per day, up to 100 g/d) over a 4-day preparation period. Each day, a simple questionnaire that documents the amount of liquid consumed, adverse effects, and the number and consistency of stool was completed by the parents. After a colonoscopy procedure, the colon preparation was assigned a number grade. The data were later assessed and were compared to determine the association between the grade of cleansing and the frequency and/or consistency of stool during preparation. Colon preparation was completed in 149 children, 133 of whom were adequately prepared. Inadequate preparation was found in 16 children; the procedure was terminated prematurely in 2 of these patients because of unacceptable conditions. No significant adverse effects were noted. A number of >or=5 stools/d, and liquid stool consistency in the last 2 days of preparation were associated with adequate colon preparation. PEG 3350 solution is safe, efficacious, and tolerable for children. Stool frequency and consistency in the last 2 days of preparation were excellent markers (positive predictive value 91%-95%), which predict an adequately clean colon before a colonoscopy in children.


Effect of Perindopril on Atrial Fibrillation Recurrence and Burden: Results of the Canadian Trial of Atrial Fibrillation (CTAF)-2.
Hypertension is a risk factor for the development and exacerbation of atrial fibrillation (AF). Angiotensin-converting enzyme inhibitors are a standard-of-care treatment option for patients with hypertension; however, there is conflicting evidence about their effects on AF recurrence. Therefore, our objective was to assess the efficacy of perindopril, compared with placebo, to reduce AF recurrence in patients with hypertension and AF. In a multicenter, double-blind, placebo-controlled trial, patients with hypertension and symptomatic AF were randomly assigned (1:1) to perindopril or placebo based on a stratification factor of antiarrhythmic drug use. Patients with terminated AF were followed up from 30 days after randomization to 7 to 13 months. The primary endpoint was AF recurrence. Secondary endpoints included AF hospitalization, cardioversion, and blood pressure control. Recurrent events, AF burden, and safety endpoints were also investigated. A total of 315 patients were randomly assigned, and 301 patients were included in the modified intent-to-treat analysis (155 vs 146 patients in the perindopril and placebo groups, respectively). The mean follow-up was 336 ± 70 days, and 91.1% of patients were compliant to the treatment medication throughout the study. After adjustment for baseline antiarrhythmic drugs, there was no statistically significant difference in the hazards of AF recurrence (hazard ratio, 1.22; 95% confidence interval, 0.92-1.61), with similar blood pressure. The incidence of secondary endpoints and adverse events also did not differ between treatment arms. Perindopril does not reduce recurrence or the number of AF episodes in patients with hypertension and AF.


A morphogenic role for transiently expressed acetylcholinesterase in developing thalamocortical systems?
Experiments in infant rats have revealed patterns of intense acetylcholinesterase (AChE) activity in primary sensory thalamic nuclei and thalamocortical recipient zones of primary sensory areas of cerebral cortex. The distribution and appearance of AChE staining indicates that the transient AChE in these areas is characteristic of thalamocortical neurons. The patterns of AChE are detectable during the first postnatal week of life, reach peak intensity during the second postnatal week, and decline to normal adult levels by the end of the third postnatal week. These temporal parameters correlate well with the time of thalamocortical axon growth into the cerebral cortex. These data suggest that the transient AChE may be playing a morphogenic role in the development of thalamocortical connections.


Prostaglandin E1 fever in the crayfish Cambarus bartoni.
Groups of 10 crayfish were injected with prostaglandin E1, at 1 of 3 pharmacological doses (0.5, 0.1 or 0.05 mg), into the haemocoel, and individually allowed to thermoregulate in electronic shuttleboxes for 24 hr. The mean preferred temperature of each group was then compared with their mean preferred temperature for 24 hr prior to injection, and with the mean preferred temperature of 10 crayfish injected with pyrogen-free saline. Dosage-dependent increases in preferred temperature were observed in the crayfish injected with PGE1, ranging from 1 degrees C at the lowest dosage to 3,4 degrees C at the highest dosage, above the normal thermal preferendum for this species of 22.1 degrees C.


The influence of dexamethasone on growth hormone (GH). Response to GH-releasing hormone in normal men.
There is evidence that glucocorticoids may have a bimodal effect on growth hormone release in vitro and in vivo. To explore the influence of a single low dose administration of dexamethasone on the hypothalamic-pituitary-somatotropic system, 11 male healthy subjects received 50 micrograms synthetic human GHRH-44 amide as an i.v. bolus dose with and without pretreatment with orally administered 1 mg dexamethasone 9 hours prior to GHRH stimulation. Dexamethasone preparation did affect neither baseline levels of GH and IGF-I nor GHRH induced GH secretory patterns assessed by delta max and by the net area under the response curves. These results add to previous reports that corticosteroids may have different effects on GH secretory dynamics dependent on dose and duration of application.


Evaluation of therapeutic gain for fractionated carbon-ion radiotherapy using the tumor growth delay and crypt survival assays.
The aim of the study was to evaluate the therapeutic gain of carbon ion (C-ion) radiotherapy using a mouse model. Transplanted fibrosarcoma (NFSa) growing in C3H/He mice and murine small intestine were irradiated with 290 MeV/nucleon C-ion beams (C-ions) in 1-12 fractions separated by 4h. The cell killing efficiencies of C-ions were measured using jejunum crypt survival and tumor growth delay (TGD) assays. The equieffect dose for crypt survival and TGD increased with increasing number of fractions after X-rays and 20 keV/μm C-ions, whereas TGD after 77 keV/μm C-ions rather decreased. Crypts showed stronger LET-dependent increase in α terms than the tumor while β terms less depended on LET irrespective of tissues. Therapeutic gain factor, i.e., a ratio of tumor RBE over crypt RBE, of 77 keV/μm C-ions was more than unity at any doses while that of 20 keV/μm C-ions increased with an increase in dose per fraction. These specific data imply that use of large dose per fraction would be suitable for C-ion radiotherapy irrespective of LET from the point of view of therapeutic gain, though small dose per fraction by high-LET radiation decreases total dose for tumor.


Cancer cell membrane-coated upconversion nanoparticles/ZnxMn1-xS core-shell nanoparticles for targeted photodynamic and chemodynamic therapy of pancreatic cancer.
Oxidative stress induced by reactive oxygen species (ROS) is promising treatment approach for pancreatic ductal adenocarcinoma (PDAC), which is typically insensitive to conventional chemotherapy. In this study, BxPC-3 pancreatic cancer cell membrane-coated upconversion nanoparticles/ZnxMn1-xS core-shell nanoparticles (abbreviated as BUC@ZMS) were developed for tumor-targeted cancer therapy via synergistically oxidative stress and overcoming glutathione (GSH) overexpression. Using a combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT), the BUC@ZMS core-shell nanoparticles were able to elicit the death of pancreatic cancer cells through the high production of ROS. Additionally, the BUC@ZMS core-shell nanoparticles could deplete intracellular GSH and increase the sensitivity of tumor cells to oxidative stress. The in vivo results indicated that BUC@ZMS nanoparticles can accumulate specifically in tumor locations and suppress PDAC without generating obvious toxicity. Thus, it was determined that the as-prepared core-shell nanoparticles would be a viable treatment option for solid malignancies.


Predictive factors for acceptance of a long-acting opiate substitution treatment studied through social representations and internalized stigma.
Opioid use disorder is a public health problem worldwide with a treatment gap partially due to sociocultural representation and stigma. Taking the opportunity of an authorization to a subcutaneous (SC) injectable solution of buprenorphine, the first and only injectable treatment for opioid dependence available in France, we investigate potential obstacles to its implementation in France. This study aimed to define the factors predicting the acceptance of a new SC form of opiate substitution treatment (OST) by comparing the social representations using an adapted version of the Explanatory Model Interview Catalogue (EMIC) and the internalized stigma of intravenous drug injection using the Internalized Stigma of Mental Illness Inventory (ISMI) between participants receiving OST likely to accept the SC form or not. We also observed whether the fear of an opiate withdrawal syndrome could influence this choice. Fifty OST patients were included, 54% of them accepted a new SC form of OST. Perceived causes of drug injection measured with EMIC were significantly lower among participants who would not accept the new SC form. No significant difference was found regarding the total score of the adapted ISMI or its items. The fear of opiate withdrawal syndrome did not seem to be statistically related to acceptance of a long-acting SC OST in either group. The most discriminating combination of factors in predicting patient acceptance of such treatment was related to the perceived causes of drug injection associated with a severe Diagnostic and Statistical Manual of Mental Disorders 5th version (DSM-5) diagnosis, and a lower alcohol consumption. We observed significant differences in social representations but not in internalized stigma between the two groups. Moreover, the predictive factors linked to the acceptance of a new SC form of OST suggest a multifactorial combination of elements that will have to be tested in a larger and prospective study delivering long-acting high-dose buprenorphine.


Fabrication of microprisms for planar optical interconnections by use of analog gray-scale lithography with high-energy-beam-sensitive glass.
For an integrated free-space optical interconnection system we suggest the use of microprisms to achieve large coupling angles at low loss. Prisms were fabricated in photoresist and quartz glass by analog lithography. High-energy-beam-sensitive glass was used as the gray-tone mask. Optical testing of the prisms shows acceptable surface quality and high efficiency (95%).


[Testicular tumors. Mortality and recurrence after inadequate therapy].
From 1983 to 1994, 293 patients with testicular germ cell tumors were treated at the Department of Urology, Bonn University, Germany. 252 patients (86%) were available for follow-up studies. 17/252 (6.8%) of patients died of disease, 41/252 (16%) had a tumor recurrence after complete remission. 20/41 (49%) patients with recurrence, who mainly had been referred for further treatment, had been treated inadequately. Inadequate treatment consisted of surgical failures after orchiectomy, incomplete retroperitoneal lymph node dissection after chemotherapy, delay of treatment, and inadequate chemotherapy. 80% of recurrences were found within the first two years after treatment, late relapses were found in 3.6%. Early recurrences were mainly pulmonary, late recurrences mostly occurred in the retroperitoneum or atypical. 20% of all recurrences were local recurrences.


Updates in Cryotherapy for Barrett's Esophagus.
Cryotherapy is an ablation modality relying on freeze-thaw cycles to promote cell death through intracellular ice crystal formation, ischemia, and apoptosis. Currently, 2 different cryotherapy systems are available for esophageal use. The first is cryospray ablation, which involves repetitive applications of liquid nitrogen. The second system, cryoballoon ablation, freezes the esophageal mucosa with liquid nitrous oxide using a compliant balloon. To date, studies have shown that cryotherapy is an effective and safe method for eradicating Barrett's esophagus; however, larger prospective series with longer follow-up are warranted to determine the clinical utility of cryotherapy in the treatment of Barrett's esophagus.


How do male germ cells handle DNA damage?
Male reproductive health has received considerable attention in recent years. In addition to declining sperm quality, fertility problems and increased incidence of testicular cancer, there is accumulating evidence that genetic damage, in the form of unrepaired DNA lesions or de novo mutations, may be transmitted via sperm to the offspring. Such genetic damage may arise from environmental exposure or via endogenously formed reactive species, in stem cells or during spermatogenesis. Damaged testicular cells not removed by apoptosis rely on DNA repair for their genomic integrity to be preserved. To identify factors with potentially harmful effects on testicular cells and to characterise associated risk, a thorough understanding of repair mechanisms in these cells is of particular importance. Based on results from our own and other laboratories, we discuss the current knowledge of different pathways of excision repair in rodent and human testicular cells. It has become evident that, in human spermatogenic cells, some repair functions are indeed non-functional.


Clinical and magnetic resonance imaging features predict microvascular invasion in intrahepatic cholangiocarcinoma.
Clinical features and magnetic resonance imaging (MRI)-related data are commonly employed in clinical settings and can be used to predict the microvascular invasion (MVI) status of intrahepatic cholangiocarcinoma (ICC) patients. To generate a clinical and MRI-based model capable of predicting the MVI status of ICC patients. Consecutive ICC patients evaluated from June 2015 to December 2018 were retrospectively enrolled in a training group to establish a predictive clinical MRI model. Consecutive ICC patients evaluated from January 2019 to June 2019 were prospectively enrolled in a validation group to test the reliability of this model. In total, 143 patients were enrolled in the training group, of whom 46 (32.2%) and 96 (67.8%) were MVI-positive and MVI-negative, respectively. Logistics analyses revealed larger tumour size (p = 0.008) and intrahepatic duct dilatation (p = 0.01) to be predictive of MVI positivity, enabling the establishment of the following predictive model: -2.468 + 0.024 × tumour size + 1.094 × intrahepatic duct dilatation. The area under the receiver operating characteristic (ROC) curve (AUC) for this model was 0.738 (p < 0.001). An optimal cut-off value of -1.0184 was selected to maximize sensitivity (71.7%) and specificity (61.9%). When the data from the validation group were incorporated into the predictive model, the AUC value was 0.716 (p = 0.009). Both larger tumour size and intrahepatic duct dilatation were predictive of MVI positivity in patients diagnosed with ICC, and the predictive model developed based on these variables can offer quantitative guidance for assessing the risk of MVI.


Effects of Radix Astragali and Radix Rehmanniae, the components of an anti-diabetic foot ulcer herbal formula, on metabolism of model CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 probe substrates in pooled human liver microsomes and specific CYP isoforms.
The present study investigated the effects of Radix Astragali (RA) and Radix Rehmanniae (RR), the major components of an anti-diabetic foot ulcer herbal formula (NF3), on the metabolism of model probe substrates of human CYP isoforms, CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, which are important in the metabolism of a variety of xenobiotics. The effects of RA or RR on human CYP1A2 (phenacetin O-deethylase), CYP2C9 (tolbutamide 4-hydroxylase), CYP2D6 (dextromethorphan O-demethylase), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A4 (testosterone 6β-hydroxylase) activities were investigated using pooled human liver microsomes. NF3 competitively inhibited activities of CYP2C9 (IC(50)=0.98mg/ml) and CYP3A4 (IC(50)=0.76mg/ml), with K(i) of 0.67 and 1.0mg/ml, respectively. With specific human CYP2C9 and CYP3A4 isoforms, NF3 competitively inhibited activities of CYP2C9 (IC(50)=0.86mg/ml) and CYP3A4 (IC(50)=0.88mg/ml), with K(i) of 0.57 and 1.6mg/ml, respectively. Studies on RA or RR individually showed that RR was more important in the metabolic interaction with the model CYP probe substrates. RR dose-dependently inhibited the testosterone 6β-hydroxylation (K(i)=0.33mg/ml) while RA showed only minimal metabolic interaction potential with the model CYP probe substrates studied. This study showed that RR and the NF3 formula are metabolized mainly by CYP2C9 and/or CYP3A4, but weakly by CYP1A2, CYP2D6 and CYP2E1. The relatively high K(i) values of NF3 (for CYP2C9 and CYP3A4 metabolism) and RR (for CYP3A4 metabolism) would suggest a low potential for NF3 to cause herb-drug interaction involving these CYP isoforms.


Altering model cell membranes by means of localized magnetic heating.
Isolated iron oxide magnetic nanoparticles (MNPs), 12 nm in diameter, coated with oleic acid molecules as capping agents have been deposited by the Langmuir-Blodgett (LB) method onto a model cell membrane incorporating 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and Cholesterol (Chol) in the 1:1 ratio, which was also fabricated by the LB technique. Atomic Force Microscopy (AFM) experiments showed that the application of an alternating magnetic field results in the embedding of the MNPs through the phospholipidic layer. These experimental results reveal that the heating of individual MNPs may induce a local increase in the fluidity of the film with a large control of the spatial and temporal specificity.


Correction to: Mitochondrial phylogeography of baboons (Papio spp.) - Indication for introgressive hybridization?
Following publication of the original article [1], we have been notified that some of the NCB accession numbers were incorrectly associated to their corresponding taxon in the Additional file 1.


Perceptual organization and artificial attention for visual landmarks detection.
In biological vision systems, attention mechanisms are responsible for selecting the relevant information from the sensed field of view, so that the complete scene can be analyzed using a sequence of rapid eye saccades. In recent years, efforts have been made to imitate such attention behavior in artificial vision systems, because it allows optimizing the computational resources as they can be focused on the processing of a set of selected regions. In the framework of mobile robotics navigation, this work proposes an artificial model where attention is deployed at the level of objects (visual landmarks) and where new processes for estimating bottom-up and top-down (target-based) saliency maps are employed. Bottom-up attention is implemented through a hierarchical process, whose final result is the perceptual grouping of the image content. The hierarchical grouping is applied using a Combinatorial Pyramid that represents each level of the hierarchy by a combinatorial map. The process takes into account both image regions (faces in the map) and edges (arcs in the map). Top-down attention searches for previously detected landmarks, enabling their re-detection when the robot presumes that it is revisiting a known location. Landmarks are described by a combinatorial submap; thus, this search is conducted through an error-tolerant submap isomorphism procedure.


Therapeutic potential of tumour necrosis factor-alpha antagonists in patients with chronic heart failure.
Elevated levels of tumour necrosis factor alpha (TNF-alpha) are associated with the development of heart failure. TNF-alpha antagonists, etanercept (ETA) and infliximab (INF) have been used for treating different clinical conditions. Anti-TNF-alpha therapy did not show favourable results in patients with chronic heart failure (CHF). This review analyses the reasons for anti-TNF-alpha therapy failure in CHF patients; potential approaches for improved clinical outcome are also addressed. Data analysis from clinical trials of CHF patients treated with ETA and INF. In heart failure patients, ETA and INF therapy did not lead to improved clinical outcomes and high doses of INF were associated with worsening of cardiac events. This contrasts with the observation that these agents are associated with reduced cardiac events when used in patients with inflammatory diseases such as rheumatoid arthritis (RA). Treatment of CHF patients with TNF-alpha antagonists did not show encouraging results. There is a need for the development of better treatment strategies for CHF. Perhaps, tailored anti-TNF-alpha therapy in relation to the TNF-alpha genotype of CHF patients and targeting of the cytokine gene expression via signalling pathway inhibitors may have useful clinical implications.


A nationwide assessment comparing nonelective open with minimally invasive complex colorectal procedures.
The use of minimally invasive colorectal surgery has increased greatly for both benign and malignant disease. Studies evaluating complex procedures have been largely limited to elective indications. We aimed to compare the outcome of a laparoscopic with an open transverse (TC) and total abdominal colectomy (TAC) in the nonelective setting. Comparative analysis was made using the Nationwide Inpatient Sample (2008-11) of patients undergoing a nonelective TC or TAC identified by ICD-9-CM procedure codes. The risk-adjusted 30-day outcome was assessed using regression modelling accounting for patient characteristics, comorbidity and surgical procedure. We identified 7261 admissions including 818 laparoscopic and 6443 open procedures. The mean age of the population was 65 ± 17 years and patients in the laparoscopic group were younger (56 ± 20 vs. 66 ± 17 years; P < 0.05). The rate of a single complication was lower in the laparoscopic group (26% vs. 38%; P < 0.01), but this did not remain significant following a logistic regression analysis. Mortality was significantly lower in the laparoscopic group (3.1% vs. 17%; P < 0.01) and this remained true after adjusting for covariates (OR = 0.62; P < 0.05). Laparoscopic cases were associated with a shorter median length of stay (10 vs. 13 days; P < 0.01) and hospital charge ($75,758 vs. $98,833; P < 0.01). A nonelective laparoscopic TC or TAC is associated with an equivalent complication rate and lower mortality compared with an open operation. The results should encourage surgeons with the appropriate skills to consider a laparoscopic approach for nonelective pathology requiring a complex colectomy.


Studies of ascorbate-dependent, iron-catalyzed lipid peroxidation.
We have previously observed that both Fe(II) and Fe(III) are required for lipid peroxidation to occur, with maximal rates of lipid peroxidation observed when the ratio of Fe(II) to Fe(III) is approximately one (J. R. Bucher et al. (1983) Biochem. Biophys. Res. Commun. 111, 777-784; G. Minotti and S. D. Aust (1987) J. Biol. Chem. 262, 1098-1104). Consistent with the requirement for both Fe(II) and Fe(III), ascorbate, by reducing Fe(III) to Fe(II), stimulated iron-catalyzed lipid peroxidation but when the ascorbate concentration was sufficient to reduce all of the Fe(III) to Fe(II), ascorbate inhibited lipid peroxidation. The rates of lipid peroxidation were unaffected by the addition of catalase, superoxide dismutase, or hydroxyl radical scavengers. Exogenously added H2O2 also either stimulated or inhibited ascorbate-dependent, iron-catalyzed lipid peroxidation apparently by altering the ratio of Fe(II) to Fe(III). Thus, it appears that the prooxidant effect of ascorbate is related to the ability of ascorbate to promote the formation of a proposed Fe(II):Fe(III) complex and not due to oxygen radical production. The antioxidant effect of ascorbate on iron-catalyzed lipid peroxidation may be due to complete reduction of iron.


Maturation of insulin response to glucose during human fetal and neonatal development. Studies with perifusion of pancreatic isletlike cell clusters.
The insulin release in response to glucose was studied in perifused isletlike cell clusters (ICCs) obtained from human fetal or neonatal pancreases at various stages of development: 12-15 gestational wk (n = 7), 17-20 wk (n = 13), 22.5 wk (n = 2, 1 diabetic pregnancy), and 26-44 wk (n = 6, postnatal samples). The ICCs were stimulated with 20 mM glucose and subsequently with 10 mM theophylline plus 20 mM glucose as a viability test. Insulin release increased to a detectable level (greater than 0.1 pg.ICC-1.min-1) during glucose stimulation in four of seven of the youngest fetuses. At 17-20 wk the basal rate of insulin release had increased by at least 15-fold above the detection limit (1.5 pg.ICC-1.min-1), and glucose promoted a sustained monophasic response that was on the average 1.6-fold higher than the basal level. The response was significant (P less than .05) in 9 of 13 experiments. With postnatal ICC (gestational age 26-44 wk), an early-phase peak response was observed in 5 of 6 experiments. The mean rates of insulin release after 5-12 min of glucose stimulation were 4.8 pg.ICC-1.min-1 in newborn infants and 2.1 pg.ICC-1.min-1 in 17- to 20-wk fetuses. The corresponding mean relative insulin responses (stimulated to basal) were 3.3-fold (range 1.1-7.5) and 1.6-fold (1.0-3.4), respectively (P less than .05, Mann-Whitney U test). The results suggest that the human fetal pancreas is already responsive to glucose during the first half of gestation, but the biphasic insulin release does not start to mature until the postnatal phase.


Design and synthesis of aminopyridine containing biaryls reducing c-MYC protein levels in cells.
The c-MYC oncogene transcription factor has been implicated in cell cycle regulation controlling cell growth and proliferation. It is tightly regulated in normal cells, but has been shown to be deregulated in cancer cells, and is thus an attractive target for oncogenic therapies. Building upon previous SAR, a series of analogues containing benzimidazole core replacements were prepared and evaluated, leading to the identification of imidazopyridazine compounds that were shown to possess equivalent or improved c-MYC HTRF pEC50 values, lipophilicity, solubility, and rat pharmacokinetics. The imidazopyridazine core was therefore determined to be superior to the original benzimidazole core and a viable alternate for continued lead optimization and medicinal chemistry campaigns.


Superior limbic keratoconjunctivitis (SLK).
Superior limbic keratoconjunctivitis (SLK) is a disease characterised by inflammation of the upper palpebral and superior bulbar conjunctiva, keratinisation of the superior limbus and corneal and conjunctival filaments. It may be associated with other diseases such as keratoconjunctivitis sicca, hyperthyroidism and hyperparathyroidism. Although its exact aetiology is unknown, a mechanical hypothesis seems most attractive. Treatment is aimed at altering the abnormal mechanical interaction of the upper lid and superior corneal limbus.