EEG-based mental fatigue measurement using multi-class support vector machines with confidence estimate.
Automatic measurement and monitoring of mental fatigue are invaluable for preventing mental-fatigue related accidents. We test an EEG-based mental-fatigue monitoring system using a probabilistic-based support vector-machines (SVM) method. Ten subjects underwent 25-h sleep deprivation experiments with EEG monitoring. EEG data were segmented into 3-s long epochs and manually classified into 5 mental-fatigue levels, based on subjects' performance on an auditory vigilance task (AVT). Probabilistic-based multi-class SVM and standard multi-class SVM were compared as classifiers for distinguishing mental fatigue into the 5 mental-fatigue levels. Accuracy of the probabilistic-based multi-class SVM was 87.2%, compared to 85.4% using the standard multi-class SVM. Using confidence estimates aggregation, accuracy increased to 91.2%. Probabilistic-based multi-class SVM not only gives superior classification accuracy but also provides a valuable estimate of confidence in the prediction of mental fatigue level in a given 3-s EEG epoch. The work demonstrates the feasibility of an automatic EEG method for assessing and monitoring of mental fatigue. Future applications of this include traffic safety and other domains where measurement or monitoring of mental fatigue is crucial.


Nivolumab dose escalation triggered immune checkpoint inhibitor-induced colitis after 147 weeks of prolonged stable use in a patient with lung cancer: a case report.
A 56-year-old man with advanced lung adenocarcinoma presented to the emergency department with a 6-day history of diarrhea. He was treated for lung cancer with nivolumab 3 mg/kg (144 mg/body) every 2 weeks (Q2W), followed by an increase to 240 mg Q2W for 147 weeks, for a total of 69 administrations. His dose was then increased to 480 mg/body every four weeks (Q4W) 12 days before his presentation. Clostridioides difficile toxin, cytomegalovirus antigenemia, and stool bacterial cultures were negative. Colonoscopy revealed diffusely edematous granular mucosa with mucosal redness, exudates, loss of vascular pattern, and aphtha throughout the colon but no ulcers. We diagnosed the patient with immune checkpoint inhibitor-induced colitis. We started prednisolone at a dose of 60 mg/day. His symptoms gradually improved, and he recovered without diarrhea on day ten after hospitalization. After prednisolone tapering, his symptoms did not worsen. Colonoscopy showed significant improvement on day 29, and the diffuse redness disappeared. The patient did not experience subsequent recurrence of diarrhea. He had no progression of lung cancer despite the termination of nivolumab for seven months. Here, we report a case of lung cancer in which nivolumab dose escalation after prolonged stable use triggered immune checkpoint inhibitor-induced colitis.


Effects of raloxifene on normal breast tissue from premenopausal women.
The objective of this study was to evaluate the effects of raloxifene on normal breast tissue. A randomized, double-blind study was carried out in 30 ovulatory, premenopausal women of 18-40 years of age, who had been diagnosed with fibroadenoma of the breast. The patients were divided into two groups: Group A (placebo, n = 16) and Group B (raloxifene 60 mg, n = 14). The medication was given for 22 days, beginning on the first day of the menstrual cycle. An excisional biopsy was carried out on the 23rd day during which a sample of normal breast tissue was collected to evaluate the presence of the proliferating cell marker Ki-67. Student's t-test was used for the statistical analysis of data (p < 0.05). Mean percentage of stained nuclei in groups A and B was 10.96 +/- 1.27 and 1.21 +/- 0.26, respectively (p < 0.001). Raloxifene significantly reduced the proliferative activity of normal breast tissue in premenopausal women.


Economic impacts and nutritional outcomes of the 2017 floods in Bangladeshi Shodagor fishing families.
As climate change continues to increase the frequency and severity of flooding in Bangladesh and globally, it becomes increasingly critical to understand the pathways through which flooding influences health outcomes, particularly in lower-income and subsistence-based communities. We aim to assess economic pathways that link flooding to nutritional outcomes among Shodagor fishing families in Bangladesh. We examine longitudinal economic data on kilograms of fish caught, the income earned from those fish, and household food expenditures (as a proxy for dietary intake) from before, during, and after severe flooding in August-September of 2017 to enumerate the impacts of flooding on Shodagor economics and nutrition. We also analyze seasonally collected anthropometric data to model the effects of flooding and household food expenditures on child growth rates and changes to adult body size. While Shodagor fishing income declined during the 2017 flooding, food expenditures simultaneously spiked with market inflation, and rice became the predominant expenditure only during and immediately following the flood. Our nutritional models show that children and adults lost more body mass in households that spent more money on rice during the flood. Shodagor children lost an average of 0.36 BMI-for-age z-scores and adults lost an average of 0.32 BMI units during the flooded 2017 rainy season, and these metrics continued to decline across subsequent seasons and did not recover by the end of the study period in 2019. These results show major flood-induced economic impacts that contributed to loss of child and adult body mass among Shodagor fishing families in Bangladesh. More frequent and severe flooding will exacerbate these nutritional insults, and more work is needed to effectively stabilize household nutrition throughout natural disasters and economic hardship.


The chloroplast genome of an exsymbiotic Chlorella-like green alga.
Chloroplast DNA was isolated and cloned from Chlorella, strain N1a, exsymbiotic with Paramecium bursaria. BamHI, SalI, KpnI and Xho I restriction fragments of the DNA were assembled into a circular map. The genome consists of approximately 120 kbp of DNA, has a G/C content of 38%, and contains only a single copy of the rRNA cistron. The rRNA cistron is small, 5000-8000 bp, and the 16S and 23S gene are separated by less than 2000 bp.


Umbilical and uteroplacental blood flow velocity waveforms in pregnancies with fetal growth retardation.
A 2 MHZ pulsed Doppler ultrasound was used to record blood flow velocity waveforms (FVW) in the umbilical and arcuate arteries of 129 singleton pregnancies where intra-uterine growth retardation (IUGR) was suspected at routine ultrasound screening in the 32nd week of gestation. All patients were examined once a fortnight, between 32nd week and delivery, the results presented being from the final examination before delivery. The FVW were characterized by the pulsatility index (PI). Sixty-six of the 129 newborns were growth-retarded at delivery (birthweight less than or equal to mean--2SD of the general population). Of the IUGR cases, 56% had an abnormal PI (greater than or equal to mean + 2SD of normals) in the umbilical artery and 47% in the arcuate artery. Significant relationships were found between abnormal umbilical artery PI and both IUGR (p less than 0.001) and operative delivery for fetal distress (ODFD) (p less than 0.001). No such relationship was found between abnormal PI in the arcuate artery and either IUGR or ODFD. Four placenta waveform classes (PWC), reflecting the FVW on either side of the placenta, are presented and compared with the outcome of pregnancy. The data show the umbilical artery FVW to be a good predictor of IUGR and intra-uterine fetal distress, whereas the arcuate artery FVW appears to have low predictive value for the above conditions.


Shape-preserving erosion controlled by the graded microarchitecture of shark tooth enameloid.
The teeth of all vertebrates predominantly comprise the same materials, but their lifespans vary widely: in stark contrast to mammals, shark teeth are functional only for weeks, rather than decades, making lifelong durability largely irrelevant. However, their diets are diverse and often mechanically demanding, and as such, their teeth should maintain a functional morphology, even in the face of extremely high and potentially damaging contact stresses. Here, we reconcile the dilemma between the need for an operative tooth geometry and the unavoidable damage inherent to feeding on hard foods, demonstrating that the tooth cusps of Port Jackson sharks, hard-shelled prey specialists, possess unusual microarchitecture that controls tooth erosion in a way that maintains functional cusp shape. The graded architecture in the enameloid provokes a location-specific damage response, combining chipping of outer enameloid and smooth wear of inner enameloid to preserve an efficient shape for grasping hard prey. Our discovery provides experimental support for the dominant theory that multi-layered tooth enameloid facilitated evolutionary diversification of shark ecologies.


Fenoterol inhalation powder and aerosol in the treatment of asthma.
Twenty patients with asthma were studied. They were given either fenoterol powder or fenoterol MDI for 2-week periods using a double-blind cross-over design. Identical doses of fenoterol (0.2-0.4 mg 2-4 times daily) were given to an individual patient throughout the 4-week study period. Both forms of treatment produced an almost identical bronchodilation, and there were no statistically significant differences in symptoms or side effects. It is concluded that fenoterol powder and fenoterol aerosol are equally effective.


Ethical issues in social science research with special reference to sexual behaviour research.
Social science research has long been concerned with ethical issues, but agencies that review and fund research are increasingly attentive to assuring that ethical considerations are being fully addressed. Research on sexual behaviour, a topic that has generated much recent attention worldwide as scientists confront the epidemics of adolescent pregnancy, AIDS and STDs, raises ethical issues that are worthy of special attention. Beginning with the philosophical origin of ethical principles that guide research, this paper discusses the key ethical issues to be considered when designing and conducting social science research. Included are special precautions for research on adolescents, the purpose and properties of an informed consent procedure, and the formation and function of an ethical review committee.


Six new C21 steroidal glycosides from Asclepias curassavica L.
Six new C(21) steroidal glycosides, named curassavosides A-F (3-8), were obtained from the aerial parts of Asclepias curassavica (Asclepiadaceae), along with two known oxypregnanes, 12-O-benzoyldeacylmetaplexigenin (1) and 12-O-benzoylsarcostin (2). By spectroscopic methods, the structures of the six new compounds were determined as 12-O-benzoyldeacylmetaplexigenin 3-O-beta-D-oleandropyranosyl-(1-->4)-beta-D-digitoxopyranoside (3), 12-O-benzoylsarcostin 3-O-beta-D-oleandropyranosyl-(1-->4)-beta-D-digitoxopyranoside (4), sarcostin 3-O-beta-D-oleandropyranosyl-(1-->4)-beta-D-canaropyranosyl-(1-->4)-beta-D-oleandropyranosyl-(1-->4)-beta-D-digitoxopyranoside (5), sarcostin 3-O-beta-D-oleandropyranosyl-(1-->4)-beta-D-canaropyranosyl-(1-->4)-beta-D-canaropyranosyl-(1-->4)-beta-D-digitoxopyranoside (6), 12-O-benzoyldeacylmetaplexigenin 3-O-beta-D-glucopyranosyl-(1-->4)-beta-D-oleandropyranosyl-(1-->4)-beta-D-canaropyranosyl-(1-->4)-beta-d-oleandropyranosyl-(1-->4)-beta-D-digitoxopyranoside (7), and 12-O-benzoylsarcostin 3-O-beta-D-glucopyranosyl-(1-->4)-beta-D-oleandropyranosyl-(1-->4)-beta-d-canaropyranosyl-(1-->4)-beta-D-oleandropyranosyl-(1-->4)-beta-D-digitoxopyranoside (8), respectively. All compounds (1-8) were tested for in vitro cytotoxicity; only compound 3 showed weak inhibitory activity against Raji and AGZY cell lines.


Location and composition of haptics of posterior chamber intraocular lenses. Histopathologic study of postmortem eyes.
Of 110 eyes with posterior chamber intraocular lenses (IOLs) examined postmortem, 37% had both haptics outside of the capsular bag; 57% had one haptic in the capsular bag and the other haptic outside of the bag. Typically, these optics were decentered by 1 to 2 mm. Only six eyes (5%) had both haptics within the capsular bag. Erosion into the ciliary sulcus produced obliteration of the major arterial circle of the iris in 12 eyes (11%). The local tissue response to eroding haptics was similar for haptics composed of polypropylene and haptics composed of polymethylmethacrylate (PMMA). The authors found considerable discrepancy between the actual location of haptics and the surgeon's desired location (i.e., capsular bag or ciliary sulcus). Most of these cases were clinically successful.


A signal-amplification electrochemiluminescence sensor based on layer-by-layer assembly of perylene diimide derivatives for dopamine detection at low potential.
Perylene diimide derivatives (PDIs) are suitable ECL luminophore candidates with low triggering potentials and strong ECL signals for fundamental studies and practical applications. However, PDIs tend to aggregate, which affects their optical properties and limits their application in bio-imaging and bio-sensing fields. In this study, an ECL sensor is fabricated based on the layer-by-layer (LBL) assembly of N, N-bis(phosphonomethyl)-3,4,9,10-perylene diimide (PMPDI) and ZrIV ions on the surface of a mesoporous indium tin oxide (ITO) substrate. When six layers of PMPDI are immobilized on ITO, the resulting PMPDI6/ITO electrode shows maximum ECL intensity with K2S2O8 as a co-reactant in the potential range 0 to -0.5 V vs. Ag/AgCl. LBL assembly decreases the aggregation and increases the loading of PMPDI on the mesoporous ITO substrate, which stabilizes and amplifies the ECL signals. The ECL method exhibits excellent sensitivity and selectivity with good stability and reproducibility, when used to detect dopamine (DA) under optimal experimental conditions.


Adolescent acceptance of different foods by obesity status and by sex.
This work investigated possible differences in food preference between obese and normal-weight adolescents, as well as between female and male seventh-grade pupils (average age = 13.1 years). Survey of affinities for nine food groups was determined with a facial hedonic scale. The children were divided according to their BMI into normal-weight and obese group, respectively. In this sample of adolescents, we could not find any proof for the theory of increased preference for fattening foods by obese compared to normal-weight people. In fact, our normal-weight group showed greater liking of sweets, meat, and cereals than the obese group. Normal-weight boys also preferred meat and sweets more than normal-weight girls. We consider psychological and social factors (e.g., perception of ideal body shape or social stigmatism of obesity) as the most logical explanations for the observed differences. Further research should clarify whether food preference plays a significant role in the etiology of adolescent obesity.


Application of region-based video surveillance in smart cities using deep learning.
Smart video surveillance helps to build more robust smart city environment. The varied angle cameras act as smart sensors and collect visual data from smart city environment and transmit it for further visual analysis. The transmitted visual data is required to be in high quality for efficient analysis which is a challenging task while transmitting videos on low capacity bandwidth communication channels. In latest smart surveillance cameras, high quality of video transmission is maintained through various video encoding techniques such as high efficiency video coding. However, these video coding techniques still provide limited capabilities and the demand of high-quality based encoding for salient regions such as pedestrians, vehicles, cyclist/motorcyclist and road in video surveillance systems is still not met. This work is a contribution towards building an efficient salient region-based surveillance framework for smart cities. The proposed framework integrates a deep learning-based video surveillance technique that extracts salient regions from a video frame without information loss, and then encodes it in reduced size. We have applied this approach in diverse case studies environments of smart city to test the applicability of the framework. The successful result in terms of bitrate 56.92%, peak signal to noise ratio 5.35 bd and SR based segmentation accuracy of 92% and 96% for two different benchmark datasets is the outcome of proposed work. Consequently, the generation of less computational region-based video data makes it adaptable to improve surveillance solution in Smart Cities.


Floral arrangements and hummingbird feeding.
The influence of simulated inflorescence design on feeding behavior of 3 male Eugenes fulgens (Rivoli's hummingbird) and one female Lampornis clemenciae (Bluethroated hummingbird) was studied in the laboratory using artificial flowers. Five two-dimensional and three three-dimensional arrangements provided constant rewards per artificial flower. Visits to two-dimensional arrangements had more flower visits per feeding bout, proportionally more flower revisits, and shorter time between flowers than visits to three-dimensional arrangements. This suggests inflorescence design may influence pollen movement by hummingbirds.


Formation and reduction of glutathione-protein mixed disulfides during oxidative stress. A study with isolated hepatocytes and menadione (2-methyl-1,4-naphthoquinone).
Incubation of isolated rat hepatocytes with menadione (2-methyl-1,4-naphthoquinone) resulted in a dose-dependent depletion of intracellular reduced glutathione (GSH), most of which was oxidized to glutathione disulfide (GSSG). Menadione metabolism was also associated with a dose- and time-dependent inhibition of glutathione reductase, impairing the regeneration of GSH from GSSG produced during menadione-induced oxidative stress. Inhibition of glutathione reductase by pretreatment of hepatocytes with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) greatly potentiated both GSH depletion and GSSG formation during the metabolism of low concentrations of menadione. Concomitant with GSH oxidation, mixed disulfides between glutathione and protein thiols were formed. The amount of mixed disulfides produced and the kinetics of their formation were dependent on both the intracellular GSH/GSSG ratio and the activity of glutathione reductase. The mixed disulfides were mainly recovered in the cytosolic fraction and, to a lesser extent, in the microsomal and mitochondrial fractions. The removal of glutathione from protein mixed disulfides formed in hepatocytes exposed to oxidative stress was dependent on GSH and/or cysteine and appeared to occur predominantly via a thiol-disulfide exchange mechanism. However, incubation of the microsomal fraction from menadione-treated hepatocytes with purified glutathione reductase in the presence of NADPH also resulted in the reduction of a significant portion of the glutathione-protein mixed disulfides present in this fraction. Our results suggest that the formation of glutathione-protein mixed disulfides occurs as a result of increased GSSG formation and inhibition of glutathione reductase activity during menadione metabolism in hepatocytes.


Effect of agave fructans on the production of short chain fatty acid in mice.
The aim of this study was to evaluate the effect of agave fructans on short chain fatty acid (SCFA) production in mice (C57BL/6). Animals were randomly divided into three groups (n = 8): control group (CG), fructans from Agave tequilana group (FG) (55 g per day/kg of body weight), and oligrofructose group (OG) (55 g per day/kg of body weight). Treatments were administered oral via for 6 weeks. After 24 days of treatment (phase 1), both treated groups exhibited elevated levels of acetic (12%) and propionic (FG 66% and OG 38%) acids in comparison with the CG. After 42 days of treatment (phase 2), FG had higher concentrations of acetic (33%) and propionic (73%) acids than the CG; while OG exhibited higher levels of butyric (12%) and propionic (35%) acids compared with the CG. Fructans from Agave tequilana improve the production of SCFA in mice, suggesting a prebiotic activity.


Elicitation of a rapid and transient antibody response to H-Y antigen by intrasplenic immunization.
Immunization of BN or HS female rats by intrasplenic implantation of syngeneic male skin results in a rapid, albeit transient, antibody response to H-Y antigen. Maximal antibody titers obtained by this protocol are of the range 1:4000-1:8000, and are substantially higher than titers obtained using other immunization protocols. Histological examination of the splenic skin implants shows appearances consistent with the conclusion that the skin remains viable during antibody production. Cellular infiltration into the BN implants suggests the onset of a rejection reaction as early as 2 weeks after implantation. The very transient nature of the antibody peak suggests rapid catabolism of the antibody or the supervention of a suppressor response as part of the rejection reaction. This immunization method may prove useful for the production of higher-titer H-Y antibodies than have hitherto been available.


The Hitchhiker's guide to the child neurologist's genetic evaluation of epilepsy.
Over the past several decades, familial aggregation studies as well as twin studies have supported a genetic component to seizures. The recent advent of the genome project has served as a catalyst in the search for elucidating the hereditary influences of various epilepsies. Overlapping seizure features may lead to ambiguity when attempting to isolate a single phenotype. Conversely, the phenomenon of genetic heterogeneity implies that multiple genetic mutations may give rise to a similar phenotype. Despite valiant attempts at strictly defining epilepsy phenotype and mode of penetrance, one must also consider the role of environment in gene expression. Genetics (testing) in epilepsy is no longer limited to the idiopathic epilepsies but may have an equally significant role in the symptomatic epilepsies. This article guides the reader through the genetics of epilepsy via discussion of the phenotypic description of known genetic childhood epilepsy syndromes, illustration of the associated gene mutations identified thus far, and the implications of genetic testing in clinical practice.


Psychopathology and health-related quality of life as patient-reported treatment outcomes: evaluation of concordance between the Brief Symptom Inventory (BSI) and the Short Form-36 (SF-36) in psychiatric outpatients.
Treatment outcome for common psychiatric disorders, such as mood and anxiety disorders, is usually assessed by self-report measures regarding psychopathology [e.g., via Brief Symptom Inventory (BSI)]. However, health-related quality of life [as measured by the 36-item Short-Form Health Survey (SF-36)] may be a useful supplementary outcome domain for routine outcome monitoring (ROM). To date, the assessment of both outcomes has become fairly commonplace with severe mental illness, but this is not yet the case for common psychiatric disorders. The present study examined among outpatients with common psychiatric disorders whether aggregate assessments of change across treatment regarding psychopathology and health-related quality of life yield similar results and effect sizes. We compared treatment outcome on the BSI and the SF-36 in a sample of 13,423 outpatients. The concordance of both instruments was assessed at various time points during treatment. Scores on both instruments were associated, but not so strongly to suggest they measure the same underlying construct. The SF-36 scales presented a varied picture of treatment outcome: understandably, patients changed more on the mental component scales than on physical component scales. Outcome according to the BSI was quite similar to outcome according to scales of the SF-36 that showed the largest change. Although (mental health) scores on both instruments are associated, adding the SF-36 in addition to the BSI in treatment evaluation research produces valuable information as the SF-36 measures a broader concept and contains physical/functional component scales, resulting in a more complete clinical picture of individual patients.


Erratum: Effective In Vivo Gene Modification in Mouse Tissue-Resident Peritoneal Macrophages by Intraperitoneal Delivery of Lentiviral Vectors.
[This corrects the article DOI: 10.1016/j.omtm.2019.10.004.].


FSH to estradiol ratio can be used as screening method for mild cognitive impairment in postmenopausal women.
To determine the role of anthropometric measurement, menopausal symptoms and biochemical marker changes as screening methods for mild cognitive impairment (MCI) in postmenopausal women Methods: A cross-sectional study included 282 postmenopausal women in Jakarta, further classified into two groups, with and without MCI. Some related variables such as age, body mass index (BMI), duration of menopause, vasomotor symptoms, hormone levels such as follicle stimulating hormone (FSH), luteinizing hormone, leptin, estradiol, and cognitive status, were assessed and analyzed. The FSH levels significantly correlated with MCI incidence (p = 0.018), along with the ratio of FSH/estradiol levels (p = 0.029) and ratio of FSH/soluble leptin receptor (p = 0.011), while other variables did not. By multivariate analysis, the ratio of FSH/estradiol was known as the most significant factor with a probability of having MCI in menopausal women of 1.15. Using the ROC curve, the threshold of the ratio FSH/estradiol to predict MCI was 1.94, with sensitivity 66.5% and specificity 46.8%. The ratio of FSH to estradiol (>1.94) can be used as a screening method for the occurrence of MCI in postmenopausal women.


Three-year follow-up after withdrawal of iron therapy in uremic patients on regular dialytic treatment.
Iron supplementation is commonly recommended in uremic patients undergoing regular dialytic treatment in order to correct a presumed iron deficiency due to impaired absorption and dialytic losses. Serum ferritin levels show an iron overload in 83% of 136 patients on 1.25 g/year i.v. iron therapy. After the withdrawal of iron therapy, directly correlated ferritin levels and percentage transferrin saturation decreased slowly, except in carriers of HLA-A3 antigens and in polytransfused patients. In these latter patients, desferrioxamine reduced but did not normalize the iron balance. The 16 patients who never received iron therapy showed a normal iron balance over a 3-year follow-up. Despite iron-ferritin therapy, 11 patients with baseline ferritin values at the lower normal limits showed a tendency toward further depletion. Orally administered bivalent iron seems to be more promising in normalizing iron-deficient patients without potentially harmful overloading.


Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 are sorted to dense-core vesicles and released via the regulated pathway in primary rat cortical neurons.
Neurotrophins (NTs) play an important role in the modulation of synaptic transmission and in morphological changes in synaptic structures. Although there is agreement that brain-derived neurotrophic factor (BDNF) is sorted to large dense-core vesicles (LDCVs) and released via the regulated secretory pathway, there has been some dispute regarding the mode of secretion of nerve growth factor (NGF) and neurotrophin-3 (NT-3), two structurally related members of the NT family. In this study, we examined the subcellular localization and release characteristics of NGF, BDNF, and NT-3 in adenovirus-infected primary cortical neurons. We found that all members of the NT family colocalized with markers for the endoplasmic reticulum and Golgi within cell bodies and in a punctate manner with a marker for LDCVs within processes. Moreover, their release was triggered by depolarization, indicating that NGF, BDNF, and NT-3 are released via the regulated secretory pathway. When neurons were coinfected with two separate adenoviruses coding for NGF or BDNF, both NTs showed almost complete vesicular colocalization within single cells, suggesting that different NTs might be packaged into shared vesicles. We also examined whether the two splice variants of NGF, the short and long precursors, differ in their release characteristics. We found that neurons infected with viruses coding for either splice variant released NGF in a regulated way. Overall, our study supports the notion that all members of the NT family undergo activity-dependent regulated release from neurons, enabling them to act as "synaptotrophins" on electrically active neurons.


Causes of larval drift of the fire salamander, Salamandra salamandra terrestris, and its effects on population dynamics.
The larval drift of the fire salamander was investigated over a period of three years in a mountain brook (Niederbergisches Land, F.R. Germany), as well in a laboratory water channel. The rate of larval drift fluctuated between 19% and 41% of the total population of larvae in a defined section of the brook during these three years. Most (83%) of the drifting larvae were hatchlings or very young stages. The drift was dependent on the strength of the current, the number of spawning females, the presence of suitable hiding places, sufficient space and adequate food. Hungry larvae drifted more often than satiated animals. The drift behaviour of hatchlings differed distinctly from that of older larvae. The significance of ecological factors on larval drift is discussed. It is evidently a more important factor in selection than has hitherto been recognized.


Fesoterodine dose response in subjects with overactive bladder syndrome.
To compare the efficacy of fesoterodine 4 mg versus 8 mg in treating subjects with overactive bladder (OAB) syndrome. This is a pooled analysis of data from 2 randomized placebo (PBO)-controlled phase III trials. Eligible subjects with frequency and urgency or urgency urinary incontinence (UUI) were randomized to PBO or fesoterodine 4 or 8 mg for 12 weeks. Subjects assessed efficacy using 3-day bladder diaries recording the time of each void, urgency, and incontinence episode. Endpoints included treatment response (based on a 4-point Treatment Benefit scale) and change from baseline in micturitions, UUI episodes, mean volume voided, urgency episodes, and continent days. We assessed tolerability and safety by evaluating adverse events, residual urine volume, laboratory parameters, and treatment withdrawals. At the end of treatment, both doses of fesoterodine showed statistically significant improvements in all efficacy endpoints versus PBO (P <0.01). These effects were seen 2 weeks after initiation of treatment (the earliest evaluation point) and were sustained throughout the treatment period. Fesoterodine 8 mg performed significantly better than fesoterodine 4 mg in improving all diary variables (P <0.05) except micturition frequency, demonstrating a dose-response relationship. Adverse events reported more frequently with fesoterodine than with PBO included dry mouth, constipation, and urinary tract infection. Both fesoterodine 4 and 8 mg are effective in improving OAB symptoms. The higher 8-mg dose provides additional benefit compared with the lower dose in improving most bladder diary variables, thus offering the possibility of dose flexibility and titration.


Extended Boltzmann kinetic equation for turbulent flows.
Complex fluid physics can be modeled using an extended kinetic (Boltzmann) equation in a more efficient way than using the continuum Navier-Stokes equations. Here, we explain this method for modeling fluid turbulence and show its effectiveness with the use of a computationally efficient implementation in terms of a discrete or "lattice" Boltzmann equation.


MR Imaging in Primary Sclerosing Cholangitis and Other Cholangitis.
Sclerosing cholangitis is characterized by irregular and ill-defined inflammation, fibrosis, and stricturing of the bile ducts and may be primary or secondary in cause. It causes progressive destruction of the biliary tree, progressive parenchymal cirrhosis, hepatic failure, and malignancy such as cholangiocarcinoma. The subtypes of sclerosing cholangitis can be broken down into primary sclerosing cholangitis (PSC), immune-mediated sclerosing cholangitis, infectious cholangitis, and ischemic cholangitis with other causes including metastatic disease and chemotherapy change. MR imaging is the gold standard test to investigate and differentiate PSC and other types of cholangitis.


Sex-Specific Effects of Vitamin D Status on the Metabolic Profile in Prediabetic Subjects.
We aim to investigate the effect of vitamin D on metabolic parameters in a population with prediabetes and to detect possible sex differences. In 621 patients with diagnosed prediabetes, glucose, lipid, and anthropometric parameters were measured. Furthermore, the interaction of 25-OH-vitamin D (25-hydroxyvitamin D) with metabolic and glucose metabolism parameters was analysed in the total prediabetic population, as well as after stratification by sex (female vs. male prediabetic subgroup), by logistic regression. 25-OH-vitamin D was negatively related to cholesterol, BMI, fatty liver index, insulin, and HOMA-IR. Especially in the male prediabetic cohort, 25-OH-vitamin D levels negatively correlated with total cholesterol levels (r = -0.17, p=0.001), with triglycerides (r = -0.17, p=0.001), and with HbA1c levels (r = -0.14, p=0.010). Only in the female cohort with prediabetes, we found a negative correlation of 25-OH-vitamin D levels with systolic (r = -0.18, p=0.005) and diastolic blood pressures (r = -0.23, p < 0.001). In this study, in females with prediabetes, 25-OH-vitamin D was notably related to a more favourable metabolic profile, including lower total cholesterol and higher HDL cholesterol levels. On the contrary, in men with prediabetes, there was a stronger association between 25-OH-vitamin D and cholesterol-HDL quotient, as well as fatty liver index was observed in the male prediabetic subgroup. Therefore, sex differences should be considered in future studies on vitamin D and glucose tolerance status.


Characteristics and outcomes of patients with grill-related Burn injuries admitted to the Cologne Burn Center, Germany.
Grilling has become increasingly common in Germany. Although grilling is considered a non-negligible household burn hazard, few reports have assessed this type of injury. This study aimed to determine the patterns and characteristics of grill-related burn injuries and to compare these with other types of burn injuries. This retrospective observational study included all grill-related burn injuries admitted to Cologne Merheim Burn Center during 1989-2017. The collected data were analyzed descriptively and compared statistically with other fire injuries. Of 1706 cases admitted with fire injuries during the study period, 160 (∼10%) involved grill-related injuries. Most cases (85%) involved men, with an average age of 34 years. Moreover, 48% and 38% of cases occurred in summer and spring, respectively. The most common mechanism of injury was ignition via fluid accelerant. The upper limb was the most commonly affected body part, followed by the head. Statistical analyses revealed that grill-related injuries were associated with a lower mean age and total body surface area, shorter in-hospital stay, and fewer complications than the other fire injury group. Grill-related injuries are a relatively common cause of admission to the Cologne Burn Center. Although grill-related injuries underwent a less aggressive approach than the other investigated fire injuries, the former represent a public health concern because they mainly affect the upper body, with both psychologic and aesthetic consequences. We recommend a German nationwide multi-centric study of the patterns and characteristics of burn injury.


Genetic Evaluation of Body Weights and Egg Production Traits Using a Multi-Trait Animal Model and Selection Index in Thai Native Synthetic Chickens (Kaimook e-san2).
To improve the genetics of both growth and egg production, which are limitations in purebred native chickens, new genetic lines can be developed using an appropriate genetic approach. The data used in this study included 2713 body weight (BW0, BW4, BW6, BW8, and BW10), breast circumference (BrC6), chicken age at first egg (AFE), and egg production (240EP, 270EP, 300EP, and 365EP) records covering the period 2015 to 2020. A multi-trait animal model with the average information-restricted maximum likelihood (AI-REML) and a selection index was used to estimate the variance components, genetic parameters, and breeding values. The results showed that males had significantly higher weights than females (p < 0.05) from 4 to 10 weeks of age and that this difference increased over the generations. The differences between BW0 and BrC6 by sex and generation were not significant (p > 0.05). The estimated heritability of body weight ranged from 0.642 (BW0) to 0.280 (BW10); meanwhile, the estimated heritability of BrC6 was moderate (0.284). For egg production traits, the estimated heritability of 240EP, 270EP, 300EP, and 365EP was 0.427, 0.403, 0.404, and 0.426, respectively, while the estimated heritability of AFE was 0.269. The genetic and phenotypic correlations among the growth traits (BW0 to BW10) were low to highly positive. The genetic and phenotypic correlations between growth (BW0 to BW10) and BrC6 traits were positive, and the genetic correlations between BW6 (0.80), BW8 (0.84), BW10 (0.93), and BrC6 were strongly positive. Genetic correlations among the egg production traits (240EP, 270EP, 300EP, and 365EP) were low to highly positive and ranged from 0.04 to 0.86. The genetic correlations between AFE and all egg production traits were low to moderately negative and ranged from -0.14 to -0.29. The positive genetic correlations between body weight (BW6, BW8, and BW10) and egg production traits were found only in 240EP. The average genetic progress of body weight traits ranged from -0.38 to 30.12 g per generation for BW0 to BW10 (p < 0.05); the genetic progress was 0.28 cm per generation for BrC6 (p > 0.05). The average genetic progress of cumulative egg production traits ranged from 4.25 to 12.42 eggs per generation for 240EP to 365EP (p < 0.05), while the average genetic progress of AFE was -7.12 days per generation (p < 0.05). In conclusion, our study suggests that the body weight at six weeks of age (BW6), breast circumference at six weeks of age (BrC6), cumulative egg production at 240 days of age (240EP), and age at first egg (AFE) are the traits that should be used as selection criteria, as they have a positive effect on the development of growth and egg production.


Solution structure of the His12 --> Cys mutant of the N-terminal zinc binding domain of HIV-1 integrase complexed to cadmium.
The solution structure of His12 --> Cys mutant of the N-terminal zinc binding domain (residues 1-55; IN(1-55)) of HIV-1 integrase complexed to cadmium has been solved by multidimensional heteronuclear NMR spectroscopy. The overall structure is very similar to that of the wild-type N-terminal domain complexed to zinc. In contrast to the wild-type domain, however, which exists in two interconverting conformational states arising from different modes of coordination of the two histidine side chains to the metal, the cadmium complex of the His12 --> Cys mutant exists in only a single form at low pH. The conformation of the polypeptide chain encompassing residues 10-18 is intermediate between the two forms of the wild-type complex.


Social phobia: the nature of the disorder.
Social phobia is characterized by a fear of social situations, which are either avoided or endured with intense anxiety or distress. There is a high prevalence of social phobia in the community and the course of the condition tends to be chronic. In spite of the personal impact of social phobia, few sufferers seek professional help. This is due to a lack of awareness about the condition on the part of health professionals and the public. Social phobia demands increased awareness, so that sufferers receive the treatment they need and deserve, so giving them the opportunity to improve their quality of life.


Dipeptidyl Peptidase-4 inhibitors use in type II diabetic patients in a tertiary hospital.
In Malaysia, for more than a decade, dipeptidyl peptidase-4 inhibitors (DPP-4i) are among the oral antidiabetic medications used as monotherapy or in combination to manage type II diabetes mellitus (T2DM). These medications are known for the efficacy in glycated haemoglobin (HbA1c) reduction and weight neutral effect with minimal hypoglycaemia occurrence. This study aimed to identify the outcomes of DPP-4i use in one of the largest tertiary public hospital in Southeast Asia. This is a retrospective cross sectional study conducted in 2016, where stratified sampling method was used. Patients with T2DM treated with available DPP-4i; namely Linagliptin, Saxagliptin, Sitagliptin and Vildagliptin, for at least 3 months were identified from the pharmacy record. Medical records from Physician Clinic in Hospital Kuala Lumpur (HKL) were reviewed. Data on demographic, anthropometric, antidiabetic treatment modalities, laboratory and documented outcomes were collected. Outcomes endpoints which include changes in HbA1c, fasting blood glucose (FBG), and body weight were recorded and analysed. Adverse drug reactions (ADR) documented were also reported. A total of one hundred and five patients were recruited. The patients were 49.5% men (n = 52), with a mean age of 57 years, mean HbA1c of 8.5% (69 mmol/mol) and mean BMI of 29.5 kg/m2. At least 50% of the patients had T2DM for more than 10 years and more than two third of these patients had both T2DM and hypertension. Thirty nine patients were on Vildagliptin, 32 on Sitagliptin, 26 on Saxagliptin and the remaining on Linagliptin. The most commonly prescribed DPP-4i were Vildagliptin and Sitagliptin. Majority of the patients (90.4%) were prescribed with Metformin, with 62.8% of patients on fixed-dose combination, and the remaining on add-on Metformin therapy. Use of DPP-4i as an adjunct was associated with a mean reduction of 0.9% (9 mmol/mol) in HbA1c (p < 0.0001) and 1.15 mmol/L (19.82 mg/dL) in FBG (p = 0.001) without significant weight changes (p = 0.745). Sitagliptin had the highest reduction in HbA1c (1.66%,19 mmol/mol; p-value< 0.0001). Twelve ADRs were reported with the highest report on gastrointestinal intolerance (n = 7). None of the ADR reported caused any significant harm to the patients. Overall, use of these DPP-4i as an adjunct antidiabetic was associated with reduction in HbA1c.


Aging in the Shadow of Violence: A Phenomenological Conceptual Framework for Understanding Elderly Women Who Experienced Lifelong IPV.
This article suggests a heuristic framework for understanding elderly women's "lived experience" of lifelong intimate partner violence (IPV). This framework is based on the phenomenological qualitative studies of 31 women, aged 60-83, using a semistructured interview guide. From the results, a matrix emerged built on two axes. The first axis consists of three phenomenological dimensions: suffering, a "ticking clock," and life wisdom. The second axis consists of four themes that emerged from the content analysis: loneliness, regret, being in a state of waiting, and being a living monument to perpetual victimhood. The practical implications of these phenomenological findings are then discussed.


Identification of different charged species of a human monocyte derived neutrophil activating peptide (MONAP).
Lipopolysaccharide-stimulated human monocytes secrete a 10 kD peptide (MONAP) of high neutrophil, not however monocyte or eosinophil stimulating activity. By reversed phase HPLC MONAP could be distinguished from Interleukin 1. Analytic isoelecto-focusing of pure MONAP (single line upon sodiumdodecylsulfate polyacrylamide gel electrophoresis, single peak after RP-18-HPLC), obtained by size exclusion HPLC followed by two different reversed phase HPLC steps revealed charge heterogeneity giving major components with isoelectric points at 4.7, 4.9, 6.4 and 6.9, all of which exhibited chemotactic activity.


History of artificial intelligence in medicine.
Artificial intelligence (AI) was first described in 1950; however, several limitations in early models prevented widespread acceptance and application to medicine. In the early 2000s, many of these limitations were overcome by the advent of deep learning. Now that AI systems are capable of analyzing complex algorithms and self-learning, we enter a new age in medicine where AI can be applied to clinical practice through risk assessment models, improving diagnostic accuracy and workflow efficiency. This article presents a brief historical perspective on the evolution of AI over the last several decades and the introduction and development of AI in medicine in recent years. A brief summary of the major applications of AI in gastroenterology and endoscopy are also presented, which are reviewed in further detail by several other articles in this issue of Gastrointestinal Endoscopy.


Gap junction uncoupling of neonatal rat astroglial cultures does not affect their expression of fibroblast growth factor 2.
Fibroblast growth factor (FGF)-2 is expressed by astroglial cells and regulates astroglial proliferation, differentiation, and gap junction communication. We show now that uncoupling of astroglial cells cultured from neonatal rat cortex, striatum and mesencephalon by 18alpha-glycirrhetinic acid (AGA) or arachidonic acid (AA) (demonstrated by intracellular injections of Lucifer Yellow) does affect neither levels of FGF-2 mRNA (investigated by a competitive RT-PCR method), nor protein (as revealed by Western blot analysis). This suggests that expression of FGF-2, which reduces gap junction communication of cortical and striatal astroglial cells [15], is not affected when astroglial cells are uncoupled. Regulation of FGF-2 expression and coupling in astroglial cells are thus not reciprocal suggesting more complex interrelationships between these two important parameters of astroglial cell differentiation.


Effect of vasoactive intestinal polypeptide infused intrapancreatically on glucagon and insulin secretion.
Synthetic vasoactive intestinal polypeptide (VIP) was infused at a dose of 50 ng/kg/min for 10 min into the cranial pancreaticoduodenal artery in anesthetized dogs. Both mean blood flow and plasma glucagon concentration in the cranial pancreaticoduodenal vein were significantly enhanced during the infusion, indicating a great augmentation in glucagon output. The pancreatic venous plasma concentration of insulin was not significantly raised, but its output increased during the infusion, again due to the increase in plasma flow. Plasma concentration of glucagon in the femoral artery was not significantly augmented, whereas that of insulin was enhanced during VIP infusion. Mean arterial plasma glucose levels rose gradually during the infusion. Intrapancreatic pretreatment with propranolol failed to exert any significant inhibiting effect upon the VIP-induced enhancement in plasma glucose, pancreatic venous blood flow, or bihormonal output. These results suggest that the vasoactive polypeptide of intestinal origin may regulate the function of the endocrine pancreas and that this effect may not be mediated mainly via the beta-adrenergic receptor system.


Interest in health information exchange in ambulatory care: a statewide survey.
Assess the interest in and preferences of ambulatory practitioners in HIE. Health information exchange (HIE) may improve the quality and efficiency of care. Identifying the value proposition for smaller ambulatory practices may help those practices engage in HIE. Survey of primary care and specialist practitioners in the State of Colorado. Clinical data were commonly (always [2%], often [29%] or sometimes [49%]) missing during clinic visits. Of 12 data types proposed as available through HIE, ten were considered "extremely useful" by most practitioners. "Clinical notes/consultation reports," "diagnosis or problem lists," and "hospital discharge summaries" were considered the three most useful data types. Interest in EKG reports, diagnosis/problem lists, childhood immunizations, and discharge summaries differed among ambulatory practitioner groups (primary care, obstetrics-gynecology, and internal medicine subspecialties). Practitioners express strong interest in most of the data types, but opinions differed by specialties on what types were most important. All providers felt that a system that provided all data types would be useful. These results support the potential benefit of HIE in ambulatory practices.


In vitro safety evaluation and anticlastogenic effect of BacoMind on human lymphocytes.
BacoMind (BM) is a standardized extract of Bacopa monnieri, which belongs to the family Scrophulariaceae and is a creeping annual plant found throughout the Indian subcontinent. It has been used by Ayurvedic medicinal practitioners in India for almost 3000 years and is classified as a medharasayana, a substance which improves memory and intellect. With the widespread traditional use as well as scientific validation of Bacopa monnieri for nootropic activity, a bioactive-rich unique phytochemical composition-BacoMind was developed from B. monnieri for use as a cognition and memory enhancing agent. The present study aimed to investigate the in vitro toxicity of this formulation of BacoMind on human lymphocytes and to rule out its possible contribution to mutagenicity. In the present investigation the active ingredients present in BM were identified and quantified by high performance liquid chromatography (HPLC) and high performance thin-layer chromatography (HPTLC). Antioxidant and anticlastogenic properties of BM were studied in vitro with and without metabolic activation. Doses of BM were chosen on the basis of mitotic index (MI) and cytokinesis-block proliferation index (CBPI). Clastogenicity assays were performed at 31.2 microg/mL, 62.5 microg/mL, and 125 microg/mL, while the Salmonella reverse mutation assay (Ames test) was performed at doses of 61.72, 185.18, 555.55, 1666.67, and 5000.00 microg/plate. HPLC and HPTLC analysis of BM revealed the presence of bacoside A3, bacopaside I, bacopaside II, jujubogenin isomer of bacopasaponin C, bacosine, luteolin, apigenin, bacosine, and beta-sitosterol D glucoside. BM demonstrated significant antioxidant activity. The number of chromosomal aberrations and the frequency of micronuclei induced by BM were not statistically significant up to a dose of 62.5 microg/mL. A subsequent dose of 125 microg/mL prior to metabolic activation induced mild clastogenicity, but it was found to be biologically insignificant as this effect was not seen post metabolic activation. BM also demonstrated a dose-dependent protection against the clastogens used in this study using the above tests for clastogenicity. Maximum protection was observed in presence of metabolic activation. Moreover, BM demonstrated no mutagenic effect on the tested strains, as observed in the Ames test. BM protected human lymphocytes against various clastogens. BM also exhibited high antioxidant activity which might be responsible for the observed protective effects against the clastogens since the used clastogens are known to induce their clastogenic effects via production of oxidative radicals.


Comprehensive analysis of predictive factors for rapid angiographic stenotic progression and restenosis risk in coronary artery disease patients underwent percutaneous coronary intervention with drug-eluting stents implantation.
This study aimed to explore the correlation of baseline, procedural, and postprocedure characteristics with the risk of rapid angiographic stenotic progression (RASP) and restenosis in coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI) with drug-eluting stents implantation. Two hundred fourteen CAD patients underwent PCI with drug-eluting stents implantation were consecutively enrolled. Baseline, procedural, and postprocedure characteristics of patients were collected for analysis. Coronary angiography was performed to evaluate coronary stenosis before PCI and at 12 months after PCI. RASP of nontarget lesions and restenosis of stent-implanted target lesions were then assessed. 37.8% CAD patients occurred RASP at 12 months after PCI and compared to non-RASP group, RASP group presented with increased diabetes mellitus (DM) complication, higher concentration of serum uric acid (SUA), cardiac troponin I, N-terminal probrain natriuretic peptide, and high sensitive C-reactive protein (hs-CRP) as well as elevated occurrence of multivessel artery lesions. In addition, DM, SUA, hs-CRP, and multivessel artery lesions independently predicted high RASP risk. For restenosis, 21.0% patients occurred restenosis at 12 months after PCI, and patients in restenosis group presented with increased hypertension and DM occurrence, higher concentrations of SUA, LDL-C, and hs-CRP, as well as longer target lesion and length of stent in surgery compared to nonrestenosis group. Also, DM, SUA, LDL-C, hs-CRP, and length of target lesion independently predicted increased restenosis risk. Diabetes mellitus, SUA, and hs-CRP are potential predictive factors for increased risk of both RASP and restenosis in CAD patients underwent PCI and drug-eluting stents implantation.


"Migration" of traumatic subarachnoid hematoma? A case report.
Traumatic spinal SAH with neurologic deficits is rare and easily misdiagnosed, especially after traumatic intracranial hemorrhage. We report a case of spinal SAH with root compression occurring after a scooter accident. Physicians should be aware of descending migration of intracranial SAH as a possible cause of spinal cord or root compression, especially in the patient with late onset spinal symptoms.


Phosphate removal model: an observational study of low-flux dialyzers in conventional hemodialysis therapy.
Precise assessing phosphate removal by hemodialysis (HD) is important to improve phosphate control in patients on maintenance HD. We reported a simple noninvasive model to estimate phosphate removal within a 4-hour HD. One hundred sixty-five patients who underwent HD 4 hours per session using low-flux dialyzers made of polysulfone (1.2 m(2)) or triacetate (1.3 m(2)) were enrolled. Blood flows varied from 180 to 300 mL/min. Effluent dialysate samples were collected during the 4-hour HD treatment to measure the total phosphate removal. Predialysis levels of serum phosphate, potassium, hematocrit, intact parathyroid hormone, total carbon dioxide (TCO(2)), alkaline phosphatase, clinical and dialysis characteristics were obtained. One hundred thirty-five observations were randomly selected for model building and the remaining 30 for model validation. Total amount of phosphate removal within the 4-hour HD was mostly 15-30 mmol. A primary model (model 1) predicting total phosphate removal was Tpo(4) = 79.6 × C(45) (mmol/L) - 0.023 × age (years) + 0.065 × weight (kg) - 0.12 × TCO(2) (mmol/L) + 0.05 × clearance (mL/min) - 3.44, where C(45) was phosphate concentration in spent dialysate measured at the 45 minute of HD and clearance was phosphate clearance of dialyzer in vitro conditions offered by manufacturer's data sheet. Since the parameter TCO(2) needed serum sample for measurement, we further derived a noninvasive model (model 2):Tpo(4) = 80.3 × C(45) - 0.024 × age + 0.07 × weight + 0.06 × clearance - 8.14. Coefficient of determination, root mean square error, and residual plots showed the appropriateness of two models. Model validation further suggested good and similar predictive ability of them. This study derived a noninvasive model to predict phosphate removal. It applies to patients treated by 4-hour HD under similar conditions.


Comparison of distal radioulnar joint reconstructions using an active joint motion simulator.
Distal radioulnar joint (DRUJ) instability can result in pain and functional disability. Numerous DRUJ reconstructive options have been described with minimal biomechanical analysis. The purpose of this study was to evaluate the ability of 4 well-described DRUJ reconstructions to restore joint kinematics using a dynamic, motion-controlled simulator. Eleven cadaveric upper extremities had computer-controlled simulated active forearm rotation. Joint kinematics were quantified by using an electromagnetic tracking system. We compared the passive and simulated active kinematics of the intact, unstable, and reconstructed DRUJ (capsular repair, 2 described radioulnar ligament reconstructions, and a radioulnar tethering procedure). All reconstructions improved significantly the kinematics of the unstable DRUJ. The capsule repair restored simulated active joint kinematics closest to the intact DRUJ. All 4 reconstructions improved DRUJ stability significantly. The capsule repair most closely matched intact DRUJ kinematics and the radioulnar ligament reconstructions were found to be superior to a radioulnar tethering procedure.


Aurantio-obtusin induces hepatotoxicity through activation of NLRP3 inflammasome signaling.
Aurantio-obtusin (AO) is a major anthraquinone (AQ) compound derived from Cassiae semen (CS). Although pharmacological studies have shown that the CS extracts can serve as effective agents in preclinical and clinical practice, AQ-induced hepatotoxicity in humans has attracted widespread attention. To explore whether AO induces hepatotoxicity and its underlying mechanisms, we exposed larval zebrafish and mice to AO. We found that AO delayed yolk sac absorption, and increased liver area and inflammation in the larval zebrafish. This inflammation was manifested as an increase in liver neutrophils and the up-regulated mRNA expression of interleukin-6 (Il-6) and tumor necrosis factor-α (Tnf-α) in the larval zebrafish. Furthermore, a pharmacokinetics study showed that AO was quickly absorbed into the blood and rapidly metabolized in the mice. Of note, AO induced hepatotoxicity in a gender-dependent manner, characterized by liver dysfunction, increased hepatocyte necrosis with inflammatory infiltration, and up-regulated mRNAs of Il-6, Tnf-α and monocyte chemotactic protein 1(Mcp1) in the female mice after 28-day oral administration. It also highlighted that AO triggered NOD-like receptor protein (NLRP) signaling in the female mice, as evidenced by the increased NLRP3, Caspase-1, pro-IL-1β, IL-1β and IL-18. Finally, we found that AO led to a significant increase in potassium calcium-activated channel, subfamily N, member 4 (KCNN4) and reactive oxygen species (ROS) levels, along with decreased nuclear factor kappa B p65 (NF-κB p65), in the female mouse livers. In conclusion, AO induced hepatotoxicity by activating NLRP3 inflammasome signaling, at least in part, through increased KCNN4 and ROS production, and NF-κB inhibition.


Fetal and oncofetal antigens - regulators of immune reactions.
This paper proposes the hypothesis that cells which express fetal antigen activate a variety of suppressor mechanisms and thus induce a state of immunological tolerance. Clinical and experimental evidence is cited which supports the hypothesis and indicates that foreign antigens, expressed in association with fetal antigen, are actively tolerated. Thus the fetus, which bears foreign histocompatibility antigens and neoplastic tumours which re-express fetal antigens, fail to evoke appropriate immunological rejection responses, but rather induce a state of active tolerance.


Revelation of Function and Inhibition of Wza Through Single-Channel Studies.
Antibacterial resistance (AR) is causing more and more bacterial infections that cannot be cured by using the antibacterial drugs that are currently available. It is predicted that 10 million people will die every year by 2050 from infections caused by antibacterial resistant strains, surpassing the predicted numbers of deaths caused by cancer. AR is therefore a global challenge and novel antibacterial strategies are in high demand. To this end, the work on exploring the pore properties of a bacterial sugar transporter, WzaK30, has led to the discovery of the first inhibitor against bacterial capsular polysaccharides export.Recently, single-molecule recapitulation of capsular polysaccharide (CPS) export and pore formation properties of Wza barrel peptides have also revealed the possibility of a next-generation of Wza strategies. These strategies are based upon the first examination and understanding of the pore properties of wild-type (WT) and mutant WzaK30 in single-molecule electrical channel recording. The initially reported experimental procedures have been further developed to enable efficient studies of other Wza homologs that are more common in bacterial pathogens causing significant bacterial infections. Therefore, this chapter presents the most recent protocols and logistics behind the research on Wza channel activity, antibacterials, and strategies. The disciplines covered here include computation, molecular biology, biochemistry, electrophysiology, microbiology, and biophysics.


A Hypoxia-Regulated Retinal Pigment Epithelium-Specific Gene Therapy Vector Reduces Choroidal Neovascularization in a Mouse Model.
Wet age-related macular degeneration (wAMD) is characterized by the presence of choroidal neovascularization (CNV). Although there are some clinical drugs targeting vascular endothelial growth factor (VEGF) and inhibiting CNV, two major side effects limit their application, including the excessive activity of anti-VEGF and frequent intraocular injections. To explore better treatment strategies, researchers developed a hypoxic modulator retinal pigment epithelium (RPE)- specific adeno-associated virus (AAV) vector expressing endostatin to inhibit CNV. However, the mechanism of endostatin is complex. Instead, soluble fms-like tyrosine kinase-1 (sFlt-1) can inhibit VEGF-induced angiogenesis through two simple and clear mechanisms, giving rise to sequestration of VEGF and forming an inactive heterodimer with the membrane-spanning isoforms of the VEGF receptor Flt-1 and kinase insert domain-containing receptor. In this study, we chose sFlt-1 as a safer substitute to treat wAMD by inhibiting VEGFinduced angiogenesis. The AAV2/8-Y733F-REG-RPE-sFlt-1 vector was delivered by intravitreal injection to the eyes of mice. AAV2/8-Y733F vector is a mutant of the AAV2/8 vector, and the REG-RPE promoter is a hypoxia-regulated RPE-specific promoter. Two animal models were used to evaluate the function of the vector. In the cobalt chloride-induced hypoxia model, the results demonstrated that the AAV2/8- Y733F-REG-RPE-sFlt-1 vector induced the expression of the sFlt-1 gene in RPE cells through hypoxia. In the laser-induced CNV model, the results demonstrated that the AAV2/8-Y733F-REG-RPE-sFlt- 1 vector reduced laser-induced CNV. Hypoxia regulated, RPE-specific AAV vector-mediated sFlt-1 gene is a hypoxiaregulated antiangiogenic vector for wAMD.


Cloning and detecting signature microRNAs from mammalian cells.
MicroRNAs (miRNAs) are about 19- to 24-nucleotides long noncoding regulatory small RNAs that could silence target gene expression through base pairing to the complementary sequences in the 3' untranslated region (3'UTR) of targeted genes. They are evolutionally conserved and play an important regulatory role in embryogenesis, cell differentiation, and proliferation. They are also involved in pathogenesis and progression of some human diseases. There are about 1000 human miRNAs predicted today, and it is estimated that they could target about 30% of all human transcripts. Profiling the miRNAs that are expressed in the experimental cells became an important issue as different cells express different signature miRNAs or express the same miRNAs at different level. Small RNA cloning is a reliable way to characterize those tissue- or cell-specific signature miRNAs. This chapter describes a relatively nonlaborious polyadenylation-mediated complementary DNA (cDNA) cloning method that will identify most of the small RNAs expressed in the cells of interest. This procedure can also be used to verify bioinformatic predictions of miRNAs/small interfering RNAs (siRNAs) as well as to identify new miRNAs/siRNAs.


Short-term bilateral keratoconus progression after deep anterior lamellar keratoplasty in one eye and intracorneal ring segments and corneal crosslinking in the other due to eye rubbing.
A 15-year-old boy had deep anterior lamellar keratoplasty in the right eye and intracorneal ring segments/corneal crosslinking in the left eye for the treatment of progressive keratoconus due to eye rubbing. He achieved a good surgical results, and 6 months later, the uncorrected distance visual acuity (UDVA) was 0.30 logarithm of the minimum angle of resolution (logMAR) in each eye, the refraction in the right eye was plano -2.75 × 135 = 0.30 logMAR and in the left eye was -0.75 -2.50 × 45 = 0.18 logMAR. Twelve months postoperatively, there was recurrence of intense eye rubbing. UDVA dropped, and bilateral corneal steepening was noted. Bilateral corneal crosslinking was performed along with an allergist consultation for eye rubbing control. Ten years later, his UDVA was 1.3 logMAR and 0.40 logMAR and corrected distance visual acuity was 0.10 logMAR and 0.18 logMAR in the right and left eyes, respectively.


[Non ST elevation acute coronary syndrome: early use of pravastatin or atorvastatin is associated with divergent changes of parameters of hemostasis].
To find out whether pravastatin and atorvastatin rapidly (in 1-2 weeks) and similarly affect hemostasis in patients with non-ST elevation acute coronary syndrome (NSTEACS). Ninety aspirin and heparin treated patients with NSTEACS were randomized <24 hours from pain onset to open pravastatin 40 mg/day (n=31), atorvastatin 10 mg/day (n=30) or atorvastatin 40 mg/day (n=29). At baseline, on days 7, 14 plasma thrombin-antithrombin complex (TAT), prothrombin fragments 1+2 (F1+2), D-dimer, von Willebrand factor (vWF) were measured by ELISA. Results were compared with data from controls (n=18) of another randomized study on similarly treated patients. In all treatment groups levels of low-density lipoprotein cholesterol (LDLCH) were lowered by days 7 (p<0,01) and 14 (p<0,01 vs. baseline and for both atorvastatin groups vs. day 7). In pravastatin group levels of TAT and F1+2 decreased, while vWF level increased. In atorvastatin groups levels of TAT and F 1+2 increased while level of vWF decreased. Contrary to pravastatin group changes in atorvastatin treated patients more resembled those in controls not receiving lipid lowering drugs. Changes of both LDLCH and TCH directly correlated only with changes of vWF (r=0.23, p=0.03 and r=0.25, p=0.02, respectively). No consistent changes of D-dimer occurred. Early use of atorvastatin and pravastatin in patients with NSTEACS was associated with rapid divergent changes of some hemostatic parameters. Except lowering of von Willebrand factor changes in atorvastatin treated patients more resembled those in controls not receiving lipid lowering drugs. Von Willebrand factor was the only parameter which changes weakly but significantly correlated with changes of CH and LDL CH levels.


The economic damage of COVID-19 on regional economies: an application of a spatial computable general equilibrium model to South Korea.
We developed a spatial computable general equilibrium model of South Korea to assess the spatial spillover effects of the COVID-19 pandemic on South Korea's regional economic growth patterns. The model measures a wide range of economic losses, including human health costs at the city and county level, through an analysis of regional producers' profit maximization on the supply side and regional households' utility maximization on the demand side. The model's findings showed that if the level of spatial interaction decreases by 10% as a result of social distancing policies, the national gross domestic product drops by 0.815-0.864%. This loss in economic growth can be further decomposed into 0.729% loss in agglomeration effect, 0.080-0.130% loss in health effect associated with medical treatment and premature mortality, and 0.005% loss in labor effect. The results of the models and simulations shed light on not only the epidemiological effects of social distancing interventions, but also their resultant economic consequences. This ex-ante evaluation of social distancing measures' effects can serve as a guide for future policy decisions made at both the national and regional level, providing policymakers with the tools for tailored solutions that address both regional economic circumstances and the spatial distribution of COVID-19 cases.


Green synthesis, characterization, and biological evaluation of gold and silver nanoparticles using Mentha spicata essential oil.
Green synthesis of bioactive nanoparticles (NPs) is getting more attractive in various fields of science including the food industry. This study investigates the green synthesizing and characterization of gold NPs (AuNPs) and silver NPs (AgNPs) produced using Mentha spicata L. (M. spicata) essential oil as well as their antibacterial, antioxidant, and in vitro cytotoxic effects. The essential oil was mixed with both Chloroauric acid (HAuCl4) and aqueous silver nitrate (AgNO3) solutions separately and incubated at room temperature for 24 h. The chemical composition of the essential oil was identified by gas chromatography coupled with a mass spectrometer detector (GC-MS). Au and Ag nanoparticles were characterized using UV-Vis spectroscopy, transmission electron microscopy, scanning electron microscopy, dynamic light scattering (DLS), X-ray diffraction (XRD) and Fourier transform infrared (FTIR). The cytotoxicity of both types of nanoparticles was evaluated using MTT assay on cancerous HEPG-2cell line by exposing them to various concentrations of both NPs for 24 h. The antimicrobial effect was evaluated by the well-diffusion technique. The antioxidant effect was determined by DPPH and ABTS tests. According to the results of GC-MS analysis, 18 components were identified, including carvone (78.76%) and limonene (11.50%). UV-visible spectroscopy showed a strong absorption peak of 563 nm and 485 nm, indicating the formation of Au NPs and Ag NPs, respectively. TEM and DLS demonstrated that AuNPs and AgNPs were predominantly spherical shaped with average sizes of 19.61 nm and 24 nm, respectively. FTIR analysis showed that biologically active compounds such as monoterpenes could assist in the formation and stabilization of both types of NPs. Additionally, XRD provided more accurate results, revealing a nano-metal structure. Silver nanoparticles exhibited better antimicrobial activity against the bacteria than AuNPs. Zones of inhibition ranging 9.0-16.0 mm were recorded for the AgNPs, while zones of 8.0-10.33 mm were observed AuNPs. In the ABTS assay, the AuNPs and AgNPs showed a dose-dependent activity and synthesized nanoparticles exhibited higher antioxidant activity than MSEO in both assays. Mentha spicata essential oil can be successfully used for the green production of Au NPs and Ag NPs. Both green synthesized NPs show antibacterial, antioxidant, and in vitro cytotoxic activity.


Disparate outcomes observed within Kidney Disease: Improving Global Outcomes (KDIGO) acute kidney injury stage 1.
The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline classifies acute kidney injury (AKI) into 3 stages defined by serum creatinine elevation or urine output decline. We evaluated the potential impact of further categorizing AKI stage 1 into two stages based on serum creatinine criteria, with a focus on how the resulting 4-stage classification would affect the association of AKI stages with clinical outcomes. We defined AKI stage 1a as an absolute increase in serum creatinine of 0.3 mg/dl within 48 hours and stage 1b as a 50% relative increase in serum creatinine within 7 days. We screened all admissions to 5 hospitals from 2012 to 2014 using standardized inclusion and exclusion criteria and included 81,651 admissions in this retrospective cohort study. The incidence of in-hospital AKI was 7.5% for stage 1a, 4.9% for stage 1b, 1.5% for stage 2, and 0.9% for stage 3. Length of stay following the first incidence of AKI was 3.9 days for stage 1a, 6.2 days for stage 1b, 8.8 days for stage 2, and 12.0 days for stage 3. Compared to patients with no AKI, the odds of in-hospital mortality were progressively higher for patients with higher AKI stages (odds ratio 4.3 for patients with stage 1a, 10.9 for stage 1b, 40.6 for stage 2, and 60.0 for stage 3 AKI). Patients with AKI stages 1a and 1b experienced clinically meaningful and statistically significant differences in length of stay and mortality. This study suggests that a modified 4-stage version of the KDIGO AKI classification may provide additional prognostic information.


Analysis of natural-occurring and synthetic sexual hormones in sludge-amended soils by matrix solid-phase dispersion and isotope dilution gas chromatography-tandem mass spectrometry.
A sensitive analytical method is presented for the simultaneous determination of four synthetic estrogens and six steroid hormones in sludge-amended soil. The method employs matrix solid-phase dispersion (MSPD) followed by isotope dilution gas chromatography-tandem mass spectrometry injecting a large volume sample (10μL) after trimethylsilyl derivatization, using the solvent vent mode. It affords good resolution, high sensitivity and reproducibility and freedom from interferences even from complex matrices as soil amended with sewage sludge. The limits of detection (LODs) ranged from 10 to 300pgg(-1) with testosterone and progesterone having the highest limits. Soil amended with sewage sludge was spiked at 2, 10, 25 and 50ngg(-1) and the recoveries after MSPD with acetonitrile:methanol (90:10, v/v), ranged from 80 to 110% with relative standard deviations ≤9%. The method was applied to the analysis of six soil samples collected from agricultural plots and forested fields that had been amended with sewage sludge using isotopically labeled surrogates. Three of the synthetic estrogens studied were found at least in one of the six samples analyzed and trans-androsterone and estrone were the only natural hormones detected, although at very low levels (≤0.4ngg(-1)).


Evaluating the reliability, validity, acceptability, and practicality of SMS text messaging as a tool to collect research data: results from the Feeding Your Baby project.
To test the reliability, validity, acceptability, and practicality of short message service (SMS) messaging for collection of research data. The studies were carried out in a cohort of recently delivered women in Tayside, Scotland, UK, who were asked about their current infant feeding method and future feeding plans. Reliability was assessed by comparison of their responses to two SMS messages sent 1 day apart. Validity was assessed by comparison of their responses to text questions and the same question administered by phone 1 day later, by comparison with the same data collected from other sources, and by correlation with other related measures. Acceptability was evaluated using quantitative and qualitative questions, and practicality by analysis of a researcher log. Reliability of the factual SMS message gave perfect agreement. Reliabilities for the numerical question were reasonable, with κ between 0.76 (95% CI 0.56 to 0.96) and 0.80 (95% CI 0.59 to 1.00). Validity for data compared with that collected by phone within 24 h (κ =0.92 (95% CI 0.84 to 1.00)) and with health visitor data (κ =0.85 (95% CI 0.73 to 0.97)) was excellent. Correlation validity between the text responses and other related demographic and clinical measures was as expected. Participants found the method a convenient and acceptable way of providing data. For researchers, SMS text messaging provided an easy and functional method of gathering a large volume of data. In this sample and for these questions, SMS was a reliable and valid method for capturing research data.


Dose-response relationships of LSD-induced subjective experiences in humans.
Lysergic acid diethylamide (LSD) is a potent classic serotonergic psychedelic, which facilitates a variety of altered states of consciousness. Here we present the first meta-analysis establishing dose-response relationship estimates of the altered states of consciousness induced by LSD. Data extracted from articles identified by a systematic literature review following PRISMA guidelines were obtained from the Altered States Database. The psychometric data comprised ratings of subjective effects from standardized and validated questionnaires: the Altered States of Consciousness Rating Scale (5D-ASC, 11-ASC) and the Mystical Experience Questionnaire (MEQ30). We performed meta-regression analyses using restricted cubic splines for data from studies with LSD doses of up to 200 μg base. Most scales revealed a sigmoid-like increase of effects, with a plateauing at around 100 μg. The most strongly modulated factors referred to changes in perception and illusory imagination, followed by positively experienced ego-dissolution, while only small effects were found for Anxiety and Dread of Ego Dissolution. The considerable variability observed in most factors and scales points to the role of non-pharmacological factors in shaping subjective experiences. The established dose-response relationships may be used as general references for future experimental and clinical research on LSD to compare observed with expected subjective effects and to elucidate phenomenological differences between psychedelics.


Novel liver vein deprivation technique that promotes increased residual liver volume (with video): A case report.
Inadequate volume of future liver remnant (FLR) is a major challenge for hepatobiliary surgeons treating large or multiple liver tumors. As an alternative to associating liver partition and portal vein ligation (ALPPS) for staged hepatectomy and liver venous deprivation (LVD) using stage 1 interventional radiology for vascular embolization combined with stage 2 open liver resection have been used. A novel modified LVD technique was performed in a patient with pancreatic neuroendocrine tumor with liver metastases by using stage 1 laparoscopic ligation of the right hepatic vein, right posterior portal vein, and short hepatic veins combined with local excision of three liver metastases in the left hemiliver. The operation was followed three days later by interventional radiology to embolize an anomalous right anterior portal vein to complete LVD. A stage 2 laparoscopic right hemihepatectomy and pancreaticosplenectomy were then carried out. The minimally invasive technique promoted a rapid increase, comparable to ALPPS, in volume of the FLR after the stage 1 operation to allow the laparoscopic stage 2 resection to be performed.


Visual function and patient satisfaction after macular hole surgery.
Over recent years success in macular hole surgery has increased in terms of anatomical closure. However, debate still continues on the benefit to the patient in terms of visual outcome. We designed a prospective study to investigate the outcome of full thickness macular hole (FTMH) surgery in terms of anatomical closure, visual outcome, incidence of complications and patient satisfaction. Thirty eyes of 30 consecutive patients with FTMH were prospectively studied (stage 2 = 2; stage 3 = 23; stage 4 = 5). All cases had surgery involving vitrectomy, injection of an autologous platelet aggregate over the hole and gas tamponade. At 3 months post-operatively all cases were assessed for closure of the FTMH, Snellen acuity and the incidence of complications. At this stage all patients completed a patient satisfaction questionnaire. Anatomical closure of the hole was achieved in 83% of cases (25/30). Visual improvement of 2 Snellen lines or more occurred in 50% of cases (15/30). A vision of 6/12 or better was achieved in 27% of cases (8/30). A post-operative lens opacity was present in 46% (13/28) of phakic patients and a temporal, peripheral wedge-shaped field defect occurred in 17% (5/30) of cases. In this study, 53%, 70%, 57% and 67% of patients gave a positive response to specific questions about satisfaction with near, intermediate and distance vision and overall visual function respectively. Although the anatomical success of FTMH surgery is high the functional outcome in terms of Snellen acuity is less rewarding. Analysis of patient satisfaction suggests that the arbitrary visual outcome measures presently used may underestimate the functional benefit to the patient. Improved objective measures of visual outcome are required to assess the benefit of surgery in these cases.


Interactions between β-lactoglobulin and casein glycomacropeptide on foaming.
The aim of this work was to study the effect of interactions between casein glycomacropeptide (CMP) and β-lactoglobulin (β-lg) at pH 6.5 and 3.5 on the foaming properties of the mixed systems with different CMP:β-lg ratios. The foaming properties were determined by the bubbling method with a Foamscan instrument. A highest overall foam capacity (OFC), foaming capacity (FC) and mainly stability of mixed foams at pH 3.5, as compared to the mixed foams at pH 6.5 or the foams of CMP and β-lg was observed. At pH 6.5, the stability of mixed foams decreased with increasing the CMP content, while OFC and FC values were similar to β-lg foam. The performance of the mixed systems was discussed in relation with the interactions between CMP and β-lg in the aqueous phase (as observed by dynamic light scattering and differential scanning calorimetry in previous works).


New mobilizable vectors suitable for gene replacement in gram-negative bacteria and their use in mapping of the 3' end of the Xanthomonas campestris pv. campestris gum operon.
We describe useful vectors to select double-crossover events directly in site-directed marker exchange mutagenesis in gram-negative bacteria. These vectors contain the gusA marker gene, providing colorimetric screens to identify bacteria harboring those sequences. The applicability of these vectors was shown by mapping the 3' end of the Xanthomonas campestris gum operon, involved in biosynthesis of xanthan.


Is ambulatory 24-h dual-probe pH monitoring useful in suspected ENT manifestations of GERD?
The present study is aimed at assessing the relationship between ear, nose and throat manifestations and proximal reflux in gastro-oesophageal reflux disease by using 24-h dual-probe pH monitoring. Fifty-eight patients were included: (;) 28 patients with suspected ear, nose and throat manifestations of gastrooesophageal reflux disease: (ii) 18 patients with typical symptoms of gastro-oesophageal reflux disease without extraoesophageal manifestations of gastro-oesophageal reflux disease; (iii) 12 healthy volunteers. Ambulatory 24-h dual-probe pH monitoring was performed in all patients. Oesophagogastroscopy was performed in all patients of groups I and II. Ear, nose and throat examination was performed in all patients with ear, nose and throat complaints. At the upper oesophageal sphincter, results of pH monitoring were significantly different between groups I and III (0.009 < P < 0.02) and between groups I and II (0.008 < P < 0.03). When comparing data at the lower oesophageal sphincter, we found a significant difference between groups II and III (0.002 < P < 0.009) and between groups I and III (0.001 < P < 0.002). Endoscopic examination of the oesophagus did not show any significant difference between groups I and II. Laryngoscopy was abnormal in 86% of the patients with ear, nose and throat symptoms. Ambulatory 24-h dual-probe pH monitoring is useful in the assessment of patients with suspected ear, nose and throat manifestations of gastro-oesophageal reflux disease, especially in the case of abnormal laryngoscopy.


Regulation of albumin and alpha-fetoprotein gene expression by colloid osmotic pressure in human hepatoma cells.
Colloid osmotic pressure has been thought to regulate albumin synthesis; however, the exact mechanism remains obscure. In the present study, the effect of colloid osmotic pressure on the albumin and alpha-fetoprotein gene expression in HuH-7 human hepatoma cells was analyzed. HuH-7 cells were treated with albumin or dextran (mean mol wt, 70,000), and changes in the levels of albumin and alpha-fetoprotein messenger RNA (mRNA) were analyzed by Northern blotting. Furthermore, in transient chloramphenicol acetyltransferase (CAT) plasmid transfection experiments, effects of colloid osmotic pressure on CAT activities were studied. By Northern blot analysis, the levels of both albumin and alpha-fetoprotein mRNA were dose-dependently suppressed by the elevation of colloid osmotic pressure and returned to pretreatment levels 48 hours after the culture medium containing dextran was replaced with a dextran-free fresh medium. In transient CAT plasmid transfection experiments, the increased level of colloid osmotic pressure resulted in the repression of both albumin and alpha-fetoprotein promoter activities. In contrast, alpha-fetoprotein enhancer activity, which possibly regulates not only alpha-fetoprotein but also albumin gene expression, was not affected by changes in colloid osmotic pressure. These results suggest that colloid osmotic pressure regulates both albumin and alpha-fetoprotein gene transcription through the modulation of their promoter activities.


A system for engineering an osteochondral construct in the shape of an articular surface: preliminary results.
A tissue-engineered articular condyle could provide a new alternative approach to joint replacement. This study describes progress made towards engineering an articular condyle in vitro using human bone marrow stromal cells (hBMSCs) in a biphasic matrix. hBMSCs were transferred to a rat collagen-I hydrogel which was then pressed onto a bovine cancellous bone matrix. The gel/cell suspensions, each at a density of approximately 5 x 10(5)cells/ml containing fourth passage cells pressed into an adult human tibial condyle form using CT scan based moulds. The osteochondral constructs fabricated in vitro were stimulated in a bioreactor using cyclic compression and continuous perfusion. Penetration and cell distribution were demonstrated as homogeneous and cells were found to be viable after gel compression. The filamentous structure of the collagen fibres was more dense and homogeneous using compression. Mechanical tests showed a significant enhancement of primary matrix stability after initial compression. Stiffness was not observed to increase significantly over 7 days under loading in a bioreactor. The successful integration of mechanical stimulation in the tissue engineering process leads to an improvement in the structural and biomechanical properties of these tissues and offers new possibilities in the management of joint injuries and degenerative diseases. Remarkably, the stiffness was enhanced in our setting after initial compression of the construct in the glass cylinder without observing a negative influence on cell viability. Further studies need to clarify the influence of compression and various mechanical and hydrostatic stress patterns over different periods of time.


A positive feedback strategy for enhanced chemotherapy based on ROS-triggered self-accelerating drug release nanosystem.
Here, a positive feedback strategy was utilized to amplify the concentration of intracellular reactive oxygen species (ROS) and a ROS-triggered self-accelerating drug release nanosystem (defined as T/D@RSMSNs) was demonstrated for enhanced tumor chemotherapy. The mesoporous silica nanoparticles (MSNs) based nanocarriers were gated by β-cyclodextrin (β-CD) through the ROS-cleavable thioketal (TK) linker to encapsulate the anticancer drug doxorubicin hydrochloride (DOX) and ROS producing agent α-tocopheryl succinate (α-TOS), whose surface was further anchored with adamantane conjugated poly(ethylene glycol) chain (AD-PEG) via host-guest interaction. It was found that in human breast cancer (MCF-7) cells, T/D@RSMSNs could not only release DOX and α-TOS initiatively, but also lead to increased concentration of intracellular ROS, which could be used as new trigger to cut away TK linkage and then in turn facilitate the further release of DOX for enhanced chemotherapy. Both in vitro and in vivo experiments demonstrated that T/D@RSMSNs exhibited more significant antitumor activity in the human breast cancer than the traditional single-DOX loaded ROS-responsive nanocarrier. This novel ROS-triggered self-accelerating drug release nanosystem with remarkably improved therapeutic effects could provide a general strategy to branch out the applications of existing ROS-responsive drug delivery systems (DDSs).


Quantification of proton dose calculation accuracy in the lung.
To quantify the accuracy of a clinical proton treatment planning system (TPS) as well as Monte Carlo (MC)-based dose calculation through measurements and to assess the clinical impact in a cohort of patients with tumors located in the lung. A lung phantom and ion chamber array were used to measure the dose to a plane through a tumor embedded in the lung, and to determine the distal fall-off of the proton beam. Results were compared with TPS and MC calculations. Dose distributions in 19 patients (54 fields total) were simulated using MC and compared to the TPS algorithm. MC increased dose calculation accuracy in lung tissue compared with the TPS and reproduced dose measurements in the target to within ±2%. The average difference between measured and predicted dose in a plane through the center of the target was 5.6% for the TPS and 1.6% for MC. MC recalculations in patients showed a mean dose to the clinical target volume on average 3.4% lower than the TPS, exceeding 5% for small fields. For large tumors, MC also predicted consistently higher V5 and V10 to the normal lung, because of a wider lateral penumbra, which was also observed experimentally. Critical structures located distal to the target could show large deviations, although this effect was highly patient specific. Range measurements showed that MC can reduce range uncertainty by a factor of ~2: the average (maximum) difference to the measured range was 3.9 mm (7.5 mm) for MC and 7 mm (17 mm) for the TPS in lung tissue. Integration of Monte Carlo dose calculation techniques into the clinic would improve treatment quality in proton therapy for lung cancer by avoiding systematic overestimation of target dose and underestimation of dose to normal lung. In addition, the ability to confidently reduce range margins would benefit all patients by potentially lowering toxicity.


Biomarkers identified with time-lapse imaging: discovery, validation, and practical application.
"Time-lapse markers," which are defined by time-lapse imaging and correlated with clinical outcomes, may provide embryologists with new opportunities for improving embryo selection. This article provides an overview of noninvasive biomarkers defined by time-lapse imaging studies. In addition to comprehensively reviewing the discovery of each time-lapse marker, it focuses on the criteria necessary for their successful integration into clinical practice, including [1] statistical and biological significance, [2] validation through prospective clinical studies, and [3] development of reliable technology to measure and quantify the time-lapse marker. Because manual analysis of time-lapse images is labor intensive and limits the practical use of the image data in the clinic, automated image analysis software platforms may contribute substantially to improvements in embryo selection accuracy. Ultimately, time-lapse markers that are based on a foundation of basic research, validated through prospective clinical studies, and enabled by a reliable quantification technology may improve IVF success rates, encourage broader adoption of single-embryo transfer, and reduce the risks associated with multiple gestation pregnancies.


Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration.
Peripherally active tetrapeptides as selective κ opioid receptor (KOR) agonists have been prepared in good overall yields and high purity following solid-phase peptide synthesis via Fmoc protection strategy. Structural modifications at the first and second position of the lead compound FF(d-Nle)R-NH2 (FE200041) were contemplated with aromatic side chains containing d-amino acids, such as (d)-pF-Phe, (d)-mF-Phe, (d)-oF-Phe, which led to highly selective and efficacious KOR agonists endowed with strong antinociceptive activity in vivo following intravenous (i.v.) and subcutaneous (s.c.) administration in the tail flick and formalin tests. These results suggest potential clinical applications in the treatment of neuropathic and inflammatory pain.


Functional polymorphisms in FAS and FASL contribute to risk of squamous cell carcinoma of the larynx and hypopharynx in a Chinese population.
Accumulating evidences indicate that the functional FAS-1377G>A, -670A>G and FASL-844T>C polymorphisms affect the risk of several kinds of cancers. However, their roles in the development of larynx and hypopharynx squamous cell carcinoma (SCC) were still unknown in the Chinese. In the current study, we examined whether these functional genetic variants were associated with the risk of larynx and hypopharynx squamous SCC in a Han Chinese population. The FAS and FASL polymorphisms were genotyped in 300 patients with laryngeal and hypopharyngeal SCC and 300 control subjects by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Logistic regression analysis revealed that subjects carrying the FASL-844CT or TT genotype had a significantly decreased risk of developing laryngeal and hypopharyngeal SCC [odds ratio (OR)=0.69; 95% confidence interval (CI)=0.51-0.93; P=0.016; or, OR=0.41; 95% CI=0.20-0.86; P=0.009] compared with those carrying the CC genotype. Joint gene-smoking and gene-drinking effects were also observed, with the OR of CC genotype for smokers or drinkers were 5.15 (95%CI=3.24-8.97) or 12.52 (95%CI=7.31-22.47), respectively. Therefore, the FASL-844T>C polymorphism is associated with genetic susceptibility of developing laryngeal and hypopharyngeal SCC in a Han Chinese population.


Mesoporous peroxidase nanozyme for synergistic chemodynamic therapy and chemotherapy.
Peroxidase nanozyme, enabling decomposition of hydrogen peroxide (H2O2) into highly toxic hydroxyl radical (•OH), is an emerging technology for tumor treatment. However, limited by the low H2O2 level in the tumor microenvironment, the standalone peroxidase nanozyme-mediated therapy usually fails to achieve desirable therapeutic outcomes. Herein, we presented a mesoporous nanozyme that not only had peroxidase-like activity but also could deliver anticancer drug for synergistic tumor therapy. The nanozyme, that was, iron-doped mesoporous silica nanoparticle (FeMSN), was prepared by a sol-gel method and then a calcination treatment. The introduction of iron endowed FeMSN with peroxidase-like activity that could decompose H2O2 into •OH under acidic condition for chemodynamic therapy of tumors. Meanwhile, the mesoporous structure enabled FeMSN to deliver anticancer drug doxorubicin (DOX) for chemotherapy and enhanced chemodynamic therapy through H2O2 production, ultimately achieving synergistic effect to improve the efficacy of tumor treatment. The in-vitro and in-vivo results demonstrated that DOX-loaded FeMSN exhibited significant cancer cell-killing effect and potently inhibited tumor growth. Collectively, this study represented a paradigm for achieving efficient tumor therapy through design of peroxidase-like nanozyme with drug delivery capability, which might advance the development of nanozyme in tumor chemodynamic therapy.


Effect of nitrogen fixation, nitrogen fertilization and viral infection on yield, tannin and protein contents and in vitro protein digestibility of faba bean.
A field investigation of two faba bean cultivars (cv.), Agabat and Silaim, showed that bean yellow mosaic virus (BYMV) infection reduced (p < or = 0.001) yield (Kg/ha), protein content and in vitro protein digestibility (IVPD) but increased (p < or = 0.05) tannin content (mg/100 ml). Nitrogen fertilization with viral infection significantly reduced yield and IVPD for cv. Silaim and increased (p < or = 0.05) protein and tannin contents. Nitrogen fertilization alone was found to increase (p < or = 0.05) yield, protein and tannin contents but slightly reduced IVPD. Rhizobium inoculation with viral infection significantly decreased yield per unit area, protein content and IVPD, but increased (p < or = 0.05) tannin content. Rhizobium inoculation alone significantly increased (p < or = 0.001) yield and tannin content and slightly increased protein content but decreased IVPD. The results indicated that nitrogen fertilization or nitrogen fixation increased yield, protein and tannin contents and decreased IVPD. Viral infection had an adverse effect on yield, protein content and IVPD but had no effect on tannin content.


Ribavirin treatment for chronic hepatitis C.
We evaluated oral ribavirin as therapy for chronic hepatitis C infection in a pilot study including 10 patients. Patients (7 men, 3 women; mean age 40 years, range 23-54) all had biopsy-proven chronic non-A, non-B hepatitis and were repeatedly positive for antibodies to hepatitis C virus. Treatment was with oral ribavirin 1000-1200 mg per day in two divided doses for 12 weeks. The median serum alanine aminotransferase concentration for all patients at enrollment was 3.15 mu kat/l (range 1.22-7.79) and decreased significantly (p less than 0.005) to 1.25 mu kat/l (0.78-2.04) after 12 weeks of treatment. Within 6 weeks of the end of treatment the median serum alanine aminotransferase concentration was not significantly different from that before treatment. Side-effects were mild and fully reversible after cessation of therapy. We conclude that ribavirin is the first drug to offer a potentially effective oral treatment for chronic hepatitis C. It should be further evaluated in controlled trials, possibly in combination with interferon alpha.