Alcohol use, military sexual trauma, expectancies, and coping skills in women veterans presenting to primary care.
Little is known regarding alcohol use and its correlates in women veterans. An understanding of these variables is of utility to providers in primary care at Veterans Affairs (VA) hospitals, who are among the first to identify and intervene for problem drinking. The objective of this study was to describe and explore the associations between posttraumatic stress disorder symptoms, experience of military sexual trauma (MST), expectancies for alcohol use, and coping skills in predicting drinking behavior. Each month all women veterans attending appointments in primary care were mailed a letter alerting them to the study. Women then received a call asking them to participate, and many were directly recruited at their primary care appointment. Participants then completed a survey of current alcohol use and related variables in a private room. Participants were 93 women veterans seeking care at VA. Measures included the Alcohol Use Disorders Identification Test, a modified version of the VA MST screen, the Davidson Trauma Scale; the Coping Inventory for Stressful Situations, and the Brief Comprehensive Effects of Alcohol Questionnaire. Positive expectancies and evaluations emerged as significant correlates of AUDIT scores, while PTSD symptoms were not related to AUDIT scores. A hierarchical regression revealed a significant positive interaction between avoidance coping and positive evaluations. Depression, positive evaluations and avoidance coping were significant independent predictors of AUDIT scores in the final model, but MST was not. Findings highlight the importance of considering of the function of alcohol use when delivering clinical interventions and the need for further research on the association between MST and drinking in women veterans.


A bile alcohol sulfate as a major component in the bile of the small skate (Raja erinacea).
The nature of bile alcohols and bile acids in gall-bladder and hepatic bile from perfused livers of the small skate (Raja erinacea) has been investigated. The main bile alcohol sulfate was isolated by thin-layer chromatography and analyzed by fast atom bombardment mass spectrometry and 13C NMR. Following solvolysis and purification on Lipidex-DEAP, the bile alcohol profile was measured by capillary gas-liquid chromatography-electron impact mass spectrometry. Based on these studies and on comparison with authentic scymmnol sulfate and scymnol, the main bile alcohol was identified as 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 xi,26,27-hexol sulfate. The mean +/- SD concentration in gallbladder bile from five different skates was 24.6 +/- 8.7 mmol/l. Only 0.1 mmol/l of cholic acid and its conjugates was found in a pool of skate bile. The main bile alcohol sulfate in the bile of the small skate seems to be a metabolic end product, present in a concentration comparable to that of bile salts in mammals.


Plasma beta-thromboglobulin in uncomplicated insulin-dependent diabetes at rest and during physical exercise.
Plasma beta-thromboglobulin (beta TG) was assayed in 10 insulin-dependent uncomplicated diabetic subjects and in 10 age- and sex-matched metabolically healthy controls, both at rest and after maximal physical exercise. Diabetic patients showed significantly higher (p less than 0.005) resting beta TG values as compared to the control group. After physical exercise, beta TG rose significantly (p less than 0.05) only in the control group, thus abolishing the difference (evaluated through beta TG values) between the two groups observed at rest. Platelet hyperactivity seems thus to be present even in uncomplicated diabetes, at rest, while exercise does not lead to a further increase in beta TG values contrary to what is observed in controls.


Tibialis anterior R-1 response: physiological behaviour, normative data and clinical utility in L4-L5 radicular compression.
A modified H-reflex, known as R-1 response, was recorded in healthy subjects by averaging 200 responses from the moderately contracting tibialis anterior muscle (TA) after repetitive submaximal stimulation of common peroneal nerve. Physiological changes to different modes of stimulation and recording were studied and normative data obtained at the most reliable parameters. Subsequently, the test is applied to 36 patients with clinical and myelographic evidences of L5 or L4-L5 radicular compression (with or without S1 radicular compression). Increasing the force of muscle contraction resulted in increase in amplitude up to a certain limit, with no change in latency. Increasing the current from subliminal to submaximal stimulation caused initial increase and subsequent fall in the amplitude without change in the latency. The change in the stimulus frequency from 0.5 to 3 Hz did not alter latency or amplitude but the higher frequencies sometimes did. On changing the position of the foot from plantarflexed to dorsiflexed, an increase in amplitude and reduction in duration of the response was noted. Fifty subjects were studied using stimulus intensity just enough to produce 200-400 microV M-response, stimulus duration of 1.0 msec, stimulus rate of 3 Hz and the muscle force sufficient to keep the foot in complete dorsiflexion. The tibialis anterior R-1 response (TAR-1) could be recorded reliably from both legs in all the subjects. The take-off point was sharp and in no subject was there any difficulty in measuring the latency to onset point. On repeating the test, the onset point of the response was superimposable. Latency showed linear correlation with height and age. Among the patients, 21 out of 25 cases of unilateral (84.0%) and 10 out of 11 cases of bilateral (90.9%) radicular compression had abnormal findings. Abnormalities included significant a right-left latency difference within the normal range of absolute latencies, unilateral or bilateral prolongation of latency to onset point and attenuation or absence of the response. It was concluded that the TAR-1 is an important and reliable test for the study of functional integrity of L4-L5 spinal segments in lumbo-sacral sensorimotor root lesions.


Pulmonary gas exchange in coronary artery surgery patients during sevoflurane and isoflurane anesthesia.
As the surgical population ages, the number of patients presenting with coronary artery disease and age-related loss of pulmonary recoil will increase. Although their influence on gas exchange in this population remains unknown, sevoflurane and isoflurane are used for an increasing variety of surgical procedures. We examined pulmonary gas exchange (multiple inert gas elimination technique) in 30 patients presenting for coronary artery bypass grafting. After a baseline measurement taken during midazolam anesthesia, patients were continued on sevoflurane (n = 10), isoflurane (n = 10), or midazolam (n = 10) for 20 min, then a second measurement was taken. During sevoflurane and isoflurane anesthesia, blood flow to lung areas with a low ventilation/perfusion ratio (Va/Q) was significantly increased in comparison with control. During sevoflurane anesthesia, blood flow to lung areas with a normal Va/Q ratio (76 +/- 12 versus control: 89 +/- 5, mean +/- SD) and PaO(2) (138 +/- 31 versus control: 156 +/- 35 mm Hg, mean +/- SD) were depressed, whereas an increase in Va/Q-dispersion (log SD(Q)) was observed during isoflurane anesthesia. We conclude that both sevoflurane and isoflurane alter the distribution of perfusion in the lung, but only sevoflurane significantly depresses PaO(2). Both sevoflurane and isoflurane modified pulmonary blood flow in patients with coronary artery disease, but only sevoflurane depresses arterial oxygenation in this population.


Evaluation of ovarian and metabolic effects of GnRH modulators in two rat models of polycystic ovary syndrome.
Gonadotropin-releasing hormone (GnRH) modulators are widely used in numerous reproductive conditions including infertility. Several clinical studies showed mixed results regarding the efficacy of GnRH modulators in patients with polycystic ovary syndrome (PCOS). Along with this, few preclinical studies focus on the effect of GnRH modulators in PCOS-induced animals. Therefore, the present study was designed to study the effect of leuprolide and cetrorelix on hormonal, metabolic, and menstrual dysfunction PCOS rats. Prepubertal female rats were divided into four groups: Group I received a normal pellet diet and Groups II, III, and IV received 40% high-fat diet for 105 days. Similarly, adult female rats were divided into four groups: Group I received 1% carboxymethylcellulose (CMC) and Groups II, III, and IV received letrozole (1 mg/kg, per oral [p.o.] in 1% CMC) for 21 days. Thereafter, leuprolide (2.5 µg/rat, s.c.) and cetrorelix (10 µg/kg, subcutaneous [s.c.]) treatment were given to Group III and Group IV animals, respectively, for 21 days. Oral glucose tolerance test, lipid profile, fasting glucose, insulin, estrus cycle, hormonal profile, ovary weight, ovarian histopathological changes, and LHR and FSHR expressions were measured. Treatment with leuprolide and cetrorelix did not improve glucose intolerance, insulin level, insulin sensitivity indices, sex hormone levels, lipid profile, and estrus cycle. Only testosterone level, total cholesterol level, and follicular development were improved. Therefore, it was concluded that both leuprolide and cetrorelix showed improvement in follicular development, which could be helpful for improving fertility in PCOS.


Effects of LETS glycoprotein on cell motility.
Addition of LETS glycoprotein to normal or transformed cells produces increased migration of the cells, as determined by formation of phagokinetic tracks on gold particle-coated coverslips. These tracks arise by a combination of phagocytosis of the gold particles and cellular migration. Increased motility is also evident on plastic in the absence of gold particles. The added LETS protein attaches to the cells in a fibrillar network, and binding is greater to normal than to transformed cells. The effects of LETS protein on migration are consistent with its effects on cell adhesion, morphology and cytoskeleton, and have potential implications for the determination of cellular migration in vivo.


[The effects of the aging of the nursing profession and the strategies to effectively retain senior nurses].
To provide an overview of the debate in the literature on the aging of the nursing profession. Review of the main articles published since year 2000. The rapid aging of the nursing workforce is a new phenomenon that Italian organizations have to face. Many nurses ready for retirement would be willing to remain in a more adequate work environment and salary. The story of a nurse retained at work is presented. A leadership careful of this phenomenon and able to re-plan work environments and supportive mechanisms need to be developed to take on this new challenge.


The association between ultra-processed foods and conventional markers of cardiovascular risk in an adult Iranian population.
According to the NOVA classification system, ultra-processed foods result from extensive industrial processing and use ingredients derived from food and non-food products, which can negatively impact on cardiovascular disease risk factors. Despite this, few studies have investigated UPFs in Middle Eastern populations regardless of high consumption in this region. This cross-sectional study was conducted on data from the Prospective Epidemiological Research Studies in Iran Kharemeh cohort (n = 6611). Food frequency questionnaires were assessed and the ratio of total UPFs energy/total energy intake was calculated. Data was categorized into tertiles of UPF consumption using the NOVA classification system. Kruskal-Wallis tests were used to assess differences in nutrient and food intakes between tertiles and logistic regression analysis was applied to assess the associations between UPFs and CVD risk factors. After adjustment for potential confounders the logistic regression analysis revealed significant positive relationships between intakes of UPFs and waist circumference (WC) (T2: OR; 1.34, 95% CI; 1.13-1.60 - T3: OR; 1.41, 95% CI; 1.18-1.69, P ˂0.001), low-density lipoprotein cholesterol (LDL-C) (T2: OR; 1.20, 95% CI; 1.05-1.37 - T3: OR; 1.27, 95% CI; 1.11-1.45, P ˂0.001), non-high-density lipoprotein cholesterol (non-HDL) (T2: OR; 1.21, 95% CI; 1.07-1.37 - T3: OR; 1.24, 95% CI; 1.10-1.41, P ˂0.001) and LDL-C to HDL-C ratio (T2: OR; 1.15, 95% CI; 1.02-1.31 - T3: OR; 1.21, 95% CI; 1.07-1.38, P = 0.002). The consumption of UPFs was positively associated with WC and atherogenic blood lipids. However, increased intakes of fiber and unsaturated fats were also found in those consuming more UPFs, which was not expected. These findings offer insights into an understudied population and warrant further research.


Influence of type of conduit and site of implantation on the outcome of continent catheterizable channels.
Continent catheterizable channels (CCC) using the Mitrofanoff principle are essential for pediatric urinary tract reconstruction. There is controversy over the influence of type of CCC (appendix vs. Yang-Monti) and site of implantation (augmentation vs. native bladder) on outcome. A retrospective record review was conducted of all patients undergoing CCC since 1999, excluding patients who underwent seromuscular colocystoplasty. We analyzed the type of channel, site of implantation, complications requiring re-operation, and the revision rate according to type of CCC, type of stoma, site of implantation (bladder vs. augmentation) and segment used for augmentation (ileum vs. sigmoid colon). There were 41 patients with a mean age of 11.2 years and a mean follow-up of 33.3 months. Of these, 33 CCC were constructed with appendix and eight with a Yang-Monti technique (4 ileal, 4 sigmoid); 31 patients also had an enterocystoplasty (19 sigmoid, 9 ileal and 3 others). Overall revision rate was 27%; revision was required in 8/33 (24%) appendiceal and 3/8 (38%) Yang-Monti CCC (P=0.7). Revisions were required in 4/21 CCC implanted in the native bladder and 7/20 implanted in augmented bladder (P=0.3). The majority of revisions were at skin level. Although there was no statistical difference in revision rate according to type of CCC, type of stoma or site of implantation, complications appeared to be more common in patients requiring a more complex reconstruction.


Granzyme B Deficiency Protects against Angiotensin II-Induced Cardiac Fibrosis.
Cardiac fibrosis is observed across diverse etiologies of heart failure. Granzyme B (GzmB) is a serine protease involved in cell-mediated cytotoxicity in conjunction with the pore-forming protein, perforin. Recent evidence suggests that GzmB also contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. However, the role of GzmB in the onset and progression of cardiac fibrosis remains elusive. The present study investigated the role of GzmB in the pathogenesis of cardiac fibrosis. GzmB was elevated in fibrotic human hearts and in angiotensin II-induced murine cardiac fibrosis. Genetic deficiency of GzmB reduced angiotensin II-induced cardiac hypertrophy and fibrosis, independently of perforin. GzmB deficiency also reduced microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro, GzmB cleaved the endothelial junction protein, vascular endothelial (VE)-cadherin, resulting in the disruption of endothelial barrier function. Together, these results suggest a perforin-independent, extracellular role for GzmB in the pathogenesis of cardiac fibrosis.


Radiotherapy for laryngeal cancers.
We present the update of the recommendations of the French society of oncological radiotherapy on radiotherapy of laryngeal cancers. Intensity modulated radiotherapy is the standard of care radiotherapy for the management of laryngeal cancers. Early stage T1 or T2 tumours can be treated either by radiotherapy or conservative surgery. For tumours requiring total laryngectomy (T2 or T3), an organ preservation strategy by either induction chemotherapy followed by radiotherapy or chemoradiotherapy with cisplatin is recommended. For T4 tumours, a total laryngectomy followed by radiotherapy is recommended when feasible. Dose regimens for definitive and postoperative radiotherapy are detailed in this article, as well as the selection and delineation of tumour and lymph node target volumes.


Effects of absorbing particles on coronas and glories.
Light scattering from small particles changes if the particles are absorbing. Whereas the effect is small for coronas and Bishop's ring, glories show pronounced attenuation with increasing absorption. Results indicate suitable wavelength regions for studies of glory scattering from cloud tops. The behavior of core-shell particles could have applications for studying the atmosphere of Venus; in addition it provides more insight into the simple ray-path model of the glory.


Interactions between spinocervicolemniscal and dorsal column pathways in thalamic ventrobasal neurons in the cat.
Ventrobasal (VB) thalamic cells responding to electrical stimulation of the dorsal column (DC) and of the dorsolateral funiculus DLF in cats with DC intact or cut at C4 and isolated, were studied. Among the cells observed, about 30% showed convergence to the two pathways. Different patterns of interaction between the two inputs were found, but the most frequent effect observed was an inhibition exerted by dorsal column (conditioning) stimulation on the activity evoked by dorsolateral funiculi (test) stimulation. From these results a dominance of the DC over the spinocervico-thalamic (SCT) inputs was confirmed.


Antioxidant status of children with steroid-sensitive nephrotic syndrome.
Eighteen children with steroid-sensitive nephrotic syndrome (SSNS) were studied. The control group comprised 20 healthy children. The following indirect parameters of reactive oxygen species activity were determined in nephrotic patients during four stages of the disease (full relapse before prednisone administration, disappearance of proteinuria, prednisone cessation, unmaintained remission): plasma malondialdehyde (MDA) levels, copper/zinc superoxide dismutase (CuZn SOD) activity and glutathione peroxidase (GPX) activity in erythrocytes, reduced glutathione (GSH) and vitamin C levels in whole blood, and vitamin E level in serum. Increased MDA levels, reduced vitamin C levels, and enhanced CuZn SOD activity were found in relapse. GSH concentration was high during all four stages. Vitamin E level was also increased, parallel to the pattern of serum lipids. GPX activity remained low during the proteinuria stage and in remission. We conclude that the majority of abnormal findings can be attributed to the hyperlipidemia of NS. Low GPX activity may be a factor limiting the antioxidant capacity in NS. The present study is inconclusive regarding the role of free radicals in the proteinuria of NS.


Atrial tachyarrhythmias and heart failure events in patients with arrhythmogenic right ventricular cardiomyopathy.
Atrial tachyarrhythmias (ATAs) are associated with an increased risk of incident heart failure (HF). The aim of this study was to evaluate the incidence of ATAs and time of ATA development during disease progression as well as the influence of ATAs on HF-related events in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). We retrospectively studied 90 ARVC patients who met the definitive diagnosis of the 2010 Task Force Criteria and were diagnosed with ARVC at our institutions between 1974 and 2012. The main outcomes were death due to HF and hospitalization due to worsening HF. Eleven patients had a history of ATAs at the time of ARVC diagnosis. Of 79 patients without a prediagnosis history of ATAs, 21 (27%) newly experienced ATAs during a median follow-up period of 11.4 (range, 0.1-29.6) years. Among them, 15 patients experienced their first hospitalization due to worsening HF a median of 1.7 (range, 0.0-9.8) years after the occurrence of ATAs. Patients with ATAs were more likely to experience death due to HF and hospitalization due to worsening HF than patients without ATAs (odds ratio 19.2, 95% confidence interval 2.0-92.3, P < 0.01 and odds ratio 29.7, 95% confidence interval 8.4-104.8, P < 0.01, respectively). Multivariable analysis revealed that ATAs were associated with an increased risk of hospitalization due to worsening HF (hazard ratio 15.55, 95% confidence interval 4.82-50.17, P < 0.01). Our study suggests that the occurrence of ATAs is associated with an increased risk of HF-related events and worsens the prognosis of ARVC patients.


Quinolones and the gastrointestinal tract.
A number of studies have evaluated the efficacy of the new fluoroquinolones for therapy of bacterial enteric diseases and for prevention of gram-negative sepsis in granulocytopenic patients. The success of the quinolones in these settings is related to several special features of these agents, including their spectrum of activity and high fecal levels, which are in turn reflected in their effect on the gastrointestinal flora. Other factors that are important, particularly for invasive disease such as typhoid fever and shigellosis, include good intracellular and bowel wall penetration, and lymph node and systemic drug concentrations many times higher than the MICs of the causative organisms. This article reviews the factors that contribute to the changes in fecal flora, and the results of clinical studies in patients with diarrhea, granulocytopenic patients, and patients with selected other infections of, or related to, the gastrointestinal tract.


Poly(lactic acid)/TiO₂ nanocomposites as alternative biocidal and antifungal materials.
Poly(lactic acid) (PLA) composites with titanium oxide (TiO2) ~10-nm nanoparticles were produced by the melting process and their main properties were evaluated. The nanoparticles are homogeneously dispersed in the matrix with a low degree of agglomeration, as seen by transmission electron microscopy (TEM). The crystallinity temperature increased ~12% when 5 wt.% of TiO2 was added, showing that the nanoparticles acted as nucleating agents this trend was confirmed by optical images. The elastic modulus increased ~54% compared to neat PLA at 5 wt.% of nanoparticles. Despite these improvements, PLA/TiO2 nanocomposites showed lower shear viscosity than neat PLA, possibly reflecting degradation of the polymer due to the particles. Regarding biocidal properties, after 2h of contact the PLA/TiO2 composites with 8 wt.% TiO2 showed a reduction of Escherichia coli colonies of ~82% under no UVA irradiation compared to pure PLA. This biocidal characteristic can be increased under UVA irradiation, with nanocomposites containing 8 wt.% TiO2 killing 94% of the bacteria. The PLA/TiO2 nanocomposites with 8 wt.% were also 99.99% effective against Aspergillus fumigatus under the UVA irradiation.


Simultaneous mutation scanning for gross deletions, duplications and point mutations in the DMD gene.
We have developed a technique to screen for gross deletions/duplications and point mutations using one streamlined approach. Fluorescent multiplex quantitative PCR is used to determine the copy number of each exon, followed by conformation sensitive capillary electrophoresis (CSCE) of the same PCR products on a multi-capillary genetic analyser. We have developed this technique to screen all 79 exons of one of the largest human genes currently known (dystrophin) using 12 multiplex PCR assays. A blind trial of 50 male and 50 female samples, in which 84 mutations had previously been found and characterized by other techniques, showed 100% sensitivity and specificity. We then applied this method to screen over 100 patient samples previously screened for deletions and duplications of 28 exons from the two hotspot regions. Our data show that combining a full deletion/duplication screen with CSCE will detect a mutation in 98% of Duchenne muscular dystrophy patients and 93% of Becker muscular dystrophy patients where the clinical diagnosis is certain. This technique is applicable to any gene and is particularly suited to mutation screening of large genes, decreasing the time taken for a complete gene screen for nearly all mutation types.


A web-based Alcohol Clinical Training (ACT) curriculum: is in-person faculty development necessary to affect teaching?
Physicians receive little education about unhealthy alcohol use and as a result patients often do not receive efficacious interventions. The objective of this study is to evaluate whether a free web-based alcohol curriculum would be used by physician educators and whether in-person faculty development would increase its use, confidence in teaching and teaching itself. Subjects were physician educators who applied to attend a workshop on the use of a web-based curriculum about alcohol screening and brief intervention and cross-cultural efficacy. All physicians were provided the curriculum web address. Intervention subjects attended a 3-hour workshop including demonstration of the website, modeling of teaching, and development of a plan for using the curriculum. All subjects completed a survey prior to and 3 months after the workshop. Of 20 intervention and 13 control subjects, 19 (95%) and 10 (77%), respectively, completed follow-up. Compared to controls, intervention subjects had greater increases in confidence in teaching alcohol screening, and in the frequency of two teaching practices - teaching about screening and eliciting patient health beliefs. Teaching confidence and teaching practices improved significantly in 9 of 10 comparisons for intervention, and in 0 comparisons for control subjects. At follow-up 79% of intervention but only 50% of control subjects reported using any part of the curriculum (p = 0.20). In-person training for physician educators on the use of a web-based alcohol curriculum can increase teaching confidence and practices. Although the web is frequently used for dissemination, in-person training may be preferable to effect widespread teaching of clinical skills like alcohol screening and brief intervention.


[Expressions of GDNF, GDNFR alpha and Ret proteins in the brain of rats with seizures induced by pilocarpine].
To observe the dynamic expression of GDNF and their receptors in the brain of rats after status epilepticus(SE). The lithium-pilocarpine-induced rat SE model was used. The expression patterns of GNDF, GDNFR alpha and Ret were observed dynamically with immunohisto-chemical technique, and the extent of neuron damage was assessed by HE stain. (1) GDNF positive cells began to appear 2 hours after SE and reached the peak in 1 and 3 days, then decreased to the normal level; (2) GDNFR alpha positive cells in the cortex increased rapidly to the peak 2 hours after SE, and only few such cells were found in hippocampus; (3) Ret positive cells were found both in the cortex and hippocampus, with the maximum of expressions 6-8 hours after SE; (4) There were some connection between GDNF expression levels and extent of neurons damage. There exist time-dependent upregulations of GDNF, GDNFR alpha and Ret protein in the cortex and hippocampus of rats after SE. GDNF and their receptors involve in the response to neuron damage after SE, which might have the protective effect of neurons.


Statins Use and Outcome of Acute Ischemic Stroke Patients after Systemic Thrombolysis.
The aim of this was to study the effects of statins and their intensity on symptomatic intracranial hemorrhage (sICH) and outcome after IV thrombolysis (IVT) for acute ischemic stroke (AIS). We retrospectively reviewed the medical records and cerebrovascular images of all the patients treated with IVT for AIS in our center in a 10-year period. Patients were further characterized as any statin users versus non-users on admission to the emergency department. Statins were categorized in high intensity or low intensity statin based on its propensity to reduce lower low-density cholesterol by ≥45% or <45%, respectively. Safety and discharge modified Rankin Score were compared between statin users versus non-users and also between high-intensity versus low-intensity groups. A total of 834 patients received IVT for AIS in our center during a 10-year period. Multivariate models were adjusted for age, NIH Stroke Scale at admission, INR, and history of DM and atrial fibrillation. There was no association between odds of sICH and any statin use (OR = 0.52 [0.26-1.03], p = 0.06). In multivariate model, any statin use was not associated with odds of poor outcome (Table 4: OR = 1.01 [0.79-1.55], p = 0.57). There was no significant association between odds of sICH among patients on high-intensity statin compared to low intensity statin (multivariate model OR = 0.39 [0.11-1.40], p = 0.15). There was 47% reduced odds of poor outcome among patients on high-intensity statin as compared to low-intensity statin (OR = 0.53[0.32-0.88] p = 0.01). However, this significant association was lost in the multivariate model (OR = 0.60 [0.35-1.05], p = 0.07). Our study does not show any significant association between risk of sICH and poor outcome after IVT for patients on prior statin therapy. We also did not find significant association between the risk of sICH and poor outcome after IVT and the intensity of the stain used.


Subtidal Benthic Invertebrates Shifting Northward Along the US Atlantic Coast.
Numerous marine and terrestrial species have shifted their ranges poleward in response to warming from global climate change. However, few studies have examined range shifts of subtidal benthic communities in estuarine and nearshore waters. This study examined 20 years (1990-2010) of occurrence and abundance data of soft-bottom, benthic invertebrates along the Atlantic coast of the USA. Data from two biogeographic provinces (Carolinian and Virginian), which spanned 15° of latitude from mid-Florida to Cape Cod, were extracted from a national coastal assessment program. Mean water temperatures increased significantly during the study period, bottom water by 1.6 °C and surface water by 1.7 °C. Of 25 species with significant changes in centers of abundance (out of the 30 most prevalent), 18 (60%) shifted northward and 7 (23%) shifted southward. Species that shifted north moved an average distance of 181 km, in contrast with 65 km for species that shifted south. The southern limits of 22 species showed significant northward shifts; because there was little change in northern limits, this resulted in an average 25% range contraction. Community composition changed during the study period, most notably in southern latitudes. Five Carolinian species surmounted their northerly biogeographic boundary. Consequences of these range shifts include changes in benthic community structure and function, which have strong implications for ecosystem functioning and services including changes in fisheries dependent upon benthic prey.


Identification of biological neurons using adaptive observers.
This paper is to investigate the use of adaptive observers for the modeling of biological neurons and networks. Assuming that a neuron can be modeled as a continuous-time nonlinear system, it is possible to determine its unknown parameters using adaptive observer, based on the concept of adaptive synchronization. The same technique can be extended for the identification of an entire biological neural network. Some conventional observer designs are studied in this paper and satisfactory results are obtained, yet with some restrictions. To further extend the applicability of adaptive observers for the modeling process, a new design is suggested. It is based on a combination of linear feedback control approach and the dynamical minimization algorithm. The effectiveness of the designed adaptive observer is confirmed with simulations.


Design, synthesis, and biological evaluation of thiazole/thiadiazole carboxamide scaffold-based derivatives as potential c-Met kinase inhibitors for cancer treatment.
As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the in vitro activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure-activity relationship, compound 51am was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, 51am exhibited potency against several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of 51am with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that 51am could be an antitumor candidate meriting further development.


Chromosomal microarray in unexplained severe early onset epilepsy - A single centre cohort.
Severe early onset epilepsy may lead to impaired cognitive and motor development, and consists of a group of specific and overlapping electro-clinical phenotypes which may be the result of an inborn error of metabolism, congenital or acquired structural brain lesion, known chromosomal or mono-genetic disorder. A significant proportion of cases however remain unexplained, representing a major diagnostic and management challenge. In this study we describe a cohort of children with severe early onset epilepsy and examine the clinical utility of chromosomal microarray (array-comparative genomic hybridisation, CGH) in this group of epilepsies. In 51 children with unexplained severe early onset epilepsy, all of whom had chromosomal array tested, copy number variants were detected in 17.6% and pathogenic variants in 5.9% of infants. Chromosomal microarray is a useful investigation in early onset refractory epilepsy and epileptic encephalopathy. Detailed review of the precise array abnormality and phenotypes associated are important for determining significance.


Ca2+-dependent actin-binding phosphoprotein in Physarum polycephalum. II. Ca2+-dependent f-actin-capping activity of subunit a and its regulation by phosphorylation of subunit b.
Cap 42 (a + b), a Ca2+-dependent, actin-binding and phosphorylatable protein consisting of two distinct subunits a and b of 42,000 Da in Physarum polycephalum, has been identified as a new F-actin-capping protein. It capped or bound to the fast growing ends of actin filaments and blocked actin polymerization at this end. The capping activity residing in subunit a and its Ca2+-dependency were regulated by phosphorylation of subunit b; subunit a required Ca2+ for its capping activity when subunit b was phosphorylated, whereas this activity became Ca2+ independent when subunit b was dephosphorylated. Subunit b contained at least two phosphorylatable threonine residues and probably three additional phosphorylation sites. Like cytochalasins and other F-actin-capping proteins, Cap 42 (a + b) was able to induce a rapid depolymerization of actin filaments at the slow growing end, and also to nucleate actin polymerization. However, unlike Physarum fragmin, Cap 42 (a + b) had no severing activity leading to the fragmentation of actin filaments. Our results indicate that Cap 42 (a + b) is the first Ca2+-dependent F-actin-capping phosphoprotein whose phosphorylation regulates its actin-binding and vice versa. A possible mechanism of the capping action of Cap 42 (a + b) in vitro and also its conceivable role in the regulation of the Ca2+/actin-dependent cytoplasmic streaming in plasmodia are discussed.


Sonoelastographic Evaluation of the Achilles Tendon in Patients With Type 2 Diabetes Mellitus.
Diabetic foot is one of the dreaded complications of diabetes mellitus (DM). Alterations of the Achilles tendon (AT) may contribute to development of foot ulcers in diabetic patients. We evaluated the sonoelastographic abnormalities of the AT in 61 healthy volunteers and 81 patients with type 2 DM. The patients were further divided into those with and without peripheral neuropathy (PN). The AT thickness was measured in the proximal, middle and distal portions. Alterations in echo pattern were noted. The patients were found to have thicker tendons than the healthy volunteers (p < 0.01). Alterations in the echo pattern of the AT were more common in patients compared with healthy volunteers (p < 0.01). The shear wave velocity in the distal one-third of the AT was measured using shear wave elasticity imaging. Mean shear wave velocity values obtained were lower in patients compared with healthy volunteers (p < 0.001). No significant difference was found in the sonoelastographic findings of the AT in patients with and without PN. We conclude that there is softening, thickening and alterations in echo pattern of the AT in the form of hypoechogenicity, loss of fibrillar pattern and calcification at insertion in patients with type 2 DM, and these alterations could occur independent of onset of PN.


Mechanism of fixation of two-loop iridocapsular lenses.
I used seven eyes obtained postmortem to study the mechanism of fixation of a Binkhorst two-loop iridocapsular lens. During the first postoperative weeks, vitreous pressure and traction on the posterior lens capsule exerted by the zonular fibers pushed the loops of the iridocapsular lens against the iris. The zonular traction maintained the posterior capsule taut so that the vitreous pressure was distributed equally over the entire surface of the capsular diaphragm. Lens epithelial cells proliferated around the margin of the capsular breaks and defects and formed plaques or masses of spindle-shaped cells. This pseudofibrous tissue bridged and sealed capsular defects and caused adhesions between the anterior and posterior lens capsule and between the anterior capsule and the iris pigment epithelium. Fixation of the lenses may be reinforced by proliferation of the iris pigment epithlium and of the fibrous tissue arising from the iris stroma.


C-reactive protein is independently associated with coronary atherosclerosis burden among octogenarians.
In contrast to the general population, individuals with primarily persistent elevation of inflammatory activity display a significant association between inflammatory biomarkers and atherosclerotic burden. In older individuals, immunosenescence upregulates the innate response and, by this way, may hypothetically favor the presence of this association. The aim of this study was to evaluate this hypothesis in healthy octogenarians. Participants (n = 208) aged 80 years or older, asymptomatic and without medical and laboratory evidence of chronic diseases or use of anti-inflammatory treatments were included in the study. Lipid profile and plasma C-reactive protein (CRP) were measured at baseline and cardiac computed tomography was performed within 1-week interval for measuring coronary calcium score (CCS). The median plasma CRP was 1.9 mg/L (1.0–3.4) and 33 % of the participants had elevated CRP defined as C3 mg/L. Among those with high CRP, there was an increased frequency of high CCS (C100) as compared with their counterparts (71 vs 50 %, p = 0.001). The association between CRP and CCS persisted even after adjustment for age, sex, cardiovascular risk factors and statin therapy. The area under the receiver-operating curve for CRP was 0.606 using CCS C100 as a binary outcome. The sensitivities for CCS C100 were 40 and 74 % for the cutoff points of CRP C3 or 1 mg/L, respectively. The present study was able to confirm that in very elderly individuals, systemic inflammatory activity is independently associated with coronary atherosclerosis burden.


Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors.
A series of 4-morpholino-2-phenylquinazolines and related derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. In this series, the thieno[3,2-d]pyrimidine derivative 15e showed the strongest inhibitory activity against p110alpha, with an IC(50) value of 2.0 nM, and inhibited proliferation of A375 melanoma cells with an IC(50) value of 0.58 microM. Moreover, 15e was found to be selective for p110alpha over other PI3K isoforms and protein kinases, making it the first example of a selective PI3K p110alpha inhibitor.


Preoperative glucocorticoids decrease pulmonary hypertension in piglets after cardiopulmonary bypass and circulatory arrest.
Glucocorticoids during cardiopulmonary bypass benefit pediatric patients undergoing repair of congenital heart defects and are routine therapy, but underlying mechanisms have not been fully examined. The hypothesis was that glucocorticoids could improve cardiopulmonary recovery after cardiopulmonary bypass and deep hypothermic circulatory arrest. Crossbred piglets (5 to 7 kg) were cooled with cardiopulmonary bypass, followed by 120-min deep hypothermic circulatory arrest. Animals were then warmed to 38 degrees C, removed from bypass, and maintained for 120 min. Methylprednisolone (60 mg/kg) was administered in the cardiopulmonary bypass pump prime (intraoperative glucocorticoids) or 6 hours before bypass (30 mg/kg) in addition to the intraoperative dose (30 mg/kg; preoperative and intraoperative glucocorticoids). Controls (no glucocorticoids) received saline. Pulmonary vascular resistance in controls increased from a baseline of 152 +/- 40 to 364 +/- 29 dynes. s/cm(5) at 2 hours of recovery (p < 0.001). Intraoperative glucocorticoids did not alleviate the increase in pulmonary vascular resistance (301 +/- 55 dynes. s/cm(5) at 2 hours of recovery, p < 0.001). However, animals receiving pre and intraoperative glucocorticoids had no increase in pulmonary vascular resistance (155 +/- 54 dynes. s/cm(5)). Plasma endothelin-1 in controls increased from 1.3 +/- 0.2 at baseline to 9.9 +/- 2.0 pg/mL at 2 hours recovery (p < 0.01), whereas glucocorticoid-treated animals had lower endothelin-1 levels (4.5 +/- 2.1 pg/ml, preoperative and intraoperative glucocorticoids; 4.9 +/- 1.7 pg/mL, intraoperative glucocorticoids) at the end of recovery (p < 0.05). Intracellular adhesion molecule-1 in lung tissue was lower in animals receiving pre and intraoperative glucocorticoids (p < 0.05). Myeloperoxidase activity was elevated in control lungs at 2 hours of recovery compared with glucocorticoid-treated groups (p < 0.05). Inhibitor kappaBalpha, the inhibitor of nuclear factor-kappaB, was higher in lungs of animals receiving glucocorticoids compared with controls (p < 0.05). Glucocorticoids prevented pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest, which was associated with reduced plasma endothelin-1. Glucocorticoids also reduced pulmonary intercellular adhesion molecule-1 and myeloperoxidase activity. Inhibition of nuclear factor-kappaB, along with reduced neutrophil activation, contributed to glucocorticoid alleviation of pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest.


Profiling Genome-Wide Specificity of CRISPR-Cas9 Using Digenome-Seq.
Digenome-seq is a highly sensitive method for analyzing the genome-wide specificity of CRISPR-Cas9 nuclease activity. In this procedure, genomic DNA is first subjected to digestion by CRISPR-Cas9 in vitro and then to whole genome sequencing, which results in unusual patterns of straight alignments at on-target and potential off-target sites. Analysis of these data with the Digenome-seq computer program allows for identification of the in vitro cleavage sites associated with the straight alignments. Here, we present a detailed Digenome-seq protocol for genome-wide profiling of in vitro CRISPR-Cas9 nuclease cleavage sites.


Screening of lignan patterns in Schisandra species using ultrasonic assisted temperature switch ionic liquid microextraction followed by UPLC-MS/MS analysis.
The ultrasonic assisted temperature-switch ionic liquid microextraction (UATS-ILME) has been successfully applied in extracting of seven lignans from Schisandra. 1-Butyl-3-methylimidazolium tetrafluoroborate ([C4MIM][BF4]) aqueous solution was selected for extracting the target analytes in raw material at 80°C. The lignans were deposited into a single drop by in situ forming 1-butyl-3-methylimidazolium hexafluorophosphate ([C4MIM][PF6]) by cooling down to 0°C and centrifuging for 10min. The extracts were analyzed by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) in a robust multiple-reaction monitoring (MRM) mode in five minutes. Meanwhile, the proposed method was validated and successfully applied to the determination of seven lignans in twelve Schisandra species. The results indicated that UATS-ILME combined with UPLC-MS/MS is a powerful and practical tool, which has great potential for comprehensive quality control of herbal medicines.


Selecting Rational Drug Combinations in Epilepsy.
Monotherapy remains the standard initial therapy of epilepsy, but when the first antiepileptic drug (AED) fails, combination therapy may be considered. The choice of combination therapy should take into consideration pharmacokinetic interactions, as well as pharmacodynamic interactions related to mechanism of action. There is evidence that an AED combination with different mechanisms of action is more likely to be successful than a combination with the same mechanisms. The combination of lamotrigine and valproate has been demonstrated to be synergistic in its efficacy. However, there are limited data to support other synergistic AED combinations.


Assessment of water quality of some swimming pools: a case study in Alexandria, Egypt.
In spite of the importance and popularity of swimming pools in summer, they have been identified as posing some public health risks to users due to either chemical or microbiological contamination. This study was carried out aiming at assessing the quality of water for some Alexandria's swimming pools in order to determine its compliance with the Egyptian standards no. 418/1995. Five swimming pools were selected randomly from different districts. Physical and chemical parameters, as well as biological examination of a total of 30 samples, were carried out using standard analytical methods. Water samples were collected from the studied swimming pools monthly over 6 months and pool water monitoring was carried out during afternoon of the weekends when the pools were most heavily used. The results indicated overall poor compliance with the standards. Compliance of the pool water to the microbial parameters, residual chlorine, pH, and turbidity were 56.7% (17 samples), 20% (6 samples), 46.7% (14 samples), and 46.7% (14 samples), respectively. Statistical analysis showed significant association between water contamination with microbial indicators and physical-chemical aspects such as residual chlorine, temperature, turbidity, and load of swimmers. Furthermore, Cryptosporidium oocysts and Giardia lamblia cysts has been found in 10% of samples. It was concluded that there is a need to improve disinfection and cleaning procedures, with consideration given to safety, and size of the pool in relation to bathing load. There is also a need to monitor swimming pool water quality continuously, and to increase bather hygienic practices and awareness of the risks as well as training of governmental inspectors.


Correction: Rapid Quantification of 3D Collagen Fiber Alignment and Fiber Intersection Correlations with High Sensitivity.
[This corrects the article DOI: 10.1371/journal.pone.0131814.].


Double-negative T cells remarkably promote neuroinflammation after ischemic stroke.
CD3+CD4-CD8- T cells (double-negative T cells; DNTs) have diverse functions in peripheral immune-related diseases by regulating immunological and inflammatory homeostasis. However, the functions of DNTs in the central nervous system remain unknown. Here, we found that the levels of DNTs were dramatically increased in both the brain and peripheral blood of stroke patients and in a mouse model in a time-dependent manner. The infiltrating DNTs enhanced cerebral immune and inflammatory responses and exacerbated ischemic brain injury by modulating the FasL/PTPN2/TNF-α signaling pathway. Blockade of this pathway limited DNT-mediated neuroinflammation and improved the outcomes of stroke. Our results identified a critical function of DNTs in the ischemic brain, suggesting that this unique population serves as an attractive target for the treatment of ischemic stroke.


Up-regulation of Proinflammatory Genes and Cytokines Induced by S100A8 in CD8+ T Cells in Lichen Planus.
Lichen planus (LP) is a chronic inflammatory mucocutaneous disease. The inflammatory status of LP may be related to S100A8 (myeloid-related protein 8; MRP8) activation of cytotoxic cells. The aims of this study were to evaluate S100A8 expression in skin lesions and the in vitro effects of S100A8 on CD8+ T cells and natural killer (NK) cells in LP. Increased levels of S100A8/S100A9 were detected in the skin lesions as well as in the sera of subjects with LP. S100A8 expression induced an increased cytotoxic response by peripheral blood CD8+CD107a+ T cells as well as by NK CD56bright cells in patients with LP. Increased expression of interleukin (IL)-1β, tumour necrosis factor (TNF) and IL-6 in the CD8+ T cells of patients with LP was induced by S100A8, in contrast to the control group that produced IL- 10 and interferon (IFN) type I genes. These data suggest that, in individuals with LP, S100A8 may exert distinct immunomodulatory and cytotoxicity functions.


Soil Selenium Concentration and Residents Daily Dietary Intake in a Selenosis Area: A Preliminary Study in Yutangba Village, Enshi City, China.
In 1963, selenosis occurred in Yutangba Village, Enshi City, China. Subsequently, local residents migrated to a new area of Yutangba to avoid high selenium (Se) exposure. In this study, 19 soil samples, 43 food samples, 60 hair samples and 58 plasma samples from local residents were randomly collected in New Yutangba Village. The mean total Se concentrations in cultivated soil samples were 1753.6 ± 742.8 µg/kg (n = 14). The estimated daily Se intake in New Yutangba Village decreased to 63.2 ± 39.8 µg/day, slightly higher than the recommended dietary Se intake for adults in China (60 µg/day). The mean Se concentrations in hair and plasma samples were 549.7 ± 165.2 µg/kg (n = 60) and 98.4 ± 32.1 µg/L (n = 58), respectively. The result indicated that appropriate activities, such as relocation, consuming a mixture of local foods and market foods containing low Se concentration, could effectively reduce the risk of high Se exposure.


Inter-species differences for polychlorinated biphenyls and polybrominated diphenyl ethers in marine top predators from the Southern North Sea: Part 2. Biomagnification in harbour seals and harbour porpoises.
Harbour porpoises (Phocoena phocoena) and harbour seals (Phoca vitulina) were found to differ in the ability to metabolize polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). Biomagnification factors (BMFs), calculated between both predators and their prey (sole--Solea solea and whiting--Merlangius merlangus), had a large range of variation (between 0.5 and 91 for PCBs and between 0.6 and 53 for PBDEs). For the higher chlorinated PCBs and the highest brominated PBDEs, the BMF values in adult males were significantly higher than in the juvenile individuals of both species. BMF values of hexa- to octa-PCBs were the highest, suggesting reduced ability to degrade these congeners. Harbour porpoises had higher BMFs for lower chlorinated PCBs and for all PBDEs compared to harbour seals. Other factors, which may influence biomagnification, such as the octanol-water partition coefficients and the trophic level position measured through stable isotope (delta15N) analysis, were found to be of lesser importance to predict biomagnification in the studied food chain.


Computer averaging of single molecules of alpha 2-macroglobulin and the alpha 2-macroglobulin/trypsin complex.
From electron micrographs single molecules of alpha 2-macroglobulin in the "closed" form, the "open" form and as the trypsin complex have been computer averaged. The molecular images are discussed. Molecules of the electrophoretically fast migrating "F-form" have the "closed" form. In the case of the alpha 2-macroglobulin/trypsin complex the two attached trypsin molecules are located very near to each other and in the central part of the alpha 2-macroglobulin molecule.


Association of heart rhythm with exercise capacity after operation for chronic mitral regurgitation.
Although atrial fibrillation (AF) and decreased exercise capacity are common in chronic mitral regurgitation patients, the relationship between rhythm status and exercise capacity after corrective surgery is largely unknown. Seventy-one patients undergoing repair or replacement of mitral valve for chronic severe mitral regurgitation were examined with preoperative and 6 months' postoperative cardiopulmonary exercise test and two-dimensional echocardiography. Patients were divided into three groups according to preoperative versus postoperative rhythm (sinus/sinus, SS [n=42]; AF/sinus, AS [n=17]; AF/AF, AA group [n=12]). Preoperative maximal oxygen consumption was lower and ventilatory efficiency was higher in the AS and AA groups compared with the SS group. However, maximal oxygen consumption improved only in the AS group at 6 months' postoperative cardiopulmonary exercise test (24.0±6.9 versus 24.6±6.1 mL·kg(-1)·min(-1) in the SS group, 19.3±5.9 versus 23.2±6.4 mL·kg(-1)·min(-1) in the AS group, 19.8±5.4 versus 18.8±5.1 mL·kg(-1)·min(-1) in the AA group; p=0.016 for maximal oxygen consumption by analysis of covariance) as well as ventilatory efficiency. Echocardiography verified more significant reduction of left atrial volume in the SS and AS groups than in the AA group (172.2±68.0 versus 96.7±31.0 mL in the SS group, 247.5±77.8 versus 129.2±25.7 mL in the AS group, 316.7±210.0 versus 192.0±95.0 mL in the AA group; p=0.001 for left atrial volume by analysis of covariance) as well as pulmonary artery systolic pressure. When analyzed for significant predictors of postoperative maximal oxygen consumption, being in the AS group but not the SS group was a significant positive predictor when compared with the AA group (β=5.475; p=0.006). Successful sinus conversion of AF, preferably by maze operation, in patients undergoing surgical correction of chronic severe mitral regurgitation confers improved exercise capacity. Reduction of left atrial volume and pulmonary artery pressure may contribute to this improvement.


A flagship species-based approach to efficient, cost-effective biodiversity conservation in the Qinling Mountains, China.
Prioritizing threatened species protection has been proposed as an efficient response to the global biodiversity crisis. We used in-situ conservation data to predict the potential habitat area of four flagship species: the giant panda (Ailuropoda melanoleuca), golden monkey (Rhinopithecus roxella quinlingensis), takin (Budorcas taxicolor bedfordi), and crested ibis (Nipponia nippon). We then designed systematic conservation planning schemes for various scenarios given species habitat preferences and anthropogenic activities and conducted a cost-effectiveness assessment. Broadly, the geographical distributions of suitable habitats for giant pandas, golden monkeys, and takins exhibited high spatial congruence (correlation coefficients of 0.59-0.90), and areas of high congruence were concentrated in the northern portion of the Qinling Mountains at high elevation (>1500 m). By contrast, the crested ibis was negatively correlated in space with its sympatric species (-0.47 to -0.29). Crested ibis habitats were clustered in the southern portion of the region at low elevation (<1500 m). A hypothetical conservation priority area (CPA) based on the giant panda, golden monkey, and takin included 39.64% of the Qinling Mountains and 100%, 99.99%, 99.59%, and 7.84% of the suitable habitats for giant pandas, golden monkeys, takins, and crested ibises, respectively. The same area included 99.07%, 70.87%, and 39.96% of the highly important areas for the ecosystem services of biodiversity conservation, water supply, and soil retention, respectively, and only 4.62%, 16.83%, and 13.4% of the area were associated with high-density residential area, impervious surfaces, and cropland, respectively. Therefore, we conclude that a CPA approach based on the specialist species could result in effective, low-cost biodiversity conservation in the Qinling Mountains. However, we note that existing protected areas account for only 26.52% of the CPA. We recommend that the main area of the proposed Qinling National Park should be based on the CPA developed here.


Spermidine antagonizes the inhibitory effect of huperzine A on [3H]dizocilpine (MK-801) binding in synaptic membrane of rat cerebral cortex.
Huperzine A, a novel cholinesterase inhibitor, was found to inhibit the N-methyl-D-aspartate (NMDA) receptors in the brain. In this study, the mechanisms of the NMDA receptor inhibition were investigated using [3H]dizocilpine (MK-801) binding in synaptic membrane of rat cerebral cortex. Changing the concentrations of L-glutamate and L-glycine did not alter the potency of huperzine A. Spermidine caused rightward shift of the concentration-response curve of huperzine A, and considerably increased its IC(50) value. Huperzine A did not affect the potency of unlabeled (+)-MK-801 in [3H]MK-801 binding. Saturation binding studies reveal that huperzine A exerts a negative allosteric modulation on the MK-801 binding site within the NMDA receptor-channel. The results suggest that huperzine A is a non-competitive antagonist of the NMDA receptors, acting at one of the polyamine binding sites.


Substrate water exchange in photosystem II core complexes of the extremophilic red alga Cyanidioschyzon merolae.
The binding affinity of the two substrate-water molecules to the water-oxidizing Mn₄CaO₅ catalyst in photosystem II core complexes of the extremophilic red alga Cyanidioschyzon merolae was studied in the S₂ and S₃ states by the exchange of bound ¹⁶O-substrate against ¹⁸O-labeled water. The rate of this exchange was detected via the membrane-inlet mass spectrometric analysis of flash-induced oxygen evolution. For both redox states a fast and slow phase of water-exchange was resolved at the mixed labeled m/z 34 mass peak: kf=52 ± 8s⁻¹ and ks=1.9 ± 0.3s⁻¹ in the S₂ state, and kf=42 ± 2s⁻¹ and kslow=1.2 ± 0.3s⁻¹ in S₃, respectively. Overall these exchange rates are similar to those observed previously with preparations of other organisms. The most remarkable finding is a significantly slower exchange at the fast substrate-water site in the S₂ state, which confirms beyond doubt that both substrate-water molecules are already bound in the S2 state. This leads to a very small change of the affinity for both the fast and the slowly exchanging substrates during the S₂→S₃ transition. Implications for recent models for water-oxidation are briefly discussed.


High-resolution neural network-driven mapping of multiple diffusion metrics leveraging asymmetries in the balanced steady-state free precession frequency profile.
We propose to utilize the rich information content about microstructural tissue properties entangled in asymmetric balanced steady-state free precession (bSSFP) profiles to estimate multiple diffusion metrics simultaneously by neural network (NN) parameter quantification. A 12-point bSSFP phase-cycling scheme with high-resolution whole-brain coverage is employed at 3 and 9.4 T for NN input. Low-resolution target diffusion data are derived based on diffusion-weighted spin-echo echo-planar-imaging (SE-EPI) scans, that is, mean, axial, and radial diffusivity (MD, AD, and RD), fractional anisotropy (FA), as well as the spherical coordinates (azimuth Φ and inclination ϴ) of the principal diffusion eigenvector. A feedforward NN is trained with incorporated probabilistic uncertainty estimation. The NN predictions yielded highly reliable results in white matter (WM) and gray matter structures for MD. The quantification of FA, AD, and RD was overall in good agreement with the reference but the dependence of these parameters on WM anisotropy was somewhat biased (e.g. in corpus callosum). The inclination ϴ was well predicted for anisotropic WM structures, while the azimuth Φ was overall poorly predicted. The findings were highly consistent across both field strengths. Application of the optimized NN to high-resolution input data provided whole-brain maps with rich structural details. In conclusion, the proposed NN-driven approach showed potential to provide distortion-free high-resolution whole-brain maps of multiple diffusion metrics at high to ultrahigh field strengths in clinically relevant scan times.


Direct Synthesis of Formamide from CO2 and H2O with Nickel-Iron Nitride Heterostructures under Mild Hydrothermal Conditions.
Formamide can serve as a key building block for the synthesis of organic molecules relevant to premetabolic processes. Natural pathways for its synthesis from CO2 under early earth conditions are lacking. Here, we report the thermocatalytic conversion of CO2 and H2O to formate and formamide over Ni-Fe nitride heterostructures in the absence of synthetic H2 and N2 under mild hydrothermal conditions. While water molecules act as both a solvent and hydrogen source, metal nitrides serve as nitrogen sources to produce formamide in the temperature range of 25-100 °C under 5-50 bar. Longer reaction times promote the C-C bond coupling and formation of acetate and acetamide as additional products. Besides liquid products, methane and ethane are also produced as gas-phase products. Postreaction characterization of Ni-Fe nitride particles reveals structural alteration and provides insights into the potential reaction mechanism. The findings indicate that gaseous CO2 can serve as a carbon source for the formation of C-N bonds in formamide and acetamide over the Ni-Fe nitride heterostructure under simulated hydrothermal vent conditions.


Association of humic acid with metal (hydr)oxide-coated sands at solid-water interfaces.
Mineral-bound humic acid (HA) can significantly modify the physicochemical properties of the mineral surfaces and vice versa, thereby influencing the fate and transport of organic pollutants in the subsurface. The effect of various mineral surfaces on the adsorption-desorption of dissolved bulk, terrestrial HA was evaluated using three model sorbents [uncoated, alpha-FeO(OH)-coated, and Al2O3-coated sands] at two equilibrium pH values. The results of SEM/EDS and XPS analyses revealed relatively uniform and stable metal (hydr)oxide coatings on quartz surface and the presence of the HA coating. Strong hysteresis effects were observed for both metal (hydr)oxide-coated sands whereas a weaker hysteresis effect was observed for uncoated sand, suggesting that the adsorption-desorption of HA to model sorbents is dependent on the affinity of chemical interactions between the HA and surface composition of model sorbents. Adsorption of HA molecules onto metal (hydr)oxide-coated sands can be attributed to ligand exchange for lower molecular weight (MW) HA fractions and hydrophobic interaction for higher MW HA fractions, illustrating that both kinetic and fractional adsorption-desorption of HA subcomponents are important considerations.


Characterization of hemangioblast in umbilical arteries of mid-gestation mouse embryos.
Hemangioblasts are the common precursors of hematopoietic and vascular cells, and are characterized as blast colony-forming cells (BL-CFCs) in vitro. We previously identified BL-CFCs in the mouse aorta-gonads-mesonephros (AGM) region, but not yolk sac, placenta, circulation, or fetal liver. Here, we aim to determine whether BL-CFCs develop in the umbilical arteries (UA) that link the dorsal aorta (sub-region of AGM) and placenta. We find that the UA cells of E11.5 mouse embryos were capable of generating typical blast colonies. On replating, these colonies produced erythroid/myeloid progenitors and B220(+) B lymphocytes in vitro, corroborating their definitive hematopoietic nature. They also generated CD31(+) or endomucin(+) tube-like structures on OP9 stromal cells, showing their endothelial potential. The proximal and distal regions of UA had equal numbers of BL-CFCs. To evaluate whether BL-CFCs can be autonomously maintained or expanded in UA or AGM, in vitro organ culture was performed. Interestingly, the BL-CFC pool in the AGM was significantly amplified, in striking contrast to a decrease in the UA. Taken together, our findings indicate that in addition to the AGM the UA serves as an important, but less supportive, niche for hemangioblast development.


A new genus and species of cestode (Rhinebothriidea) from Mobula kuhlii (Rajiformes: Mobulidae) from Malaysian Borneo.
The cestode fauna of the shortfin devilray, Mobula kuhlii (Müller & Henle, 1841) was examined for the first time. The work resulted in the discovery of a new genus and species of rhinebothriidean tapeworm. Crassuseptum pietrafacei, n. gen. n. sp. is erected here on the basis of its unique scolex and proglottid morphology. Histological sections and examination by light and scanning electron microscopy demonstrated that this new genus differs from all other rhinebothriidean genera in its possession of bothridia in which the proximal and distal sides are confluent, i.e., not separated by a rim of tissue, and in its possession of testes that extend to the posterior margin of the ovary. This new species is characterized in part by its possession of stalked, elongate bothridia lacking lateral constrictions, with 13-15 prominent transverse bothridial septa and 4 reduced transverse septa, craspedote proglottids, each with 2-3 layers of testes in cross section, and a vas deferens that joins the cirrus sac at its anterior margin. Histological and optical sections through bothridial septa revealed that the transverse septa are formed by septal muscles separate from bothridial radial musculature, extending from the anterior side to the posterior side of each septum. This is only the second species rhinebothriidean cestode reported from mobulids. This study adds to the number of new species and genera of elasmobranch cestodes discovered off of the island of Borneo.


Autoradiographic visualization of corticotropin releasing hormone type 1 receptors with a nonpeptide ligand: synthesis of [(76)Br]MJL-1-109-2.
A high-affinity, nonpeptide radioligand for the CRHR1 was synthesized and showed distribution in rat brain consistent with CRHR1 using in vitro autoradiography. This is the first nonpeptide radiotracer combining high affinity and appropriate lipophilicity that penetrates the blood-brain barrier and hence has the potential to be used for PET imaging studies. In vivo visualization of changes in the CRH1 receptor or its occupancy would further the understanding of the pathophysiology of stress related diseases.


Primary prostatic lymphoma: a rare prostatic malignancy.
Primary prostatic lymphoma is a very rare condition for which the treatment is ill defined. A case of this condition from Australia is reported and treatment recommendations reviewed.


Redox control of exofacial protein thiols/disulfides by protein disulfide isomerase.
Protein disulfide isomerase (PDI) facilitates proper folding and disulfide bonding of nascent proteins in the endoplasmic reticulum and is secreted by cells and associates with the cell surface. We examined the consequence of over- or underexpression of PDI in HT1080 fibrosarcoma cells for the redox state of cell-surface protein thiols/disulfides. Overexpression of PDI resulted in 3.6-4. 2-fold enhanced secretion of PDI and 1.5-1.7-fold increase in surface-bound PDI. Antisense-mediated underexpression of PDI caused 38-53% decreased secretion and 10-33% decrease in surface-bound PDI. Using 5,5'-dithio-bis(2-nitrobenzoic acid) to measure surface protein thiols, a 41-50% increase in surface thiols was observed in PDI-overexpressing cells, whereas a 29-33% decrease was observed in underexpressing cells. Surface thiol content was strongly correlated with cellular (r = 0.998) and secreted (r = 0.969) PDI levels. The pattern of exofacial protein thiols was examined by labeling with the membrane-impermeable thiol reactive compound, 3-(N-maleimidylpropionyl)biocytin. Fourteen identifiable proteins on HT1080 cells were labeled with 3-(N-maleimidylpropionyl)biocytin. The intensity of labeling of 11 proteins was increased with overexpression of PDI, whereas the intensity of labeling of 3 of the 11 proteins was clearly decreased with underexpression of PDI. These findings indicated that secreted PDI was controlling the redox state of existing exofacial protein thiols or reactive disulfide bonds.


Domestic cats and dogs are susceptible to H9N2 avian influenza virus.
Replication and transmission of avian influenza virus (AIV) in domestic dogs and cats may pose a risk to humans. The susceptibility of cats and dogs to H9N2 influenza virus was evaluated by intranasally or orally inoculating animals with an H9N2 influenza virus. Cats had recoverable virus in respiratory tissues and the olfactory bulb three days post-inoculation and shed H9N2 virus into nasal washes and pharyngeal swabs from day 2 through day 10 post-inoculation. Virus was recovered from respiratory tissues of dogs three days post-inoculation, but was not detected in nasal washes or pharyngeal swabs. While no virus shedding or replication was detected in cats or dogs following consumption of H9N2-infected chicks, one of two cats and one of two dogs seroconverted. Two of three naïve contact cats seroconverted following co-housing with cats that were intranasally inoculated with H9N2 virus, whereas none of the three naïve contact dogs seroconverted. Our results demonstrate that H9N2 AIV can infect domestic cats and dogs via the upper respiratory tract and indicate that cats are more susceptible than dogs to H9N2 AIV. These findings suggest that domestic dogs and cats may serve as host species contributing to the adaptation of H9N2 viruses in mammals.


Urinary zinc and metallothionein in children with spina bifida.
Defective embryonic cellular zinc utilization may contribute to abnormal neural tube formation and such a defect may be detectable in children with spina bifida (SB). To investigate this possibility, we examined urinary excretion of zinc and metallothionein (Mt), a cytoplasmic metal-binding protein, in 10 girls and 6 boys (ages 6 months to 19 years) with SB and 16 age-matched control subjects. Mean urinary zinc and Mt concentrations in the SB group were 65% and 72% greater than controls, respectively (p less than 0.05). There was was no evidence of renal dysfunction as judged by urinary creatinine and total protein excretion in the SB children. Increased excretion of zinc and Mt in some children with SB may reflect one or more underlying defects of zinc utilization.


Adverse perinatal outcomes after Roux-en-Y Gastric Bypass vs. Sleeve Gastrectomy: a systematic review.
Pregnancies occurring after bariatric surgery are associated with various perinatal complications. However, there may be differences in the type of perinatal complications occurring after different methods of bariatric surgery. The aim of the current study was to compare adverse perinatal outcomes in pregnant women following Roux-en-Y Gastric Bypass (RYGB) vs. Sleeve Gastrectomy (SG). A systematic database search was performed in PubMed, Embase, Scopus and CINAHL. Observational studies comparing perinatal outcomes post-bariatric (RYGB and SG) surgery to pregnancies without prior surgery were selected. Outcomes of interest were: maternal body mass index (BMI) at the time of conception, mode of delivery, time from surgery to conception, birth weight, gestational age and intrauterine fetal death. Article selection, risk of bias assessment and data extraction, were performed by two authors. The study protocol was published in its revised form in PROSPERO, registration number: CRD42021234480. A total of 3201 records were extracted. After duplicates were removed, 3143 records were screened for inclusion. Six studies fitted the selection criteria, of which four studies were RYGB and two SG (1100 post-RYGB vs. 209 post-SG). For the included studies, higher incidence of both SGA (22.9%, 11.9%, 14.2%) and LGA (4.2%, 4.8%, 1.7%) in SG compared to Roux-en-Y (SGA: 8.8%, 7.7%, 11.5%, 8.3% and LGA: 3.4%, 0.7%) were observed. SG had a shorter surgery to conception interval as compared to RYGB. Risk of bias assessment was moderate to serious for the studies included in the review, with bias in selection of participants being the major reason. Our systematic review demonstrated no major differences in BMI, mode of delivery, birthweight, gestational age, or rates of intrauterine death between women having undergone RYGB vs. SG. The rate of SGA and LGA births were higher in the SG group, but this group also had a shorter surgery to conception interval. Future studies are indicated to counsel women of reproductive age on the most appropriate type of bariatric surgery that is associated with the best perinatal outcomes.


Healthcare seeking for constipation: a population-based survey in the Mediterranean area of Spain.
The use of healthcare resources for the management of constipation is not well-known. To analyse healthcare seeking for constipation, defined by three different criteria, and its related factors and to assess the frequency of use of laxatives, suppositories and enemas for the treatment of constipation. A cross-sectional study in the general community. A questionnaire comprising 21-items was developed and delivered by mail to a random sample of 506 subjects aged 18-65 years, and belonging to a Spanish population. Seeking of health care was high in the sample (16%) and was similar for all definitions of constipation (over 40% of constipated subjects). It was associated with female gender, a higher educational level and two symptoms, such as prolonged defecation and abdominal pain. A 14% of the sample used laxatives, and about a 25% of constipated subjects used laxatives at least once a week. Utilization was more frequent in women, with no differences by age group. Chronic constipation is a problem that causes an important consumption of resources in our setting, derived from laxative use and the seeking of medical help to combat the problem. The use of these resources is higher in women.


Naproxen kinetics and disease activity in rheumatoid arthritis: a within-patient study.
The effects of rheumatoid arthritis disease activity on the pharmacokinetics of the highly albumin-bound nonsteroidal anti-inflammatory drug naproxen were studied in six patients during chronic therapy. In the same patients, kinetics during active disease were compared with those in improvement. Active disease is commonly associated with hypoalbuminemia: 30 +/- 4 gm/L vs. 41 +/- 2 gm/L (mean +/- SD) at the time of improvement. Total naproxen concentrations were significantly lower in active disease, together with a larger apparent volume of distribution (10.6 +/- 1.8 L vs. 8.4 +/- 1.3 L; P less than 0.05) and total body clearance (0.79 +/- 1.8 L/hr vs. 0.59 +/- 0.14 L/hr; P less than 0.001). Peak unbound naproxen concentrations were 29% +/- 19% (P less than 0.05) lower at the time of improvement. The unbound clearance was found diminished during active disease (390 +/- 277 L/hr) in comparison with improvement (488 +/- 343 L/hr; P less than 0.05). Clinical implications of the alterations in naproxen kinetics induced by polyarticular inflammation in patients with rheumatoid arthritis are discussed.


Prevention and control of lameness in dairy cattle.
The prevention and control of lameness are essential if a dairy herd is to return a profit. Breeding, feeding, housing, and management practices are all involved, and errors or omissions in any of these areas can result in catastrophic lameness. An accurate diagnosis and proper treatment are necessary to minimize losses when lameness occurs.


High rate of ceramic sandwich liner fracture.
Ceramic bearing surfaces for THA were introduced to reduce the risk of wear. However, owing to liner fracture in some of the early series and presumption that the fractures were the result of the modulus mismatch of the implant and the bone, a ceramic sandwich liner with lower structural rigidity was introduced. Fractures of these devices also were reported subsequently, although the incidence is unclear and it is unknown whether there are any risk factors associated with the fractures. We therefore determined the incidence of these fractures. We retrospectively reviewed 298 active patients in whom we implanted 353 ceramic-polyethylene sandwich liner acetabular components between November 1999 and February 2008. The mean age of the patients was 53.6 years (range, 17-84 years). The minimum followup was 6 months (mean, 41 months; range, 6-106 months). All patients were assessed clinically and radiographically. Seven of the 353 (2%) ceramic sandwich liners fractured at a mean of 4.3 years (range, 1.3-7.6 years) after surgery without trauma. Neither patient-related factors nor radiographic position of the implants were risk factors for fracture. Owing to the high rate of fractures of the sandwich ceramic polyethylene liners in our patients, we have discontinued use of this device. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.


Neuromuscular and hormonal responses in elite athletes to two successive strength training sessions in one day.
Acute neuromuscular and endocrine adaptations to weight-lifting were investigated during two successive high intensity training sessions in the same day. Both the morning (I) (from 9.00 to 11.00 hours) and the afternoon (II) (from 15.00 hours to 17.00 hours) training sessions resulted in decreases in maximal isometric strength (p less than 0.01 and less than 0.05), shifts (worsening) in the force-time curve in the absolute scale (p less than 0.05 and ns.) and in decreases in the maximal integrated EMG (p less than 0.01 and less than 0.05) of the selected leg extensor muscles. Increases in serum total (p less than 0.05) and free testosterone (p less than 0.01) and in cortisol (p less than 0.01) concentrations were found during training session II. These were followed by decreases (p less than 0.001 and p less than 0.01 and ns.) in the levels of these hormones one hour after the termination of the session. The responses during the morning training session were different with regard to the decreases in serum total testosterone (p less than 0.05), free testosterone (ns.) and cortisol (p less than 0.05). Only slight changes were observed in the levels of luteinizing hormone and sex hormone-binding globulin during the training sessions. Increases (p less than 0.01) took place in somatotropin during both training sessions. The present findings suggest that high intensity strengthening exercises may result in acute adaptive responses in both the neuromuscular and endocrine systems. The diurnal variations may, however, partly mask the exercise-induced acute endocrinological adaptations in the morning.(ABSTRACT TRUNCATED AT 250 WORDS)


A novel method for extraction, clean-up and analysis of per- and polyfluoroalkyl substances (PFAS) in different plant matrices using LC-MS/MS.
Per- and polyfluoroalkyl substances (PFAS) are chemicals of concern due to their persistence, bioaccumulation, and toxic properties. PFAS accumulation in plants poses a risk of human and animal exposure due to consumption of the affected plants, but also allows plants to be used in remediation of PFAS-contaminated soils and groundwater. Therefore, effective extraction, cleanup, and analytical methods for measuring PFAS concentrations in plants are fundamental for research on animal and environmental health. PFAS analysis in plant matrices is complex, due to high matrix interference, and scarcity of methods for analyzing different classes of PFAS. In this study, a simple sample preparation method for PFAS analysis in various plant tissues (leaves, needles, twigs, stems, roots from 10 different species) was developed and validated. Instrumental analysis was performed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The method was optimized considering six different extraction conditions and three different cleanup techniques. Methanol as extraction solvent, combined with 1 g ENVI carb cartridges, showed best performance among all extraction conditions and cleanup techniques tested. Method validation showed good recovery (90-120%), high within-day and between-day precision (<20% relative standard deviation), and low method detection limit (0.04-4.8 ng g-1 dry weight (dw)) for different plant matrices. In tests of the method on soil and different plant tissues of silver birch (Betula pendula) and Norway spruce (Picea abies) at a PFAS-contaminated site, 16 of 24 target PFAS were detected in plants and 17 in soil. ƩPFAS concentration in soil was 43 ng g-1 dw. PFAS distribution in silver birch tissues ranged from 7.1 ng g-1 dw in roots to 64 ng g-1 dw in leaves, and in Norway spruce from 14 ng g-1 dw in roots to 16 ng g-1 dw in needles. This novel method for PFAS analysis in plants can be valuable in future monitoring, process understanding, remediation, and risk assessments.


Nanoengineered particles for sustainable crop production: potentials and challenges.
Nanoengineered nanoparticles have a significant impact on the morphological, physiology, biochemical, cytogenetic, and reproductive yields of agricultural crops. Metal and metal oxide nanoparticles like Ag, Au, Cu, Zn, Ti, Mg, Mn, Fe, Mo, etc. and ZnO, TiO2, CuO, SiO2, MgO, MnO, Fe2O3 or Fe3O4, etc. that found entry into agricultural land, alter the morphological, biochemical and physiological system of crop plants. And the impacts on these parameters vary based on the type of crop and nanoparticles, doses of nanoparticles and its exposure situation or duration, etc. These nanoparticles have application in agriculture as nanofertilizers, nanopesticides, nanoremediator, nanobiosensor, nanoformulation, phytostress-mediator, etc. The challenges of engineered metal and metal oxide nanoparticles pertaining to soil pollution, phytotoxicity, and safety issue for food chains (human and animal safety) need to be understood in detail. This review provides a general overview of the applications of nanoparticles, their potentials and challenges in agriculture for sustainable crop production.


Understanding the role of endotoxin tolerance in chronic inflammatory conditions and periodontal disease.
This review aims to present the current understanding of endotoxin tolerance (ET) in chronic inflammatory diseases and explores the potential connection with periodontitis. Subsequent exposure to lipopolysaccharides (LPS) triggers ET, a phenomenon regulated by different mechanisms and pathways, including toll-like receptors (TLRs), nuclear factor kappa-light-chain enhancer of activated B-cells (NFκB), apoptosis of immune cells, epigenetics, and microRNAs (miRNAs). These mechanisms interconnect ET with chronic inflammatory diseases including periodontitis. While the direct correlation between ET and periodontal destruction has not been fully elucidated, emerging reports point towards the potential tolerization of human periodontal ligament cells (hPDLCs) and gingival tissues with a significant reduction of TLR levels. There is a potential link between ET and periodontal diseases. Future studies should explore the crucial role of ET in the pathogenesis of periodontal diseases, as evidence of a tolerized oral mucosa may represent an intrinsic mechanism capable of regulating the oral immune response. A clear understanding of this host immune regulatory mechanism might lead to effective and more predictable therapeutic strategies to treat chronic inflammatory diseases and periodontitis.


Ethical hazards of health data governance in the metaverse.
Metaverse-enabled healthcare is no longer hypothetical. Developers must now contend with ethical, legal and social hazards if they are to overcome the systematic inefficiencies and inequities that exist for patients who seek care in the real world.


The recommended treatment algorithms of the BCLC and HKLC staging systems: does following these always improve survival rates for HCC patients?
Several staging systems have been proposed for hepatocellular carcinoma (HCC). Among them, only the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC) staging systems also recommend treatment modality. This study was designed to see whether BCLC and HKLC staging can guide treatment strategy, so analyzed whether patients survival is better for those who received recommended therapy by each staging system. A total of 3515 treatment-naïve, newly diagnosed HCC patients at a single centre were analyzed. Five-year survival rates according to BCLC stages: 0 = 79.1%, A = 62.9%, B = 40.3%, C = 21.3% and D = 27.0%; 5-year survival rates according to HKLC stages: I = 72.3%, IIa = 54.9%, IIb = 50.6%, IIIa = 21.3%, IIIb = 10.2%, IVa = 16.7%, IVb = 7.2%, Va = 47.1% and Vb = 11.3%. The C-indices of the BCLC and HKLC staging systems were 0.708 and 0.732 respectively. Patient survival was better when patients received the recommended treatment in stages 0 or A; survival was worse if treatment began at stage B, C or D. For HKLC staging system, survival was better when patients received the recommended treatment in stages I, IIa, IIb, IIIa or Va but was worse when treatment began in stages IIIb, IVa, IVb or Vb. Both the BCLC and HKLC staging systems effectively stratified patient prognosis, but neither could direct therapy for a large proportion of patients; for some stages, recommended therapy was associated with worse prognosis.


Response of deciduous trees spring phenology to recent and projected climate change in Central Lithuania.
The analysis of long-term time series of spring phenology for different deciduous trees species has shown that leaf unfolding for all the investigated species is the most sensitive to temperatures in March and April and illustrates that forcing temperature is the main driver of the advancement of leaf unfolding. Available chilling amount has increased by 22.5 % over the last 90 years, indicating that in the investigated geographical region there is no threat of chilling shortage. The projection of climatic parameters for Central Lithuania on the basis of three global circulation models has shown that under the optimistic climate change scenario (RCP 2.6) the mean temperature tends to increase by 1.28 °C and under the pessimistic scenario (RCP 8.5) by 5.03 °C until the end of the current century. Recently, different statistical models are used not only to analyze but also to project the changes in spring phenology. Our study has shown that when the data of long-term phenological observations are available, multiple regression models are suitable for the projection of the advancement of leaf unfolding under the changing climate. According to the RCP 8.5 scenario, the projected advancement in leaf unfolding for early-season species birch consists of almost 15 days as an average of all three used GSMs. Markedly less response to the projected far future (2071-2100), climate change is foreseen for other investigated climax species: -9 days for lime, 10 days for oak, and 11 days for maple.


Roadmap towards an institutional Impella programme for high-risk coronary interventions.
Coronary artery disease (CAD) and its complications remain the main cause of morbidity and mortality worldwide. Patients with extensive CAD and multiple comorbidities who require complex, high-risk percutaneous coronary intervention (HR-PCI) are at risk of haemodynamic instability and may require short-term mechanical circulatory support (MCS) during the procedure to maintain sufficient perfusion and prevent ischaemia. Impella is a microaxial continuous blood flow pump used for percutaneous support of the left ventricle in patients undergoing HR-PCI. Data from randomized controlled trials and registries suggested an advantage for Impella devices in patients undergoing HR-PCI, compared with other types of MCS. As a thorough understanding of the benefits and drawbacks of the Impella technology is crucial for patient outcomes, we provide a technological overview of Impella and share our experiences gathered during the implementation of institutional Impella programmes in Poland as a roadmap of selection and periprocedural care for patients treated with Impella in the setting of HR-PCI. We propose 10 steps for implementation of an institutional Impella programme for HR-PCI, including (i) dedicated staff training; (ii) standard operating procedure and troubleshooting algorithms prior to the first intervention; (iii) patient selection by the multidisciplinary Heart Team; (iv) patient preparation using multimodality imaging; (v) procedure planning in terms of large-bore access, equipment, and complete revascularization; (vi) starting with HR-PCI support; (vii) starting with femoral artery access in a patient without extensive peripheral artery disease; (viii) multidisciplinary care after the procedure; (ix) haemodynamic and laboratory monitoring to ensure immediate diagnosis of access-site complications, bleeding, haemolysis, acute kidney injury, and infections; and (x) careful revision of every HR-PCI case with the team.


Comparing Single- and Dual-Antiplatelet Therapies After Transcatheter Aortic Valve Implantation.
Transcatheter aortic valve implantation has been an established treatment in patients with symptomatic severe aortic stenosis. However, the postoperative antiplatelet regimen after transcatheter aortic valve implantation has not been established with certainty. This meta-analysis compared the safety and efficacy of single- antiplatelet therapies (SAPTs) and dual-antiplatelet therapies (DAPT) in patients undergoing transcatheter aortic valve implantation. Eligible randomized controlled trials and cohort studies published before February 2021 were retrieved from PubMed, Embase, and the Cochrane Library. We calculated odds ratios (ORs) with 95% CIs. Nine articles, involving 19 277 patients, met the selection criteria. In the short-term outcome, compared with SAPT, DAPT was associated with a significantly higher rate of bleeding (OR, 3.00; 95% CI, 1.67-5.38) and showed no significant differences in thrombotic events (OR, 1.25; 95% CI, 0.74-2.11) and all-cause mortality (OR, 0.84; 95% CI, 0.42-1.69). In the long-term outcome, DAPT was associated with a significantly higher bleeding rate (OR, 1.85; 95% CI, 1.24-.78) and showed no differences in thrombotic events (OR, 1.13; 95% CI, 0.86-1.48) and all-cause mortality (OR, 1.12; 95% CI, 0.95-1.32). Our trial sequential analysis confirmed DAPT did not confer any benefit for reducing all-cause mortality and thrombotic events and carried a higher risk of bleeding than SAPT. SAPT should be a sufficient antiplatelet strategy in patients after transcatheter aortic valve implantation who do not have indications for oral anticoagulation medication, especially in the long-term follow-up period.


Iloprost Use in Patients with Persistent Intestinal Ischemia Unsuitable for Revascularization.
Persistent or chronic intestinal ischemic injury (i3) can lead to severe malnutrition and acute mesenteric ischemia. Although recommended, revascularization of splanchnic arteries is sometimes unrealizable. We report a case series of iloprost use in consecutive stable patients with persistent i3 unsuitable for revascularization followed in a tertiary care center. The feasibility of revascularization was discussed and ruled out by a multidisciplinary team, and informed consent was obtained prior to consideration of a vasoactive therapy. Therapeutic response was defined at 6 months by a decrease in the use of analgesic and parenteral nutrition, and no need for intestinal resection. Between 2006 and 2015, 6 patients (mean age: 51) were included. Splanchnic vascular insufficiency was due to superior mesenteric artery (SMA) thrombosis (n = 4), dissection of the celiac trunk and SMA (n = 1), or repeated vasospasm resulting in chronic nonocclusive mesenteric ischemia (n = 1). Iloprost was delivered via continuous intravenous perfusion at a maximum dosage of 2 ng/kg/min for 6 hours/day on 4 consecutive days, without severe adverse events. Therapeutic response was observed in 4 patients, 3 of which completely stopped parenteral nutrition and analgesic with no need for intestinal resection. Our results are consistent with findings of a favorable effect of iloprost in patients with persistent splanchnic ischemia that should be confirmed in prospective trials.


Hepatitis B virus reactivation after heart transplant: Incidence and clinical impact.
Occult hepatitis B infection consists of persistence of HBV genomes in hepatocytes,absence of serum HBsAg, low/undetectable serum HBVDNA. Reactivation of HBV infection may occur during immunosuppression, but few data are available in heart transplant. We followed-up heart recipients with or without markers of previous HBV infection,evaluating prevalence of HBV markers, incidence of HBV reactivation and its virological and clinical features. Heart failure patients listed for heart transplant (2007-2013) were screened for current or past HBV infection. Transplanted patients with past HBV infection (anti-HBc+/±anti-HBs+/HBVDNA-) were followed up as cases, and an equal number of HBV negative patients as controls. Virological reactivation was detected by standard real-time and home-made highly sensitive PCR (surface/core HBVDNA regions). Clinical status and progression were assessed by liver histology, ultrasound or elastography. 67 patients underwent heart transplant, including 4 (5.9%) HBsAg+ subjects. Cases were 11/67 (16.4%). During a median follow-up of 30 months, only one of these 11 patients presented viral reactivation (HBVDNA 209IU/mL) at month 22, and started antiviral treatment. Four other recipients showed virological events of uncertain significance (sensitive PCR-only intermittently positive). Clinical signs of liver disease were observed in only one case at the last follow-up. A nonsignificant difference in survival was observed between cases and all other heart recipients without prior HBV contact (death rate 5/11 vs 15/52, respectively; p=0.097). HBV genotypic reactivation in HBsAg-/anti-HBc+/HBVDNA- heart recipients is uncommon. Virological events of uncertain significance occur more frequently; their clinical impact seems to be negligible.


Advanced colorectal cancer resulting in acute bowel obstruction during pregnancy; a case report.
Abdominal pain is frequently found in the pregnant population; however life-threatening pathology such as colorectal cancer does occur rarely. As such, intestinal obstructions are usually attributed to pregnancy-related issues. We present the case of a young woman with an acute bowel obstruction caused by advanced colorectal carcinoma. A 34-year old pregnant woman was referred to our emergency department with complaints of severe upper abdominal pain. Initial investigations did not show abdominal pathology and conservative treatment for obstipation was commenced. However, complaints persisted and a near blowout of the colon was diagnosed, prompting a caesarean section and diagnostic laparotomy. An obstructing tumour was found and a left-sided hemi-colectomy was performed. Unfortunately, skeletal, lymphatic and additional hepatogenic metastasis were discovered during chemotherapy and treatment was discontinued. The mainstay of abdominal complaints during pregnancy can be attributed to normal physiological alterations associated with gravidity. Nonetheless serious pathology should be considered, especially when conservative treatment fails. On this note, diagnostic imaging during pregnancy should be used promptly upon suspicion of serious abdominal pathology.


Characterization of fibrillation process of alpha-synuclein at the initial stage.
alpha-Synuclein is the major component of the filamentous Lewy bodies and Lewy-related neurites, neuropathological hallmarks of Parkinson's disease. Although numerous studies on alpha-synuclein fibrillation have been reported, the molecular mechanisms of aggregation and fibrillation at the initial stage are still unclear. In the present study, structural properties and propensities to form fibrils of alpha-synuclein at the initial stage were investigated using 2D (1)H-(15)N NMR spectroscopy, electron microscope, and small angle X-ray scattering (SAXS). Observation of the 2D (1)H-(15)N HSQC spectra indicated significant attenuation of many cross peak intensities in the regions of KTKEGV-type repeats and the non-Abeta component of Alzheimer's disease amyloid (NAC), suggesting that these regions contributed fibril formation. Oligomerization comprising heptamer was successfully monitored at the initial stage using the time-dependent SAXS measurements.


Health-related quality of life in curatively-treated patients with esophageal or gastric cancer: A systematic review and meta-analysis.
Surgery and chemoradiotherapy can potentially cure esophageal and gastric cancer patients, although they may impact health-related quality of life (HRQoL). We aim to systemically review and meta-analyze literature to determine the effect of curative treatments on HRQoL in esophageal and gastric cancer.- A systematic search was performed identifying studies assessing HRQoL. Meta-analyses were performed on baseline and subsequent time-points.- From the 6067 articles retrieved, 49 studies were included (61 % low quality). Meta-analyses showed short-term HRQoL differences between esophageal cancer patients receiving definitive chemoradiotherapy (dCRT), neoadjuvant chemo(radio)therapy (nC(R)T), or surgery alone (p < 0.001), with better HRQoL with nC(R)T and surgery compared to dCRT. Over the course of 12 months, no HRQoL difference was identified between treatments in esophageal cancer (p = 0.633). Esophagectomy, but not gastrectomy, resulted in a clinically relevant decline in HRQoL. No long-term HRQoL differences were identified between curative treatments in esophageal and gastric cancer. More high-quality HRQoL studies are warranted.