Estrogenic activity of glycitein, a soy isoflavone.
Glycitein (4',7-dihydroxy-6-methoxyisoflavone) accounts for 5-10% of the total isoflavones in soy food products. The biological activity of this compound has not been reported to date, although numerous studies have been performed with the other soy isoflavones, daidzein and genistein. Glycitein was isolated from soy germ to 99% purity. Weaning female B6D2F1 mice were dosed with glycitein (3 mg/day), genistein (3 mg/day), and diethylstilbestrol (DES) (0.03 microg/day) in 5% Tween 80 by gavage for 4 days. A control group received an equal volume of 5% Tween 80 solution daily. The uterine weight increased 150% with glycitein (p < 0.001), 50% with genistein (p < 0. 001), and 60% with DES (p < 0.001) compared with the control group. DES, 17beta-estradiol, and three isoflavones (daidzein, genistein, and glycitein) were examined for their competitive binding abilities with 17beta-((3)H)estradiol to the estrogen receptor proteins of the B6D2F1 mouse uterine cytosol. The concentrations of each compound required to displace 50% of the ((3)H)estradiol at 5 nM in the competitive binding assay were 1.15 nM DES, 1.09 nM 17beta-estradiol, 0.22 microM genistein, 4.00 microM daidzein, and 3.94 microM glycitein. These data indicated that glycitein has weak estrogenic activity, comparable to that of the other soy isoflavones but much lower than that of DES and 17beta-estradiol.


Gay and Bisexual Men's Willingness to Use a Self-Collected Anal Cancer Screening Test.
We investigated gay and bisexual men's willingness to self-administer an anal cancer screening test at home. We conducted 2 national, online cross-sectional surveys of self-identified gay and bisexual men: Study I in 2009 with men ages 20 to 59 (n = 306) and Study II in 2013 with men ages 18 to 26 (n = 428). We used multivariate logistic regression analyses to determine variables associated with willingness to self-administer the screening test. Most men were willing to self-administer an anal cancer screening test (78% Study I; 67% Study II). In Study I, willingness was higher among men who trusted anal Paps to find treatable cancer (adjusted odds ratio [aOR] = 1.47; 95% CI, 1.04-2.09) and who believed that men who have sex with men should be screened for anal cancer between 1 and 3 years vs. other intervals (aOR = 2.19; 95% CI, 1.17-4.10). In Study II, willingness was higher among men who perceived greater likelihood of anal cancer (aOR = 1.57; 95% CI, 1.12-2.20). Their most common concerns were not performing the test correctly and inaccuracy of results. Many gay and bisexual men were willing to self-administer anal cancer screening tests at home. If routine screening is warranted, self-collected home testing could improve participation.


Exercise training during hemodialysis reduces blood pressure and increases physical functioning and quality of life.
Hypertension and cardiovascular diseases are highly prevalent in hemodialysis patients and are associated with the reduction of physical functioning and quality of life. We evaluated the effects of supervised aerobic exercise training on physical functioning, blood pressure, quality of life, and laboratory data in hemodialysis patients. Fourteen patients were evaluated at the beginning and after 12 weeks of stretching exercises (control phase) and at the end of 12 weeks of aerobic exercise training performed during hemodialysis sessions (intervention phase). Patients underwent a 6-min walking test (6MWT), 24-h ambulatory blood pressure monitoring, a Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) quality of life questionnaire, and blood sample collections. After the intervention phase, the 6MWT distance increased from 508.7 +/- 91.9 m to 554.9 +/- 105.8 m (P = 0.001), systolic and diastolic blood pressure decreased respectively from 150.6 +/- 18.4 mm Hg to 143.5 +/- 14.7 mm Hg and from 94.6 +/- 10.5 mm Hg to 91.4 +/- 9.7 mm Hg (P < 0.05), while hemoglobin levels increased from 10.8 +/- 1.2 g/dL to 11.6 +/- 0.8 g/dL (P < 0.05). Moreover, there was a significant increase in the physical functioning, social functioning, and mental health dimensions of the SF-36. Aerobic exercise training during hemodialysis increased physical functioning, reduced blood pressure levels, and improved the control of anemia and quality of life in patients with end-stage renal disease.


Wetting characteristics of addition silicon materials subjected to immersion disinfection--an in-vitro study.
An in-vitro study was conducted to assess wetting characteristic of four brands of addition silicon materials subjected to immersion disinfection using four different disinfectants. Among the non-disinfected specimens, the lowest contact angle was recorded for Aquasil ultra (21.63), followed by Imprint II (29.06), Aquasil LV (44.10) and Take 1 (44.55). While 5.25% phenol increased the contact angle of all the silicon materials; 0.05% iodophor increased the angle of Take 1 and Imprint II and 0.5% sodium hypochlorite increased the angle of Imprint II and decreased for Aquasil ultra. However, 2% glutaraldehyde did not significantly change the contact angle of any of the four impression materials.


Violent film characters' portrayal of alcohol, sex, and tobacco-related behaviors.
To determine the extent to which movies popular with adolescents feature characters who jointly engage in violence and other risk behaviors. We hypothesized that violent characters engage in other risk behaviors equally often in films rated appropriate for children over 12 (PG-13) and Restricted (R)-rated films. Content analysis of a sample of top-grossing movies from 1985 to 2010 (n = 390). We coded movies for the presence of at least 1 main character who was involved in violence and either sex, tobacco, or alcohol use within a 5-minute movie segment and throughout a film. Approximately 90% of the movies contained a segment with a main character involved in violence, and ~77% of the films had the same character engaging in at least 1 other risk behavior. A violent character was portrayed most often partaking in alcohol-related and sexual behaviors. G and PG movies had less co-occurrence than PG-13 or R-rated movies, but there was no statistical difference between PG-13 and R-rated movies with regards to violence co-occurring with other risk behaviors. These trends did not vary over time. Popular films that contain violent characters also show those characters engaging in other risk behaviors. Similar rates of co-occurrence between PG-13 and R-rated films suggest that the Motion Picture Association of America ratings system is not sensitive to the joint portrayal of violence and alcohol, sex, and tobacco-related risk behaviors. The on-screen clustering of violence with other risk behaviors is cause for concern and worthy of additional research.


Generalized and scalable trajectory inference in single-cell omics data with VIA.
Inferring cellular trajectories using a variety of omic data is a critical task in single-cell data science. However, accurate prediction of cell fates, and thereby biologically meaningful discovery, is challenged by the sheer size of single-cell data, the diversity of omic data types, and the complexity of their topologies. We present VIA, a scalable trajectory inference algorithm that overcomes these limitations by using lazy-teleporting random walks to accurately reconstruct complex cellular trajectories beyond tree-like pathways (e.g., cyclic or disconnected structures). We show that VIA robustly and efficiently unravels the fine-grained sub-trajectories in a 1.3-million-cell transcriptomic mouse atlas without losing the global connectivity at such a high cell count. We further apply VIA to discovering elusive lineages and less populous cell fates missed by other methods across a variety of data types, including single-cell proteomic, epigenomic, multi-omics datasets, and a new in-house single-cell morphological dataset.


Persistent racial discrimination among vascular surgery trainees threatens wellness.
Racial/ethnic discrimination is one form of mistreatment and a known risk factor for physician burnout. In the present study, we aimed to characterize the forms and identify the sources of racial/ethnic discrimination among vascular surgery trainees. We performed a cross-sectional study of U.S. vascular surgery trainees who had voluntarily participated in an anonymous survey administered after the 2021 Vascular Surgery In-Training Examination. The primary outcome measures were self-reported mistreatment and sources of mistreatment between race and ethnicity groups. We used χ2 tests and logistic regression for bivariate and multivariable analyses, respectively. Representing all 123 vascular surgery training programs, 510 trainees (66.9% men) participated in the survey (83.6% response rate). Most of the trainees had self-identified as White (53.1%), followed by Asian (24.4%), Hispanic/Latinx (7.6%), Black (4.2%), and other/prefer not to say (10.8%). No significant differences were found in the self-reported duty hour violations among the groups. Black (56.3%) and Asian (36.3%) trainees reported higher rates of racial/ethnic discrimination compared with the White, Hispanic/Latinx, and other/prefer not to say groups (P < .001). Patients and their families were reported as the most common source (74.7%). Other reported sources of discrimination included nurses or staff (60%), attendings (37.4%), co-residents (31.3%), and administration (16.9%). Regarding specific forms of racial discrimination, Black and Asian trainees reported the highest rates of different standards of evaluation (20% and 5.9%, respectively), being mistaken for a nonphysician (50.0% and 5.9%, respectively), slurs and/or hurtful comments (13.3% and 5.9%, respectively), social isolation (13.0% and 1.0%, respectively), and being mistaken for another trainee of the same race/ethnicity (60.0% and 33.7%, respectively). Only 62.5% of Black trainees reported their program/institution would take their mistreatment report seriously compared with the White (88.9%), Hispanic/Latinx (88.2%), Asian (83.2%), and other/prefer not to say (71.4%) trainees (P = .01). On multivariable analysis, female gender (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.44-4.33), Asian race (OR, 6.9; 95% CI, 3.53-13.3), Black race (OR, 13.6; 95% CI, 4.25-43.4), and training in the Southeastern United States (OR, 3.8; 95% CI, 1.17-12.80) were risk factors for racial/ethnic discrimination. The results from the survey revealed that racial/ethnic discrimination persists in surgical training programs, with Asian and Black trainees reporting higher rates than other racial and ethnic groups. Overall, patients and family members were the most common source of racial/ethnic discrimination. However, faculty, staff, and co-trainees also contributed to racial/ethnic discrimination. Further interventions that optimize diversity, equity, and inclusion strategies and policies to address all forms of racial/ethnic discrimination with faculty, staff, and patients within the hospital are critically needed.


[Effect of a levopromazine-thymalin combination on the development of toxic edema and swelling in the brain].
The development of toxic edematous brain swelling in rats is accompanied by disproteinemia of the blood plasma and buildup of the gamma-globulin fraction. The administration of levopromazine (5 mg/kg), thymalin (1.2 mg/kg), or their combination reduces this disorder in the blood protein fractions. The antiedematous effect of the levopromazine--thymalin combination has an additive synergistic interaction.


Laboratory diagnosis of acute measles infections in hospitalized children in Zambia.
Laboratory diagnosis of measles infection is rarely performed in developing countries and tends to depend on clinical symptoms alone. We evaluated detection of immunoglobulin M (IgM) antibodies for confirmation of acute measles infection in Zambia. In 149 hospitalized children with clinical diagnosis of measles, IgM antibodies were detected in 88.6% (132/149). The IgM-positive rate increased with time after onset of skin rash and all samples were positive after 4 days. In addition to IgM antibody test, virus isolations from throat swabs using B95a cells were also performed. These were positive in only 20.9% (14/67), and both IgM and virus isolation in combination increased the positive rate to 92.5% (62/67). Vaccinated children had higher neutralizing (Nt) antibody responses and, among IgM-negative patients, all 4 vaccinated children had high Nt antibodies while all 10 unvaccinated children had negative or low Nt results. The IgM antibody test was proved to be a sensitive method for laboratory confirmation of measles virus infection in developing countries.


Specifically targeted killing of carcinoembryonic antigen (CEA)-expressing cells by a retroviral vector displaying single-chain variable fragmented antibody to CEA and carrying the gene for inducible nitric oxide synthase.
The generation of retroviral vectors that infect specific cell types through recognition of cell surface antigens is a promising and effective approach to targeted gene therapy of cancer. Carcinoembryonic antigen (CEA), a highly characterized, cell surface glycoprotein overexpressed by various tumor cells, provides a specific tool for tumor tissue-specific targeting by retroviral vectors. The conventional suicidal gene delivery systems need additional drugs other than their gene products. The inducible nitric oxide synthase (iNOS) gene product yields nitric oxide (NO), which directly induces autocytotoxicity and cytolysis of bystander cells. In the present study, we have developed a novel bifunctional Moloney murine leukemia virus-based recombinant retroviral vector that displays a chimeric envelope protein containing a single-chain variable fragmented (scFv) antibody to CEA and carries the iNOS gene in the genome. The resultant bifunctional retroviral vector showed a specific delivery of the iNOS gene to human CEA-expressing carcinoma cells, resulting in the direct and efficient killing of CEA-expressing carcinoma cells by induction of apoptosis. This is the first report of successful killing of CEA-expressing cells by specific targeting of the iNOS gene. This approach may offer a one-step procedure for effective gene therapy of CEA-expressing tumors.


Mechanism responsible for altered propranolol disposition in adjuvant-induced arthritis in the rat.
Arthritis was induced in Sprague-Dawley rats by the injection of a heat-killed bacterial suspension into the right hind foot pad. The animals were deemed arthritic if their erythrocyte sedimentation rate was greater than 2 mm/hr. A pithed rat preparation was employed to investigate simultaneously the pharmacokinetics and pharmacodynamics of propranolol in this disease state. Propranolol administered via the hepatic portal vein to simulate oral administration resulted in elevated blood concentrations in the arthritic rats, but the pharmacological effect, measured by the inhibition of an electrically induced tachycardia, was not altered. Propranolol administered iv also resulted in increased blood drug concentrations, but, in addition, the pharmacological effect was decreased. Hepatic blood flow was determined in control and arthritic rats using radiolabeled microspheres, but no change was observed. These results, taken together with previous in vitro studies, suggest that the elevated blood concentrations of propranolol can be attributed to increased plasma protein binding, rather than to decreased hepatic metabolism or altered hepatic blood flow.


Impact of future climate on radial growth of four major boreal tree species in the Eastern Canadian boreal forest.
Immediate phenotypic variation and the lagged effect of evolutionary adaptation to climate change appear to be two key processes in tree responses to climate warming. This study examines these components in two types of growth models for predicting the 2010-2099 diameter growth change of four major boreal species Betula papyrifera, Pinus banksiana, Picea mariana, and Populus tremuloides along a broad latitudinal gradient in eastern Canada under future climate projections. Climate-growth response models for 34 stands over nine latitudes were calibrated and cross-validated. An adaptive response model (A-model), in which the climate-growth relationship varies over time, and a fixed response model (F-model), in which the relationship is constant over time, were constructed to predict future growth. For the former, we examined how future growth of stands in northern latitudes could be forecasted using growth-climate equations derived from stands currently growing in southern latitudes assuming that current climate in southern locations provide an analogue for future conditions in the north. For the latter, we tested if future growth of stands would be maximally predicted using the growth-climate equation obtained from the given local stand assuming a lagged response to climate due to genetic constraints. Both models predicted a large growth increase in northern stands due to more benign temperatures, whereas there was a minimal growth change in southern stands due to potentially warm-temperature induced drought-stress. The A-model demonstrates a changing environment whereas the F-model highlights a constant growth response to future warming. As time elapses we can predict a gradual transition between a response to climate associated with the current conditions (F-model) to a more adapted response to future climate (A-model). Our modeling approach provides a template to predict tree growth response to climate warming at mid-high latitudes of the Northern Hemisphere.


Effect of the Addition of Soluble Dietary Fiber and Green Tea Polyphenols on Acrylamide Formation and In Vitro Starch Digestibility in Baked Starchy Matrices.
Starch digestibility may be affected by food microstructural changes, as well as by specific interactions with some biomolecules, such as soluble dietary fibers (SDFs). It is well-known that acrylamide (AA) is a toxic and potentially carcinogenic compound formed in starchy food products processed at temperatures above 120 °C. This study aimed to investigate the effect of the addition of SDF and green tea polyphenols (GTP) on AA formation and in vitro starch digestibility in baked starchy matrices. The formulations were prepared using gluten and wheat starch, ensuring ~40 ± 2% (wet basis, w.b.) moisture in the doughs. In some samples, 7.5% (dry basis, d.b.) of starch was replaced with inulin (IN), polydextrose (PD) or partially hydrolyzed guar gum (PHGG), and/or with GTP at 1% (d.b). Acrylamide was determined by gas chromatography-mass spectrometry, and the in vitro starch digestibility using the Englyst method. The GTP was able to reduce AA content by ~48%, and a combination of IN-GTP allowed it to be reduced by up to ~64%, revealing the lowest rapidly available glucose content (~17 mg/g glucose). While a PD-GTP mixture reduced the AA content by around ~57% and gave the highest unavailable glucose fraction (~74 mg/g glucose) compared to the control. This study showed how functional ingredients could be used to develop successfully healthier starchy bakery foods.


Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes.
We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure-activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGR5. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGR5 (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13-22% reduction in the area under the blood glucose curve (AUC)0-120 min in oral glucose tolerance tests (OGTT).


Impact of unhealthy lifestyle on cardiorespiratory fitness and heart rate recovery of medical science students.
Medical science students represent valuable labour resources for better future medicine and medical technology. However, little attention was given to the health and well-being of these early career medical science professionals. The aim of this study is to investigate the impact of lifestyle components on cardiorespiratory fitness and heart rate recovery measured after moderate exercise in this population. Volunteers without documented medical condition were recruited randomly and continuously from the first-year medical science students during 2011-2014 at the University of Surrey, UK. Demographics and lifestyle components (the levels of smoking, alcohol intake, exercise, weekend outdoor activity and screen-time, daily sleep period, and self-assessment of fitness) were gathered through pre-exercise questionnaire. Cardiorespiratory fitness (VO2max) and heart rate recovery were determined using Åstrand-Rhyming submaximal cycle ergometry test. Data were analysed using SPSS version 25. Among 614 volunteers, 124 had completed both lifestyle questionnaire and the fitness test and were included for this study. Within 124 participants (20.6 ± 4 years), 46.8% were male and 53.2% were female, 11.3% were overweight and 8.9% were underweight, 8.9% were current smokers and 33.1% consumed alcohol beyond the UK recommendation. There were 34.7% of participants admitted to have < 3 h/week of moderate physical activity assessed according to UK Government National Physical Activity Guidelines and physically not fit (feeling tiredness). Fitness test showed that VO2max distribution was inversely associated with heart rate recovery at 3 min and both values were significantly correlated with the levels of exercise, self-assessed fitness and BMI. Participants who had < 3 h/week exercise, or felt not fit or were overweight had significantly lower VO2max and heart rate recovery than their peers. One in three new medical science students were physically inactive along with compromised cardiorespiratory fitness and heart rate recovery, which put them at risk of cardiometabolic diseases. Promoting healthy lifestyle at the beginning of career is crucial in keeping medical science professionals healthy.


Young, intact and nested retrotransposons are abundant in the onion and asparagus genomes.
Although monocotyledonous plants comprise one of the two major groups of angiosperms and include >65 000 species, comprehensive genome analysis has been focused mainly on the Poaceae (grass) family. Due to this bias, most of the conclusions that have been drawn for monocot genome evolution are based on grasses. It is not known whether these conclusions apply to many other monocots. To extend our understanding of genome evolution in the monocots, Asparagales genomic sequence data were acquired and the structural properties of asparagus and onion genomes were analysed. Specifically, several available onion and asparagus bacterial artificial chromosomes (BACs) with contig sizes >35 kb were annotated and analysed, with a particular focus on the characterization of long terminal repeat (LTR) retrotransposons. The results reveal that LTR retrotransposons are the major components of the onion and garden asparagus genomes. These elements are mostly intact (i.e. with two LTRs), have mainly inserted within the past 6 million years and are piled up into nested structures. Analysis of shotgun genomic sequence data and the observation of two copies for some transposable elements (TEs) in annotated BACs indicates that some families have become particularly abundant, as high as 4-5 % (asparagus) or 3-4 % (onion) of the genome for the most abundant families, as also seen in large grass genomes such as wheat and maize. Although previous annotations of contiguous genomic sequences have suggested that LTR retrotransposons were highly fragmented in these two Asparagales genomes, the results presented here show that this was largely due to the methodology used. In contrast, this current work indicates an ensemble of genomic features similar to those observed in the Poaceae.


Lung clearance index is a repeatable and sensitive indicator of radiological changes in bronchiectasis.
In bronchiectasis there is a need for improved markers of lung function to determine disease severity and response to therapy. To assess whether the lung clearance index is a repeatable and more sensitive indicator of computed tomography (CT) scan abnormalities than spirometry in bronchiectasis. Thirty patients with stable bronchiectasis were recruited and lung clearance index, spirometry, and health-related quality of life measures were assessed on two occasions, 2 weeks apart when stable (study 1). A separate group of 60 patients with stable bronchiectasis was studied on a single visit with the same measurements and a CT scan (study 2). In study 1, the intervisit intraclass correlation coefficient for the lung clearance index was 0.94 (95% confidence interval, 0.89 to 0.97; P < 0.001). In study 2, the mean age was 62 (10) years, FEV1 76.5% predicted (18.9), lung clearance index 9.1 (2.0), and total CT score 14.1 (10.2)%. The lung clearance index was abnormal in 53 of 60 patients (88%) and FEV1 was abnormal in 37 of 60 patients (62%). FEV1 negatively correlated with the lung clearance index (r = -0.51, P < 0.0001). Across CT scores, there was a relationship with the lung clearance index, with little evidence of an effect of FEV1. There were no significant associations between the lung clearance index or FEV1 and health-related quality of life. The lung clearance index is repeatable and a more sensitive measure than FEV1 in the detection of abnormalities demonstrated on CT scan. The lung clearance index has the potential to be a useful clinical and research tool in patients with bronchiectasis.


Distribution of PGP 9.5, TH, NPY, SP and CGRP immunoreactive nerves in the rat and guinea pig atrioventricular valves and chordae tendineae.
The distribution of nerves immunoreactive to protein gene product 9.5 (PGP 9.5), tyrosine hydroxylase (TH), neuropeptide Y (NPY), substance P (SP) and calcitonin gene related peptide (CGRP) antisera was investigated in the atrioventricular valves of the Sprague-Dawley rat and the Dunkin-Hartley guinea pig using confocal and epifluoresence microscopy. No major differences were noted between the innervation of the mitral and tricuspid valves in either species. For all antisera the staining was more extensive in the guinea pig valves. Two distinct nerve plexuses separated by a 'nearly nerve free' zone were identified in both species with each antiserum tested. This was most apparent on the anterior cusp of the mitral valve. The major nerve plexus extends from the atrioventricular ring through the basal, intermediate and distal zones of the valves towards the free edge of the valve cusp. These nerve bundles, arranged as primary, secondary and tertiary components, ramify to the free edge of the valve and extend to the attachment of the chordae. They do not contribute to the innervation of the chordae tendineae. The second, minor chordal plexus, runs from the papillary muscles through the chordae tendineae and passes parallel to the free edge of the cusp. The nerves of this minor plexus are interchordal, branching to terminate mainly in the distal zone, free edge of the valve cusp and adjacent chordae tendineae. Some interchordal nerve fibres loop from a papillary muscle up through a chorda, along the free edge and pass down an adjacent chorda into another papillary muscle. The nerve fibres of the major and minor plexuses intermingle although no evidence was found for interconnectivity between them. In the distal zone between the major plexus which extends from the base of the valve and the minor chordal plexus there is a zone completely free of nerves staining with antisera to TH and NPY. Occasional nerves which stained positive for PGP 9.5, SP and CGRP immunoreactivities crossed this 'nearly nerve free zone' passing either from the chordal/free edge nerves to the intermediate and basal zones or vice versa. An additional small nerve plexus which displayed immunoreactivity to CGRP antiserum extended from the atrioventricular ring into the basal zone of the valve cusp. Not all chordae tendineae displayed immunoreactive nerve fibres. It is concluded that the innervation patterns of the sensory and sympathetic neurotransmitters and neuropeptides examined in the atrioventricular valves of the rat and guinea pig are ubiquitous in nature. The complexity of the terminal innervation network of the mammalian atrioventricular valves and chordae tendineae may contribute to the complex functioning of these valves in the cardiac cycle.


Polyphyllin II Induces Protective Autophagy and Apoptosis via Inhibiting PI3K/AKT/mTOR and STAT3 Signaling in Colorectal Cancer Cells.
Polyphyllin II (PPII) is a natural steroidal saponin occurring in Rhizoma Paridis. It has been demonstrated to exhibit anti-cancer activity against a variety of cancer cells. However, the anti-colorectal cancer (CRC) effects and mechanism of action of PPII are rarely reported. In the present study, we showed that PPII inhibited the proliferation of HCT116 and SW620 cells. Moreover, PPII induced G2/M-phase cell cycle arrest and apoptosis, as well as protective autophagy, in CRC cells. We found that PPII-induced autophagy was associated with the inhibition of PI3K/AKT/mTOR signaling. Western blotting results further revealed that PPII lowered the protein levels of phospho-Src (Tyr416), phospho-JAK2 (Tyr1007/1008), phospho-STAT3 (Tyr705), and STAT3-targeted molecules in CRC cells. The overactivation of STAT3 attenuated the cytotoxicity of PPII against HCT116 cells, indicating the involvement of STAT3 inhibition in the anti-CRC effects of PPII. PPII (0.5 mg/kg or 1 mg/kg, i.p. once every 3 days) suppressed HCT116 tumor growth in nude mice. In alignment with the in vitro results, PPII inhibited proliferation, induced apoptosis, and lowered the protein levels of phospho-STAT3, phospho-AKT, and phospho-mTOR in xenografts. These data suggest that PPII could be a potent therapeutic agent for the treatment of CRC.


Effects of experimental chronic pneumonia on bodyweight, feed intake and carcase composition of lambs.
The growth rate, feed consumption and carcase composition of nine untreated wether lambs (controls) were compared with those of lambs in which a chronic pneumonia had been experimentally induced. Six pneumonic lambs (group 1) were killed with the controls on day 109 and eight (group 2) lambs were killed when they had a similar mean liveweight to the controls (42 kg) on day 172. The mean liveweight gain of infected animals to day 108 was 59 per cent, the mean feed intake 69 per cent and the mean carcase weight of group 1 was 73.5 per cent that of the controls. Group 2 lambs required 25 per cent more feed and nine weeks longer than the controls to reach similar live and carcase weights. This depression of appetite and growth rate was most marked in the first 35 days after inoculation, but growth rates of infected lambs continued to be lower than those of the controls throughout the experiment. At slaughter, all infected lambs had consolidated lesions of pneumonia and a significant correlation was noted between the extent of lung lesions and total liveweight gain in individual lambs. Carcases of group 1 lambs had a proportionately low fat, high lean meat and bone content, indicative of immature development and consistent with a lowered feed intake. Carcases of group 2 lambs showed a similar trend but differences from the controls were not significant.


Impact of neurocognition on social and role functioning in individuals at clinical high risk for psychosis.
Cognitive deficits have been well documented in schizophrenia and have been shown to impair quality of life and to compromise everyday functioning. Recent studies of adolescents and young adults at high risk for developing psychosis show that neurocognitive impairments are detectable before the onset of psychotic symptoms. However, it remains unclear how cognitive impairments affect functioning before the onset of psychosis. The authors assessed cognitive impairment in adolescents at clinical high risk for psychosis and examined its impact on social and role functioning. A sample of 127 treatment-seeking patients at clinical high risk for psychosis and a group of 80 healthy comparison subjects were identified and recruited for research in the Recognition and Prevention Program. At baseline, participants were assessed with a comprehensive neurocognitive battery as well as measures of social and role functioning. Relative to healthy comparison subjects, clinical high-risk patients showed significant impairments in the domains of processing speed, verbal memory, executive function, working memory, visuospatial processing, motor speed, sustained attention, and language. Clinical high-risk patients also displayed impaired social and role functioning at baseline. Among patients with attenuated positive symptoms, processing speed was related to social and role functioning at baseline. These findings demonstrate that cognitive and functional impairments are detectable in patients at clinical high risk for psychosis before the onset of psychotic illness and that processing speed appears to be an important cognitive predictor of poor functioning.


Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy.
To estimate the incidence and describe the characteristics of immune recovery uveitis in patients with acquired immunodeficiency syndrome (AIDS) and cytomegalovirus retinitis treated with highly active antiretroviral therapy. The records of all patients with AIDS and cytomegalovirus retinitis from 1995 to 1998 seen at the AIDS Ophthalmology Service of the Johns Hopkins Medical Institutions were reviewed. Eighty-two patients with cytomegalovirus retinitis treated with highly active antiretroviral therapy were identified. Thirty-three patients (40.2%) were classified as responders to highly active antiretroviral therapy, defined as an increase in CD4+ T-cell count by 50 cells/microL or more to a level of 100 cells/microL or more. Immune recovery uveitis occurred in six patients. Among the 33 patients with an immunologic response to highly active antiretroviral therapy, the incidence rate of immune recovery uveitis was 0.109/person-year. Ocular complications associated with immune recovery uveitis included cystoid macular edema (four patients), epiretinal membranes (two patients), and optic disk neovascularization (one patient). Immune recovery uveitis was uncommon in our population but may have vision-impairing complications.


Shoe collar height effect on athletic performance, ankle joint kinematics and kinetics during unanticipated maximum-effort side-cutting performance.
Side-step cutting manoeuvres comprise the coordination between planting and non-planting legs. Increased shoe collar height is expected to influence ankle biomechanics of both legs and possibly respective cutting performance. This study examined the shoe collar height effect on kinematics and kinetics of planting and non-planting legs during an unanticipated side-step cutting. Fifteen university basketball players performed maximum-effort side-step cutting to the left 45° direction or a straight ahead run in response to a random light signal. Seven successful cutting trials were collected for each condition. Athletic performance, ground reaction force, ankle kinematics and kinetics of both legs were analysed using paired t-tests. Results indicated that high-collar shoes resulted in less ankle inversion and external rotation during initial contact for the planting leg. The high-collar shoes also exhibited a smaller ankle range of motion in the sagittal and transverse planes for both legs, respectively. However, no collar effect was found for ankle moments and performance indicators including cutting performance time, ground contact time, propulsion ground reaction forces and impulses. These findings indicated that high-collar shoes altered ankle positioning and restricted ankle joint freedom movements in both legs, while no negative effect was found for athletic cutting performance.


Early time course of myocardial electrical impedance during acute coronary artery occlusion in pigs, dogs, and humans.
Changes in myocardial electrical impedance (MEI) and physiological end points have been correlated during acute ischemia. However, the importance of MEI's early time course is not clear. This study evaluates such significance, by comparing the temporal behavior of MEI during acute total occlusion of the left anterior descending coronary artery in anesthetized humans, dogs, and pigs. Here, interspecies differences in three MEI parameters (baseline, time to plateau onset, and plateau value normalized by baseline) were evaluated using Kruskal-Wallis ANOVA and post hoc tests (P < 0.05). Noteworthy differences in the MEI time to plateau onset were observed: In dogs, MEI ischemic plateau was reached after 46.3 min (SD 12.9) min of occlusion, a significantly longer period compared with that of pigs and humans [4.7 (SD 1.2) and 4.1 min (SD 1.9), respectively]. However, no differences could be observed between both animal species regarding the normalized MEI ischemic plateau value (15.3% (SD 4.7) in pigs, vs. 19.6% (SD 2.6) in dogs). For all studied MEI parameters, only swine values resembled those of humans. The severity of myocardial supply ischemia, resulting from coronary artery occlusion, is known to be dependent on collateral flow. Thus, because dogs possess a well-developed collateral system (unlike humans or pigs), they have shown superior resistance to occlusion of a coronary artery. Here, the early MEI time course after left anterior descending coronary artery occlusion, represented by the time required to reach ischemic plateau, was proven to reflect such interspecies differences.


Evaluating the Prospects of Ti-Base Lattice Infiltrated with Biodegradable Zn-2%Fe Alloy as a Structural Material for Osseointegrated Implants-In Vitro Study.
The term "osseointegrated implants" mainly relates to structural systems that contain open spaces, which enable osteoblasts and connecting tissue to migrate during natural bone growth. Consequently, the coherency and bonding strength between the implant and natural bone can be significantly increased, for example in operations related to dental and orthopedic applications. The present study aims to evaluate the prospects of a Ti-6Al-4V lattice, produced by selective laser melting (SLM) and infiltrated with biodegradable Zn2%Fe alloy, as an OI-TiZn system implant in in vitro conditions. This combined material structure is designated by this study as an osseointegrated implant (OI-TiZn) system. The microstructure of the tested alloys was examined both optically and using scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis. The mechanical properties were assessed in terms of compression strength, as is commonly acceptable in cases of lattice-based structures. The corrosion performance was evaluated by immersion tests and electrochemical analysis in terms of potentiodynamic polarization and electrochemical impedance spectroscopy (EIS), all in simulated physiological environments in the form of phosphate buffered saline (PBS) solution. The cytotoxicity was evaluated in terms of indirect cell viability. The results obtained demonstrate the adequate performance of the OI-TiZn system as a non-cytotoxic structural material that can maintain its mechanical integrity under compression, while presenting acceptable corrosion rate degradation.


Receptors, gephyrin and gephyrin-associated proteins: novel insights into the assembly of inhibitory postsynaptic membrane specializations.
The synaptic localization of ion channel receptors is essential for efficient synaptic trans-mission and the precise regulation of diverse neuronal functions, such as signal integration and synaptic plasticity. Emerging evidence points to an important role of cytoskeleton-associated proteins that assemble receptors and components of the subsynaptic machinery at postsynaptic membrane specializations. This article reviews interactions of inhibitory postsynaptic neurotransmitter receptors with the receptor anchoring protein gephyrin and intracellular components involved in downstream signalling and/or control of signal transduction processes. The presently available data suggest a central synaptic organizer function for gephyrin in inhibitory postsynaptic membrane assembly and stabilization.


Investing in HIV services while building Kenya's health system: PEPFAR's support to prevent mother-to-child HIV transmission.
Trade-offs may exist between investments to promote health system strengthening, such as investments in facilities and training, and the rapid scale-up of HIV/AIDS services. We analyzed trends in expenditures to support the prevention of mother-to-child transmission of HIV in Kenya under the President's Emergency Plan for AIDS Relief (PEPFAR) from 2005 to 2010. We examined how expenditures changed over time, considering health system strengthening alongside direct treatment of patients. We focused on two organizations carrying out contracts under PEPFAR: the Elizabeth Glaser Pediatric AIDS Foundation and FHI360 (formerly Family Health International), a nonprofit health and development organization. We found that the average unit expenditure, or the spending on goods and services per mother living with HIV who was provided with antiretroviral drugs, declined by 52 percent, from $567 to $271, during this time period. The unit expenditure per mother-to-infant transmission averted declined by 66 percent, from $7,117 to $2,440. Meanwhile, the health system strengthening proportion of unit expenditure increased from 12 percent to 33 percent during the same time period. The analysis suggests that PEPFAR investments in prevention of mother-to-child transmission of HIV in Kenya became more efficient over time, and that there was no strong evidence of a trade-off between scaling up services and investing in health systems.


Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin.
Serotonin is a major neurotransmitter in the central nervous system (CNS). Dysregulation of serotonin transmission in the CNS is reported to be related to different psychiatric disorders in humans including depression, impulsive aggression and anxiety disorders. The most frequently prescribed antidepressants and anxiolytics target the serotonergic system. However, these drugs are not effective in 20-30% of cases. The causes of this failure as well as the molecular mechanisms involved in the origin of psychological disorders are poorly understood. Biosynthesis of serotonin in the CNS is initiated by tryptophan hydroxylase 2 (TPH2). In this study, we used Tph2-deficient (Tph2(-/-)) mice to evaluate the impact of serotonin depletion in the brain on mouse behavior. Tph2(-/-) mice exhibited increased depression-like behavior in the forced swim test but not in the tail suspension test. In addition, they showed decreased anxiety-like behavior in three different paradigms: elevated plus maze, marble burying and novelty-suppressed feeding tests. These phenotypes were accompanied by strong aggressiveness observed in the resident-intruder paradigm. Despite carrying only one copy of the gene, heterozygous Tph2(+/-) mice showed only 10% reduction in brain serotonin, which was not sufficient to modulate behavior in the tested paradigms. Our findings provide unequivocal evidence on the pivotal role of central serotonin in anxiety and aggression.


The opinion of patients with inflammatory bowel disease on healthcare received.
an item to consider in analyzing a healthcare model for a population group suffering from chronic disease is necessary health-care resources, their use, and their rating by end-users. Regarding inflammatory bowel disease (IBD), healthcare resources used by patients are numerous and varied, and yet they have been never assessed. an anonymous self-rated questionnaire has been developed with 24 basic questions on overall disease, who is monitoring the patient, how are visits scheduled, need for urgent care, patient view on how control may be improved, etc. This questionnaire was sent to 393 patients who were asked to fill it out and then return it by mail. two hundred and thirty-seven patients returned a filled-out questionnaire. Most patients were followed up in a hospital, and only 8.8% were being monitored by a general practitioner or area specialist. Ninety-two percent of patients reported visits were routinely scheduled irrespective of clinical status, and 79.6% of patients reported having occasionally presented to an emergency department, because of not knowing what to do or due to having no other resources available in 25.2% of times. This entails that 38% of visits to an emergency unit may be prevented with a better understanding of disease or by means of a phone call. Thirty percent of patients reported that current healthcare is inadequate in terms of contents, form, or waiting time. In all, 97.8% of patients feel that information and knowledge on their disease would help in its control, and 69.6% consider that adequate information would allow them to initiate a proper treatment before visiting their doctor. Family care is another poorly looked-after aspect that 74.6% of subjects believe would be of help in controlling their disease. overall, the opinion of patients with IBD on healthcare received is good; however, a number of deficiencies were detected, as is the case with insufficient information, care of family members, and healthcare resources accessibility/agility.


Controlled microwave heating in modern organic synthesis.
Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of "microwave flash heating" in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.


Antithrombotic strategies after transcatheter aortic valve implantation: Insights from a network meta-analysis.
We aimed to investigate the efficacy and safety of different antithrombotic strategies in patients undergoing transcatheter aortic valve implantation (TAVI) using network meta-analyses. Meta-analyses comparing single antiplatelet therapy (SAPT) vs. dual antiplatelet therapy (DAPT), ± oral anticoagulant (OAC) was conducted to determine the appropriate post TAVI antithrombotic regimen. However, there was limited direct comparisons across the different therapeutic strategies. MEDLINE and EMBASE were searched through December 2018 to investigate the efficacy and safety of different antithrombotic strategies (SAPT, DAPT, OAC, OAC + SAPT, and OAC + DAPT) in patients undergoing TAVI. The main outcome were all-cause mortality, major or life-threatening bleeding events, and stroke. Our search identified 3 randomized controlled trials and 10 nonrandomized studies, a total of 20,548 patients who underwent TAVI. All OACs were vitamin K antagonists. There was no significant difference on mortality except that OAC + DAPT had significantly higher rates of mortality compared with others (p < .05, I2 = 0%). SAPT had significantly lower rates of bleeding compared with DAPT, OAC+SAPT, and OAC+DAPT (hazard ratio [HR]: 0.59 [0.46-0.77], p < .001, HR: 0.58 [0.34-0.99], p = .045, HR: 0.41 [0.18-0.93], p = .033, respectively, I2 = 0%). There was no significant difference on stroke among all antithrombotic strategies. Patients who underwent TAVI had similar all-cause mortality rates among different antithrombotic strategies except OAC+DAPT. Patients on SAPT had significantly lower bleeding risk than those on DAPT, OAC + SAPT, and OAC + DAPT. Our results suggest SAPT is the preferred regimen when there is no indication for DAPT or OAC. When DAPT or OAC is indicated, DAPT + OAC should be avoided.


Aridity promotes bet hedging via delayed hatching: a case study with two temporary pond crustaceans along a latitudinal gradient.
Climate change does affect not only average rainfall and temperature but also their variation, which can reduce the predictability of suitable conditions for growth and reproduction. This situation is problematic for inhabitants of temporary waters whose reproductive success depends on rainfall and evaporation that determine the length of the aquatic phase. For organisms with long-lived dormant life stages, bet hedging models suggest that a fraction of these should stay dormant during each growing season to buffer against the probability of total reproductive failure in variable environments. Thus far, however, little empirical evidence supports this prediction in aquatic organisms. We study geographic variation in delayed hatching of dormant eggs in natural populations of two crustaceans, Branchinella longirostris and Paralimnadia badia, that occur in temporary rock pools along a 725 km latitudinal aridity gradient in Western Australia. Consistent with bet hedging theory, populations of both species were characterised by delayed hatching under common garden conditions and hatching fractions decreased towards the drier end of the gradient where the probability of reproductive success was shown to be lower. This decrease was most pronounced in the species with the longer maturation time, presumably because it is more sensitive to the higher prevalence of short inundations. Overall, these findings illustrate that regional variation in climate can be reflected in differential investment in bet hedging and hints at a higher importance of delayed hatching to persist when the climate becomes harsher. Such strategies could become exceedingly relevant as determinants of vulnerability under climate change.


Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection.
An effective therapeutic vaccine that could augment immune control of HIV-1 replication may abrogate or delay the need for antiretroviral therapy. AIDS Clinical Trials Group (ACTG) A5187 was a phase I/II, randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of an HIV-1 DNA vaccine (VRC-HVDNA 009-00-VP) in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. (clinicaltrials.gov NCT00125099) Twenty healthy HIV-1 infected subjects who were treated with antiretroviral therapy during acute/early HIV-1 infection and had HIV-1 RNA<50 copies/mL were randomized to receive either vaccine or placebo. The objectives of this study were to evaluate the safety and immunogenicity of the vaccine. Following vaccination, subjects interrupted antiretroviral treatment, and set-point HIV-1 viral loads and CD4 T cell counts were determined 17-23 weeks after treatment discontinuation. Twenty subjects received all scheduled vaccinations and discontinued antiretroviral therapy at week 30. No subject met a primary safety endpoint. No evidence of differences in immunogenicity were detected in subjects receiving vaccine versus placebo. There were also no significant differences in set-point HIV-1 viral loads or CD4 T cell counts following treatment discontinuation. Median set-point HIV-1 viral loads after treatment discontinuation in vaccine and placebo recipients were 3.5 and 3.7 log(10) HIV-1 RNA copies/mL, respectively. The HIV-1 DNA vaccine (VRC-HIVDNA 009-00-VP) was safe but poorly immunogenic in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. Viral set-points were similar between vaccine and placebo recipients following treatment interruption. However, median viral load set-points in both groups were lower than in historical controls, suggesting a possible role for antiretroviral therapy in persons with acute or early HIV-1 infection and supporting the safety of discontinuing treatment in this group. Clinicaltrials.gov NCT00125099.


The Adherence Estimator: a brief, proximal screener for patient propensity to adhere to prescription medications for chronic disease.
To conceptualize, develop, and provide preliminary psychometric evidence for the Adherence Estimator--a brief, three-item proximal screener for the likelihood of non-adherence to prescription medications (medication non-fulfillment and non-persistence) for chronic disease. Qualitative focus groups with 140 healthcare consumers and two internet-based surveys of adults with chronic disease, comprising a total of 1772 respondents, who were self-reported medication adherers, non-persisters, and non-fulfillers. Psychometric tests were performed on over 150 items assessing 14 patient beliefs and skills hypothesized to be related to medication non-adherence along a proximal-distal continuum. Psychometric tests included, but were not limited to, known-groups discriminant validity at the scale and item level. The psychometric analyses sought to identify: (1) the specific multi-item scales that best differentiated self-reported adherers from self-reported non-adherers (non-fulfillers and non-persisters) and, (2) the single best item within each prioritized multi-item scale that best differentiated self-reported adherers from self-reported non-adherers (non-fulfillers and non-persisters). The two rounds of psychometric testing identified and cross-validated three proximal drivers of self-reported adherence: perceived concerns about medications, perceived need for medications, and perceived affordability of medications. One item from each domain was selected to include in the Adherence Estimator using a synthesis of psychometric results gleaned from classical and modern psychometric test theory. By simple summation of the weights assigned to the category responses of the three items, a total score is obtained that is immediately interpretable and completely transparent. Patients can be placed into one of three segments based on the total score--low, medium, and high risk for non-adherence. Sensitivity was 88%--of the non-adherers, 88% would be accurately classified as medium or high risk by the Adherence Estimator. The three risk groups differed on theoretically-relevant variables external to the Adherence Estimator in ways consistent with the hypothesized proximal-distal continuum of adherence drivers. The three-item Adherence Estimator measures three proximal beliefs related to intentional non-adherence (medication non-fulfillment and non-persistence). Preliminary evidence of the validity of the Adherence Evidence supports its intended use to segment patients on their propensity to adhere to a newly-prescribed prescription medication. The Adherence Estimator is readily scored and is easily interpretable. Due to its brevity and transparency, it should prove to be practical for use in everyday clinical practice and in disease management for adherence quality improvement. Study limitations related to sample representation and self reports of chronic disease and adherence behaviors were discussed.


Classification of eastward propagating waves on the spherical Earth.
Observational evidence for an equatorial non-dispersive mode propagating at the speed of gravity waves is strong, and while the structure and dispersion relation of such a mode can be accurately described by a wave theory on the equatorial β-plane, prior theories on the sphere were unable to find such a mode except for particular asymptotic limits of gravity wave phase speeds and/or certain zonal wave numbers. Here, an ad hoc solution of the linearized rotating shallow-water equations (LRSWE) on a sphere is developed, which propagates eastward with phase speed that nearly equals the speed of gravity waves at all zonal wave numbers. The physical interpretation of this mode in the context of other modes that solve the LRSWE is clarified through numerical calculations and through eigenvalue analysis of a Schrödinger eigenvalue equation that approximates the LRSWE. By comparing the meridional amplitude structure and phase speed of the ad hoc mode with those of the lowest gravity mode on a non-rotating sphere we show that at large zonal wave number the former is a rotation-modified counterpart of the latter. We also find that the dispersion relation of the ad hoc mode is identical to the n = 0 eastward propagating inertia-gravity (EIG0) wave on a rotating sphere which is also nearly non-dispersive, so this solution could be classified as both a Kelvin wave and as the EIG0 wave. This is in contrast to Cartesian coordinates where Kelvin waves are a distinct wave solution that supplements the EIG0 mode. Furthermore, the eigenvalue equation for the meridional velocity on the β-plane can be formally derived as an asymptotic limit (for small (Lamb Number)-1/4) of the corresponding second order equation on a sphere, but this expansion is invalid when the phase speed equals that of gravity waves i.e. for Kelvin waves. Various expressions found in the literature for both Kelvin waves and inertia-gravity waves and which are valid only in certain asymptotic limits (e.g. slow and fast rotation) are compared with the expressions found here for the two wave types.


Image cytometric method for quantifying the relative amount of DNA in bacterial nucleoids using Escherichia coli.
An image cytometric method for quantifying integrated fluorescence was developed to measure the relative DNA contents of bacterial nucleoids. Image analysis was performed with newly developed macros in combination with the program Object-Image, all downloadable from http://simon.bio.uva.nl/object-image.html. Four aspects of the method were investigated. (i) Good linearity was found over a ten-fold range of fluorescence intensity in a test with a calibration kit of fluorescent latex spheres. (ii) The accuracy of the method was tested with a narrowly distributed Escherichia coli population, which was obtained by growing cells into stationary phase. The width of the image cytometric distribution was approximately 6%, in good agreement with results obtained by flow cytometry. (iii) The error contribution of manual focusing could be kept below 2%, although a strong dependency between integrated fluorescence and focus position was observed. (iv) The results were verified with a flow cytometer, which gave similar distributions for the DNA contents per cell expressed in chromosome equivalents (4.8 fg of DNA). We used the presented method to evaluate whether the DNA conformation had any effect on the total fluorescence of bacterial nucleoids. Experiments using nucleoids with the same amount of DNA in either a dispersed or a compact conformation showed no significant difference in integrated fluorescence, indicating that it is possible to determine the DNA content per nucleoid independently of the actual organization of the DNA.


Interaction of AnxA6 with isolated and artificial lipid microdomains; importance of lipid composition and calcium content.
Niemann-Pick type C (NPC) disease is a lipid storage disorder characterized by accumulation of lipids in the late endosome/lysosome (LE/LY) compartment. In our previous report we isolated membranes of the LE/LY compartment from NPC L1 skin fibroblasts with a mutation in the NPC1 gene and found that they were characterized by low fluidity which likely contributed to the impaired function of membrane proteins involved in storage and turnover of cholesterol. In this report we isolated lipid microdomains (DRMs) from membranes of various cellular compartments and observed an increased amount of DRMs in the LE/LY compartment of NPC L1 cells in comparison to control cells, with no change in the DRM content in the plasma membrane. In addition, in the NPC cells, the majority of the cholesterol-interacting protein, AnxA6, which participates in the transport and distribution of cholesterol, translocated to DRMs upon a rise in Ca(2+) concentration. The mechanism of this translocation was further studied in vitro using Langmuir monolayers. We found that Ca(2+) is the main factor which regulates the interaction of AnxA6 with monolayers composed of neutral lipids, such as DPPC and sphingomyelin, and may also determine AnxA6 localization in cholesterol and sphingomyelin enriched microdomains, thus contributing to the etiology of the NPC disease.


Unplanned Admissions, Emergency Department Visits, and Epilepsy After Critical Neurological Illness Requiring Prolonged Mechanical Ventilation in Children.
Long-term outcomes after pediatric neurocritical illness are poorly characterized. This study aims to characterize the frequency and risk factors for post-discharge unplanned health resource use in a pediatric neurocritical care population using insurance claims data. Retrospective cohort study evaluating children who survived a hospitalization for an acute neurologic illness or injury requiring mechanical ventilation for >72 hours and had insurance eligibility in Colorado's All Payers Claims database. Insurance claims identified unplanned readmissions and emergency department [ED] visits during the post-discharge year. For patients without pre-existing epilepsy/seizures, we evaluated for post-ICU epilepsy identified by claim(s) for a maintenance anti-seizure medication during months 6-12 post-discharge. Multivariable logistic regression identified factors associated with each outcome. 101 children, median age 3.7 years (interquartile range (IQR) .4-11.9), admitted for trauma (57%), hypoxic-ischemic injury (17%) and seizures (15%). During the post-discharge year, 4 (4%) patients died, 26 (26%) were readmitted, and 48 (48%) had an ED visit. Having a pre-existing complex chronic condition was independently associated with readmission and emergency department visit. Admission for trauma was protective against readmission. Of those without pre-existing seizures (n = 86), 25 (29%) developed post-ICU epilepsy. Acute seizures during admission and prolonged ICU stays were independently associated with post-ICU epilepsy. Survivors of pediatric neurocritical illness are at risk of unplanned healthcare use and post-ICU epilepsy. Critical illness risk factors including prolonged ICU stay and acute seizures may identify cohorts for targeted follow up or interventions to prevent unplanned healthcare use and post-ICU epilepsy.


Localization of brain electrical activity via linearly constrained minimum variance spatial filtering.
A spatial filtering method for localizing sources of brain electrical activity from surface recordings is described and analyzed. The spatial filters are implemented as a weighted sum of the data recorded at different sites. The weights are chosen to minimize the filter output power subject to a linear constraint. The linear constraint forces the filter to pass brain electrical activity from a specified location, while the power minimization attenuates activity originating at other locations. The estimated output power as a function of location is normalized by the estimated noise power as a function of location to obtain a neural activity index map. Locations of source activity correspond to maxima in the neural activity index map. The method does not require any prior assumptions about the number of active sources of their geometry because it exploits the spatial covariance of the source electrical activity. This paper presents a development and analysis of the method and explores its sensitivity to deviations between actual and assumed data models. The effect on the algorithm of covariance matrix estimation, correlation between sources, and choice of reference is discussed. Simulated and measured data is used to illustrate the efficacy of the approach.


The cellular origin of glyoxysomal proteins in germinating castor-bean endosperm.
The capacity of castor-bean endosperm tissue to incorporate [35S]methionine into proteins of the total particulate fraction increased during the first 3 days of germination and subsequently declined. At the onset of germination 66% of the incorporated 35S was found in the separated endoplasmic-reticulum fraction, with the remainder in mitochondria, whereas at later developmental stages an increasing proportion of 35S was recovered in glyoxysomes. The kinetics of [35S]methionine incorporation into the major organelle fractions of 3-day-old endosperm tissue showed that the endoplasmic reticulum was immediately labelled, whereas a lag period preceded the labelling of mitochondria and glyoxysomes. When kinetic experiments were interrupted by the addition of an excess of unlabelled methionine, incorporation of [35S]methionine into the endoplasmic reticulum rapidly ceased, but incorporation into mitochondia and glyoxysomes continued for a further 1h. Examination of isolated organelle membranes during this period showed that the addition of unlabelled methionine resulted in a stimulated incorporation of [35S]no methionine into the endoplasmic-reticulum membrane for 30 min, after which time the 35S content of this fraction declined, whereas that of the glyoxysomal membranes continued to increase slowly. The 35S-labelling kinetics of organelles and fractions derived therefrom are discussed in relation to the role of the endoplasmic reticulum in protein synthesis during glyoxysome biogenesis.


Host cell factors in filovirus entry: novel players, new insights.
Filoviruses cause severe hemorrhagic fever in humans with high case-fatality rates. The cellular factors exploited by filoviruses for their spread constitute potential targets for intervention, but are incompletely defined. The viral glycoprotein (GP) mediates filovirus entry into host cells. Recent studies revealed important insights into the host cell molecules engaged by GP for cellular entry. The binding of GP to cellular lectins was found to concentrate virions onto susceptible cells and might contribute to the early and sustained infection of macrophages and dendritic cells, important viral targets. Tyrosine kinase receptors were shown to promote macropinocytic uptake of filoviruses into a subset of susceptible cells without binding to GP, while interactions between GP and human T cell Ig mucin 1 (TIM-1) might contribute to filovirus infection of mucosal epithelial cells. Moreover, GP engagement of the cholesterol transporter Niemann-Pick C1 was demonstrated to be essential for GP-mediated fusion of the viral envelope with a host cell membrane. Finally, mutagenic and structural analyses defined GP domains which interact with these host cell factors. Here, we will review the recent progress in elucidating the molecular interactions underlying filovirus entry and discuss their implications for our understanding of the viral cell tropism.


How fisheries management can benefit from genomics?
Fisheries genomics is an emerging field that advocates the application of genomic tools to address questions in fisheries management. Genomic approaches bring a new paradigm for fisheries management by making it possible to integrate adaptive diversity to understand fundamental aspects of fisheries resources. Hence, this review is focused on the relevance of genomic approaches to solve fisheries-specific questions. Particularly the detection of adaptive diversity (outlier loci) provides unprecedented opportunity to understand bio-complexity, increased power to trace processed sample origin to allow enforcement and the potential to understand the genetic basis of micro-evolutionary effects of fisheries-induced evolution and climate change. The understanding of adaptive diversity patterns will be the cornerstone of the future links between fisheries and genomics. These studies will help stakeholders anticipate the potential effects of fishing or climate change on the resilience of fisheries stocks; consequently, in the near future, fisheries sciences might integrate evolutionary principles with fisheries management.


Interaction of body mass index and diabetes as modifiers of cardiovascular mortality in a cohort study.
Diabetes and obesity each increases mortality, but recent papers have shown that lean Asian persons were at greater risk for mortality than were obese persons. The objective of this study is to determine whether an interaction exists between body mass index (BMI) and diabetes, which can modify the risk of death by cardiovascular disease (CVD). Subjects who were over 20 years of age, and who had information regarding BMI, past history of diabetes, and fasting blood glucose levels (n=16 048), were selected from the Korea Multi-center Cancer Cohort study participants. By 2008, a total of 1290 participants had died; 251 and 155 had died of CVD and stroke, respectively. The hazard for deaths was calculated with hazard ratio (HR) and 95% confidence interval (95% CI) by Cox proportional hazard model. Compared with the normal population, patients with diabetes were at higher risk for CVD and stroke deaths (HR, 1.84; 95% CI, 1.33 to 2.56; HR, 1.82; 95% CI, 1.20 to 2.76; respectively). Relative to subjects with no diabetes and normal BMI (21 to 22.9 kg/m(2)), lean subjects with diabetes (BMI <21 kg/m(2)) had a greater risk for CVD and stroke deaths (HR, 2.83; 95% CI, 1.57 to 5.09; HR, 3.27; 95% CI, 1.58 to 6.76; respectively), while obese subjects with diabetes (BMI ≥25 kg/m(2)) had no increased death risk (p-interaction <0.05). This pattern was consistent in sub-populations with no incidence of hypertension. This study suggests that diabetes in lean people is more critical to CVD deaths than it is in obese people.


KNOWLEDGE ABOUT THE BENEFITS OF BREASTFEEDING AND DISADVANTAGES OF THE PACIFIER RELATED TO THE MOTHER'S PRACTICE WITH PRETERM INFANTS.
To evaluate the knowledge and expectations of mothers of preterm newborn infants admitted in a neonatal intensive care unit about breastfeeding and pacifier use, and to analyze their experience in dealing with the sucking urge in the first months of life. Mothers were interviewed during hospitalization of the newborn in the neonatal intensive care unit and when the infant was six months old. All mothers with availability to participate in the study were included. Exclusion criteria comprised infants with syndromes and neurological disorders and mothers with cognitive impairment, depression, and drug users. Data were analyzed with the SPSS software, with descriptive statistics and chi-square test. Sixty-two mothers were interviewed in the beginning and 52 at a six-month follow-up. Mothers' expectations concerning breastfeeding were positive when they listed the benefits to the mother (90.3%) and infant (100%). However, they had difficulties maintaining exclusive breastfeeding and used the baby bottle (75.0%), which most mothers (69.4%) had already acquired before the infant was born. The fact of having a pacifier in the infant's layette (43.6%) did not influence its use (p=0.820). This also occurred among mothers who said they would not offer the pacifier due to disadvantages to the mother (80.7%) and infant (96.8%). The previous expectation that the pacifier could bring benefits for mother and infant did not affect its use (p=0.375 and p=0.158). Mothers demonstrated prior knowledge about breastfeeding benefits and disadvantages of the pacifiers. However, they changed their view when dealing with the infant and introduced bottles and pacifiers.


Assessing HIV acquisition risks among men who have sex with men in the United States of America.
Men who have sex with men (MSM) can reduce their risk of acquiring human immunodeficiency virus (HIV) by using various prevention strategies and by understanding the effectiveness of each option over the short- and long-term. Strategies examined were: circumcision; insertive anal sex only; consistent, 100% self-reported condom use; and pre-exposure prophylaxis (PrEP). PrEP efficacy was based on three levels of adherence. The cumulative HIV acquisition risk among MSM over periods of 1 year and 10 years were estimated with and without single and combinations of prevention strategies. A Bernoulli process model was used to estimate risk. In the base case with no prevention strategies, the 1-year risk of HIV acquisition among MSM was 8.8%. In contrast, the 1-year risk associated with circumcision alone was 6.9%; with insertive sex only, 5.5%; with 100% self-reported condom use, 2.7%; and with average, high, and very high PrEP adherence, 5.1%, 2.5%, and 0.7%, respectively. The 10-year risk of HIV acquisition among MSM with no prevention strategy was 60.3%. In contrast, that associated with circumcision alone was 51.1%; with insertive sex only, 43.1%; with 100% self-reported condom use, 24.0%; and with average, high, and very high PrEP adherence, 40.5%, 22.2%, and 7.2%, respectively. While MSM face substantial risk of HIV, there are now a number of prevention strategies that reduce risk. Very high adherence to PrEP alone or with other strategies appears to be the most powerful tool for HIV prevention.


Studies on pleuromutilin and some of its derivatives.
A number of derivatives of pleuromutilin (I) and of its degradation product, mutilin (II1, was prepared. The new monotosylation product of pleuromutilin (IIIc) served as the key substance for modification of the glycolic acid side chain. From the pleuromutilin monosuccinate (IIIk) water-soluble salts were obtained, among them the crystallized diethylaminoethanol salt that was investigated more closely. Some of the pleuromutilin derivatives showed antimicrobial activity.


Necrotizing enterocolitis. Controlled study of 3 years' experience in a neonatal intensive care unit.
During the 3 years 1972-74, 17 infants were treated for necrotizing enterocolitis (NEC) in the Neonatal Unit at University College Hospital. The incidence of the illness was 0.2% of live births in the hospital and 2.7% of those referred from elsewhere. The mean birthweight of the affected infants was 1832 g (range 878-3850 g) and mean gestational age 33 weeks (range 28-40 weeks). The illness was diagnosed at a mean age of 16 days (range 3-33 days). 14 infants (82%) survived. One infant developed NEC because of a volvulus, and another because of an apparently abnormal arterial supply to a segment of bowel. Each of the remaining 15 infants was matched with 3 control infants in order to see whether any factors predisposing to the development of NEC could be identified. Birth asphysia, the use of umbilical catheters, the length of time that these catheters were in place, and complications of catheterization were all significantly more frequent in the infants who developed NEC than in the controls. These findings support the view that hypoxia and ischaemia of the gut wall are important in the pathogenesis of NEC.


Virtual reality implementation in neurosurgical practice: the "can't take my eyes off you" effect.
During the last few years, virtual reality (VR) has been increasingly implemented in the neurosurgical practice. The scope of this paper is to briefly outline the educational role of this novel technology in training surgeons. At the same time, the ability of VR workstations such as the Dextroscope® to consistently simulate the surgical trajectory to the lesion-target is highlighted. The authors shed light to the current applications of VR systems in the neurosurgical field by describing not only the advantages of those systems, but their principal drawbacks as well. It seems that VR has come to stay and it is already the new best friend of residents due to its "Can't take my eyes off you effect".


Activation domain-mediated targeting of the SWI/SNF complex to promoters stimulates transcription from nucleosome arrays.
The yeast SWI/SNF complex is required for the transcription of several yeast genes and has been shown to alter nucleosome structure in an ATP-dependent reaction. In this study, we show that the complex stimulated in vitro transcription from nucleosome templates in an activation domain-dependent manner. Transcription stimulation by SWI/SNF required an activation domain with which it directly interacts. The acidic activation domains of VP16, Gcn4, Swi5, and Hap4 interacted directly with the purified SWI/SNF complex and with the SWI/SNF complex in whole-cell extracts. The similarity of activation domain interactions and transcriptional stimulation between SWI/SNF and the SAGA histone acetyltransferase complex may account for their apparent overlapping functions in vivo.


HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral.
Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4-4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.


Fungal Cultivars of Higher Attine Ants Promote Escovopsis Chemotropism.
In varied environments, microorganisms search for partners or nutritional resources using chemical signals. Microbes are drawn (chemotaxis) or grow directionally (chemotropism) towards the chemical source, enabling them to establish and maintain symbiosis. The hypocrealean fungi Escovopsis enhance their growth towards the basidiomycete fungus Leucoagaricus gongylophorus, which is cultivated by leaf-cutting attine ants for food. Although directional growth is well documented in this symbiosis, it is unclear whether non-volatile or volatile organic compounds participate in the interaction between cultivar and Escovopsis, and which specific chemical compounds might attract and induce chemotropism. In this study, we examined the growth responses of Escovopsis isolates to non-volatile and volatile organic compounds produced by fungal cultivars of higher attine ants. We also isolated and identified molecules released by the ant-cultivar and assessed the chemotropism of Escovopsis towards them. Our results indicate that the growth of Escovopsis is stimulated in the presence of both non-volatile and volatile compounds from fungal cultivars. We also identified three isomeric diketopiperazines molecules from crude extracts of the ant cultivar, suggesting that these might play a role in Escovopsis chemotropism. Our findings provide insights into the complex chemical interactions that govern the association between Escovopsis and fungal cultivars.


Intestinal anti-inflammatory activity of xique-xique (Pilosocereus gounellei A. Weber ex K. Schum. Bly. Ex Rowl) juice on acetic acid-induced colitis in rats.
Inflammatory bowel disease (IBD) is characterized by severe mucosal damage in the intestine and a deregulated immune response. Natural products derived from plants that are rich in bioactive compounds are used by many patients with IBD. Xique-xique (Pilosocereus gounellei) is a cactus of the Caatinga family that has been used by the local population for food and medicinal purposes. The intestinal anti-inflammatory effect of xique-xique cladode juice was evaluated in the present study. A dose of 5 mL kg-1 had a protective effect on intestinal inflammation, with an improvement in macroscopic damage, and a decrease in pro-inflammatory markers and oxidative stress, in addition to preserving the colonic tissue. Immunohistochemical analysis revealed the downregulation of IL-17, NF-κB, and iNOS, and upregulation of SOCs-1, ZO-1, and MUC-2. These protective effects could be attributed to the phenolic compounds as well as the fibers present in xique-xique juice. Further studies are needed before suggesting the use of xique-xique juice as a new alternative for treating IBD.


Engineering of the hydrophobic core of an alpha-helical coiled coil.
The amino acid sequence that forms the alpha-helical coiled coil structure has a representative heptad repeat denoted by defgabc, according to their positions. Although the a and d positions are usually occupied by hydrophobic residues, hydrophilic residues at these positions sometimes play important roles in natural proteins. We have manipulated a few amino acids at the a and d positions of a de novo designed trimeric coiled coil to confer new functions to the peptides. The IZ peptide, which has four heptad repeats and forms a parallel triple-stranded coiled coil, has Ile at all of the a and d positions. We show three examples: (1) the substitution of one Ile at either the a or d position with Glu caused the peptide to become pH sensitive; (2) the metal ion induced alpha-helical bundles were formed by substitutions with two His residues at the d and a positions for a medium metal ion, and with one Cys residue at the a position for a soft metal ion; and (3) the AAB-type heterotrimeric alpha-helical bundle formation was accomplished by a combination of Ala and Trp residues at the a positions of different peptide chains. Furthermore, we applied these procedures to prepare an ABC-type heterotrimeric alpha-helical bundle and a metal ion-induced heterotrimeric alpha-helical bundle.


Cardiovascular changes in children with obstructive sleep apnea and obesity after treatment with noninvasive ventilation.
Adults with obesity and obstructive sleep apnea (OSA) are at risk for cardiometabolic disease, and this risk likely extends to children with both conditions. Noninvasive ventilation (NIV; including continuous and bilevel positive airway pressure) is often used to treat OSA in children with obesity. The aim of this study was to examine the impact of NIV treatment on heart rate variability (HRV), as a marker of cardiovascular risk, in children with obesity and newly diagnosed OSA. A prospective multicenter cohort study was conducted in children with obesity prescribed NIV therapy for newly diagnosed moderate-severe OSA. Measurements of HRV were derived from polysomnography recordings at baseline and after 12 months of treatment. HRV parameters were examined by sleep stage, before and after arousal and oxygen desaturation events. HRV parameters were compared between time points using pair t tests as well as mixed model analysis. Twelve children had appropriate data for analysis at baseline and 12 months. Heart rate decreased by 4.5 beats/min after NIV treatment, with no change in HRV parameters. HRV parameters differed by sleep stage and showed an increase in arousal-related sympathetic-parasympathetic balance after 12 months of NIV treatment. HRV parameters did not differ before and after oxygen desaturation events. NIV for the treatment in children with obesity and OSA resulted in a small decrease in heart rate and an increase in arousal-related sympathetic-parasympathetic balance. These findings suggest small, potentially positive impacts of NIV on cardiovascular risk in children with concurrent obesity and OSA.


Roles of prostaglandin E2 in cardiovascular diseases.
Prostaglandin E2 (PGE(2)) is produced in inflammatory responses and regulates a variety of immunological reactions through 4 different receptor subtypes; EP1, 2, 3 and 4. However, the precise role of each receptor in cardiovascular disease has not yet been elucidated. Enhanced expression of some EPs has been observed in clinical and experimental cardiovascular diseases. EP agonists have been developed to clarify the role of each receptor. Recently, we developed a novel selective agonist to examine the effects of EP4 on cardiac transplantation, myocardial ischemia, and myocarditis. Of note, a selective EP4 agonist attenuated inflammatory cytokines and chemokines via attenuation of macrophage activation in inflammatory heart diseases. In this review article, we discuss the effects of PGE(2) receptor agonists on the development of cardiovascular diseases.


Dual Roles for CXCL4 Chemokines and CXCR3 in Angiogenesis and Invasion of Pancreatic Cancer.
The CXCL4 paralog CXCL4L1 is a less studied chemokine that has been suggested to exert an antiangiogenic function. However, CXCL4L1 is also expressed in patient tumors, tumor cell lines, and murine xenografts, prompting a more detailed analysis of its role in cancer pathogenesis. We used genetic and antibody-based approaches to attenuate CXCL4L1 in models of pancreatic ductal adenocarcinoma (PDAC). Mechanisms of expression were assessed in cell coculture experiments, murine, and avian xenotransplants, including through an evaluation of CpG methylation and mutation of critical CpG residues. CXCL4L1 gene expression was increased greatly in primary and metastatic PDAC. We found that myofibroblasts triggered cues in the tumor microenvironment, which led to induction of CXCL4L1 in tumor cells. CXCL4L1 expression was also controlled by epigenetic modifications at critical CpG islands, which were mapped. CXCL4L1 inhibited angiogenesis but also affected tumor development more directly, depending on the tumor cell type. In vivo administration of an mAb against CXCL4L1 demonstrated a blockade in the growth of tumors positive for CXCR3, a critical receptor for CXCL4 ligands. Our findings define a protumorigenic role in PDAC development for endogenous CXCL4L1, which is independent of its antiangiogenic function. Cancer Res; 76(22); 6507-19. ©2016 AACR.


Investigation of enhanced and suppressed optical transmission through a cupped surface metallic grating structure.
Two-dimensional finite-difference time-domain (FDTD) method has been performed to numerically investigate the transmission through a one-dimension cupped surface metallic grating structure. The concept of coupling of optical modes in the notches and main slits, introduced by Crouse and Keshavareddy [1], is examined further in our work. Unexpected phenomenon is shown that even horizontal surface plasmons (HSPs) are inhibited, the transmission still can be enhanced or suppressed. And the periodicity of transmission depending on the phase change of the light striking on the grating surface is discovered. A hybrid optical mode combined by cavity mode and diffracted evanescent wave mode [2] is introduced to analyze the phenomenon.


A novel ganglioside with a free amino group in bovine brain.
A novel ganglioside which binds cholera-toxin B-subunit was purified from bovine brain by an h.p.l.c. system using an Aquasil column subsequent to Q-Sepharose column chromatography. T.l.c./immunostaining showed that the isolated ganglioside had about 60% of the binding reactivity of the authentic ganglioside GM1 for cholera-toxin B-subunit. On h.p.l.c., this ganglioside migrated between ganglioside GD1a and GD1b, and was found to give positive reactions with ninhydrin and fluorescamine reagents which specifically react with amino groups. The presence of a free amino group was further confirmed by chemical re-N-acetylation. The N-acetylated product had an identical RF value on h.p.l.c. and similar reactivity with cholera-toxin B-subunit as the authentic GM1. H.p.t.l.c., t.l.c./immunostaining, negative-ion fast-atom-bombardment (f.a.b.)-m.s., and 1H-n.m.r. spectroscopy of the novel ganglioside unequivocally demonstrated that it has the basal structure of GM1 with de-N-acetylated neuraminic acid instead of N-acetylneuraminic acid. In the present study we report for the first time that a ganglioside derivative containing de-N-acetylated neuraminic acid, de-N-acetylated GM1, exists in natural brain tissues.


Cumulative Impact of HIV and Multiple Concurrent Human Papillomavirus Infections on the Risk of Cervical Dysplasia.
Infection with HIV is known to increase the risk of cervical cancer. In addition, evidence suggests that concurrent infection with multiple human papillomavirus (HPV) genotypes increases the risk of cervical dysplasia more than infection with a single HPV genotype. However, the impact of the combination of HIV coinfection and presence of multiple concurrent HPV infections on the risk of cervical dysplasia is uncertain. We compared the results of HPV testing and Pap smears between HIV-infected and HIV-uninfected young women to assess the cumulative impact of these two conditions. We found that both HIV and the presence of multiple concurrent HPV infections are associated with increased risk of associated Pap smear abnormality and that the impact of these two risk factors may be additive.


Structural stability of liposome-stabilized oil-in-water pickering emulsions and their fate during in vitro digestion.
Most current research on food-relevant Pickering emulsions has been conducted using inorganic or food-compatible organic particles as emulsifiers. A key challenge is maintaining a favourable structure while being able to resist displacement or destabilisation by surfactants and controlling transport of substrates during digestion. Liposome stabilised emulsions have demonstrated some potential for being smart, responsive delivery systems for poorly available bioactives and drugs. We developed a liposome-stabilized oil-in-water Pickering emulsion utilising macromolecular crowding- with polyethylene glycol (PEG). They were pH-controllable and had surfactant-dependent deformability whilst displaying dual delivery routes from both the liposome and oil phases. Dynamic light scattering, confocal microscopy and emulsion stability measurements indicated the liposomes containing 10% PEG at neutral pH remained intact at the interface for extended time. Various degrees of interfacial coverage still existed in the presence of PEG, under acidic environment and with added bile salts. Emulsions with added PEG maintained a more integrated structure after in vitro oral-gastric digestion, and showed greater lipolysis with more free fatty acids (14.7 ± 0.5% for with PEG vs. 12.7 ± 0.1% for without PEG) released during in vitro intestinal digestion. These Pickering emulsions could provide a flexible approach to controlled release under a broad range of conditions.


Totally implantable venous access devices: The supraclavicular percutaneous approach and early complications.
The background of this study was to explore the success rate and early complications concerning the implantation of totally implantable venous access devices (TIVADs) by percutaneous venipuncture and management strategies for early complications. This was a retrospective study of 1923 patients who received TIVAD implantation by percutaneous venipuncture (mostly via the supraclavicular route). The percutaneous access sites were internal jugular vein (810 patients; right/left: 158/652) or proximal right internal jugular vein, brachiocephalic vein, and proximal subclavian vein (1113 patients). Success rates and early complications related to TIVAD placement techniques were summarized, and strategies for managing complications were also analyzed. In 627 patients, TIVAD implantation was first performed by interventional radiologists using a "blind" approach relying on anatomical landmarks, having a 91.9% success rate. In contrast, there was a 100% success rate among the remaining 1296 patients who received ultrasound-guided implantation, a difference which was statistically significant (P < 0.05). Ultrasound-guided implantation was also successful for the 51 patients for whom the first attempt failed using the blind technique. Further, we found that the incidence of early complications was 5.41% (104/1923) and that the occurrence of immediate complications was significantly higher in the blind technique group compared to the ultrasound-guided group (37 vs. 12; P < 0.05). It is safe and feasible to implant TIVADs by supraclavicular venipuncture. Ultrasound guidance combined with X-ray monitoring during operation significantly improves the surgery success rate and reduces the risk of early complications. Unclear anatomical landmarks and vascular variation are the main factors affecting success using a blind (nonguided) technique.


Four-year follow-up of poly-L-lactic Acid cages for lumbar interbody fusion in goats.
New applications of bioabsorbable polymer implants demand for histologic evaluation because a host tissue response is elicited and late complications after polymer implantation have been reported. Furthermore, in load-bearing regions an accelerated polymer degradation and foreign body reaction may be observed. Lumbar interbody fusion procedures were performed using poly-L-lactic acid (PLLA) and titanium cages in 43 goats. At 3, 6, 12, 24, 36, and 48 months after surgery, sequential histologic analysis of instrumented motion segments, lymph nodes, and nervous structures was performed. Blood samples were retrieved for laboratory analysis. No adverse local or distant histologic or systemic effects were observed during the absorption of the poly-L-lactic acid cages. Interbody fusion was maintained, and only a very mild inflammatory response was observed. In half the specimens complete absorption was observed, and in the remaining specimens an estimated 1-10% of the original PLLA was present at the 3-year follow-up. At the 4-year follow-up, five out of seven PLLA specimens showed no PLLA particles under polarized light microscopy. In the remaining two specimens an estimated 1% of the original PLLA could be observed. Poly-L-lactic acid cages are feasible for lumbar interbody fusion, and the biocompatibility under high load bearing conditions is excellent during the complete absorption of the PLLA interbody fusion cages.


Calligonum comosum (Escanbil) extract exerts anti-angiogenic, anti-proliferative and anti-inflammatory effects on endometriotic lesions.
Calligonum comosum is a desert plant that is applied in traditional folkloric medicine for the treatment of abnormally heavy or prolonged menstruation and menstrual cramps. Moreover, it has been suggested for the treatment of infertility-causing conditions. Its bioactive chemical constituents inhibit multiple processes, such as angiogenesis, inflammation and invasive tissue growth, which may be beneficial in the therapy of endometriosis. We investigated the effects of Calligonum comosum on the development of endometriotic lesions. We evaluated the anti-angiogenic activity of Calligonum comosum ethyl acetate fraction (CCEAF) in different in vitro angiogenesis assays. Moreover, we surgically induced endometriotic lesions in BALB/c mice, which received 50 mg/kg Calligonum comosum total extract (CCTE) or vehicle (control) over 4 weeks. The growth, cyst formation, vascularization and immune cell infiltration of the lesions were assessed with high-resolution ultrasound imaging, caliper measurements, histology and immunohistochemistry. CCEAF doses of up to 10 μg/mL did not impair the viability of human dermal microvascular endothelial cells (HDMEC), but dose-dependently suppressed their migration, tube formation and sprouting, indicating a substantial anti-angiogenic effect of CCEAF. Furthermore, CCTE significantly inhibited the growth and cyst formation of developing murine endometriotic lesions when compared to vehicle-treated controls. This was associated with a reduced vascularization, cell proliferation and immune cell infiltration. Our findings show that Calligonum comosum targets multiple, fundamental processes in the pathogenesis of endometriosis, which may be beneficial for the treatment of this common gynecological disorder.