Interlaboratory random amplified polymorphic DNA typing of Yersinia enterocolitica and Y. enterocolitica-like bacteria.
A random amplified polymorphic DNA (RAPD) protocol was developed for interlaboratory use to discriminate food-borne Yersinia enterocolitica O:3 from other serogroups of Y. enterocolitica and from Y. enterocolitica-like species. Factors that were studied regarding the RAPD performance were choice of primers and concentration of PCR reagents (template DNA, MgCl(2), primer and Taq DNA polymerase). A factorial design experiment was performed to identify the optimal concentrations of the PCR reagents. The experiment showed that the concentration of the PCR reagents tested significantly affected the number of distinct RAPD products. The RAPD protocol developed was evaluated regarding its discrimination ability using 70 different Yersinia strains. Cluster analysis of the RAPD patterns obtained revealed three main groups representing (i) Y. pseudotuberculosis, (ii) Y. enterocolitica and (iii) Y. kristensenii, Y. frederiksenii, Y. intermedia and Y. ruckeri. Within the Y. enterocolitica group, the European serovar (O:3) and the North American serovar (O:8) could be clearly separated from each other. All Y. enterocolitica O:3 strains were found in one cluster which could be further divided into two subclusters, representing the geographical origin of the isolates. Thus, one of the subclusters contained Y. enterocolitica O:3 strains originating from Sweden, Finland and Norway, while Danish and English O:3 strains were found in another subcluster together with O:9 and O:5,27 strains. The repeatability (intralaboratory) and reproducibility (interlaboratory) of the RAPD protocol were tested using 15 Yersinia strains representing different RAPD patterns. The intralaboratory and the interlaboratory studies gave similarity coefficients of the same magnitude (generally >70%) for the individual strains. In the present study, it was shown that interreproducible RAPD results could be achieved by appropriate optimisation of the RAPD protocol. Furthermore, the study reflects the heterogeneous genetic diversity of the Y. enterocolitica species.


Substantial contribution of northern high-latitude sources to mineral dust in the Arctic.
In the Arctic, impurities in the atmosphere and cryosphere can strongly affect the atmospheric radiation and surface energy balance. While black carbon has hence received much attention, mineral dust has been in the background. Mineral dust is not only transported into the Arctic from remote regions but also, possibly increasingly, generated in the region itself. Here we study mineral dust in the Arctic based on global transport model simulations. For this, we have developed a dust mobilization scheme in combination with the Lagrangian particle dispersion model FLEXPART. A model evaluation, based on measurements of surface concentrations and annual deposition at a number of stations and aircraft vertical profiles, shows the suitability of this model to study global dust transport. Simulations indicate that about 3% of global dust emission originates from high-latitude dust sources in the Arctic. Due to limited convection and enhanced efficiency of removal, dust emitted in these source regions is mostly deposited closer to the source than dust from for instance Asia or Africa. This leads to dominant contributions of local dust sources to total surface dust concentrations (~85%) and dust deposition (~90%) in the Arctic region. Dust deposition from local sources peaks in autumn, while dust deposition from remote sources occurs mainly in spring in the Arctic. With increasing altitude, remote sources become more important for dust concentrations as well as deposition. Therefore, total atmospheric dust loads in the Arctic are strongly influenced by Asian (~38%) and African (~32%) dust, whereas local dust contributes only 27%. Dust loads are thus largest in spring when remote dust is efficiently transported into the Arctic. Overall, our study shows that contributions of local dust sources are more important in the Arctic than previously thought, particularly with respect to surface concentrations and dust deposition.


A qualitative study of unmet healthcare needs in chronic obstructive pulmonary disease. A potential role for specialist palliative care?
Patients with chronic obstructive pulmonary disease (COPD) have high symptom burdens and poor health-related quality of life. The American Thoracic Society issued a consensus statement outlining the need for palliative care for patients with chronic respiratory diseases. A better understanding of the unmet healthcare needs among patients with COPD may help determine which aspects of palliative care are most beneficial. To identify the unmet healthcare needs of patients with COPD hospitalized for exacerbation using qualitative methods. We conducted 20 semistructured interviews of patients admitted for acute exacerbations of COPD focused on patient understanding of diagnosis and prognosis, effect of COPD on daily life and social relationships, symptoms, healthcare needs, and preparation for the end of life. Transcribed interviews were evaluated using thematic analysis. Six themes were identified. (1) Understanding of disease: Most participants correctly identified their diagnosis and recognized their symptoms worsening over time. Only half understood their disease severity and prognosis. (2) SYMPTOMS: Breathlessness was universal and severe. (3) Physical limitations: COPD prevented participation in activities. (4) Emotional distress: Depressive symptoms and/or anxiety were present in most participants. (5) Social isolation: Most participants identified social limitations and felt confined to their homes. (6) Concerns about the future: Half of participants expressed fear about their future. There are many unmet healthcare needs among patients hospitalized for COPD exacerbation. Relief of symptoms, physical limitations, emotional distress, social isolation, and concerns about the future may be better managed by integrating specialist palliative care into our current care model.


Establishing a Three Rs programme at the Canadian Council on Animal Care.
The anniversary of the Fund for the Replacement of Animals in Medical Experiments (FRAME) provides an opportunity to celebrate the Charity's achievements over the past 40 years, and in particular, its contribution to the international acceptance of the Three Rs as the basis of an ethic for animal experimentation, and its role as a leader in the implementation of the Three Rs in the life sciences. The Canadian Council on Animal Care (CCAC) has based its work on the Three Rs, especially since the establishment of its fundamental CCAC Policy Statement on the Ethics of Animal Investigation (1989). Following recommendations from the evaluation of its programmes by external committees established by the national granting agencies, the CCAC recently launched a Three Rs Program. This programme will build on the work of FRAME and other similar Three Rs organisations, to further the promotion and implementation of the Three Rs in Canadian science.


Reappraising the long-term course and outcome of psychotic disorders: the AESOP-10 study.
Studies of the long-term course and outcome of psychoses tend to focus on cohorts of prevalent cases. Such studies bias samples towards those with poor outcomes, which may distort our understanding of prognosis. Long-term follow-up studies of epidemiologically robust first-episode samples are rare. AESOP-10 is a 10-year follow-up study of 557 individuals with a first episode of psychosis initially identified in two areas in the UK (South East London and Nottingham). Detailed information was collated on course and outcome in three domains (clinical, social and service use) from case records, informants and follow-up interviews. At follow-up, of 532 incident cases identified, at baseline 37 (7%) had died, 29 (6%) had emigrated and eight (2%) were excluded. Of the remaining 458, 412 (90%) were traced and some information on follow-up was collated for 387 (85%). Most cases (265, 77%) experienced at least one period of sustained remission; at follow-up, 141 (46%) had been symptom free for at least 2 years. A majority (208, 72%) of cases had been employed for less than 25% of the follow-up period. The median number of hospital admissions, including at first presentation, was 2 [interquartile range (IQR) 1-4]; a majority (299, 88%) were admitted a least once and a minority (21, 6%) had 10 or more admissions. Overall, outcomes were worse for those with a non-affective diagnosis, for men and for those from South East London. Sustained periods of symptom remission are usual following first presentation to mental health services for psychosis, including for those with a non-affective disorder; almost half recover.


Investigation of congestive heart failure in beef cattle in a feedyard at a moderate altitude in western Nebraska.
Right-sided congestive heart failure (brisket disease) commonly occurs in cattle raised at elevations >2,500-3,500 m. We investigated clinical cases resembling brisket disease at a western Nebraska feedyard at a moderate altitude (1,369 m). Over a 15-mo period (2009-2010), we examined 17 cases (16 steers and 1 heifer), all purebred Angus. All animals had clinical right-sided heart failure: brisket and ventral abdominal edema, and severe chronic passive congestion of the liver. Gross examination confirmed right ventricular hypertrophy (left ventricle plus septum: right ventricle weight ratio mean: 1.33 vs. 2.8-4.0 reference interval). Microscopically, all 17 cases had interstitial fibrosis (mean score: 2.4 ± 0.8) and 6 had replacement fibrosis of the right ventricle, whereas 14 had interstitial fibrosis (mean score: 1.2 ± 0.2) and 0 had replacement fibrosis of the left ventricle. Lesions of arteriosclerosis were seen in 9 of 16 cases in 51 of 571 (8.9%) right ventricular coronary arteries, and in 10 of 16 cases in 52 of 366 (14.2%) left ventricular coronary arteries. The probability of coronary arteriosclerosis was greater in papillary ventricular muscle (OR = 11.3; p < 0.0001), left ventricle (OR = 4.8; p < 0.0001), and larger arteries (OR = 1.01; p < 0.0001). Pulmonary arteries and arterioles had lesions compatible with hypoxia-induced pulmonary hypertension. We hypothesize that moderate hypobaric conditions significantly contributed to disease in cattle genetically predisposed to hypoxia-induced pulmonary hypertension. Adiposity, coronary arteriosclerosis, and left ventricular fibrosis may have contributed to the condition; however, the cattle died prior to development of advanced obesity.


The identification and cloning of the murine genes encoding the liver specific F alloantigens.
The liver specific F alloantigen is a highly conserved abundant protein found in hepatic cytoplasm; smaller amounts are detected in renal tubule cells and the perikaryon cells of the central nervous system. Although the biological function of the F alloantigen is unknown, the immune response to F has been extensively studied as a murine model of tolerance and autoimmunity. Murine F exists in two allelic forms, designated F type 1 and type 2, each of approximately 43 kDa. The immune response to the allotypic form is restricted to mouse strains of I-Ak. Responding strains immunized with allotypic F break tolerance and produce precipitating antibody that reacts with both allelic forms, i.e., immunogen and self. Thus an autoantibody is produced. Using the previously isolated rat F cDNA as a probe, we report the cloning and sequencing of the two murine F allotypes. These two alleles are nearly homologous except at the extremes of the coding sequence. There are a number of regions within the F sequence that are similar to peptides that interact specifically with I-Ak. In particular, there is a sequence near the carboxy terminus, where the two allotypes differ, that has homology to the I-Ak restricted malarial antigen peptide of the ring-infected erythrocyte surface antigen (RESA).


The social development of children with severe learning difficulties: a case study of an inclusive education initiative between two primary schools in Oxfordshire, UK.
This case study of primary age children in two linked Oxfordshire schools investigated the contribution of staff attitudes and practices to inequalities in education, and contrasted the socialisation of children with similar learning difficulties in different educational placements. Participant observation of a group of children and carers in a special school suggested areas of more rigorous inquiry. Structured observations compared this group with a matched sample of children with similar learning difficulties in a mainstream setting. Staff on both sites were invited to comment on findings arising from analysed data in order to identify attitudes and policies which might account for the observed differences in practice. The study was engendered by experience of differences arising from educational placement. The theoretical stance arose through reviewing previous work, predominantly the debate on inclusive education, and the wider issues of human rights and equal opportunities embedded in the social development of people with disabilities. The theoretical framework underpinning this study is established in some depth. The project was designed to investigate issues of the wider social perspective, by conducting a micro-study of one model of educational inclusion whose outcomes have direct relevance to those issues.


Comparing different approaches for assessing the impact of COVID-19 lockdown on urban air quality in Reading, UK.
Many studies investigated the impact of COVID-19 lockdown on urban air quality, but their adopted approaches have varied and there is no consensus as to which approach should be used. In this paper we compare three of the main approaches and assess their performance using both estimated and measured data from several air quality monitoring stations (AQMS) in Reading, Berkshire UK. The approaches are: (1) Sequential approach - comparing pre-lockdown and lockdown periods 2020; (2) Parallel approach - comparing 2019 and 2020 for the equivalent time of the lockdown period; and (3) Machine learning modelling approach - predicting pollution levels for the lockdown period using business as usual (BAU) scenario and comparing with the observations. The parallel and machine learning approaches resulted in relative higher reductions and both showed strong correlation (0.97) and less error with each other. The sequential approach showed less reduction in NO and NOx, showed positive gain in PM10 and NO2 at most of the sites and demonstrated weak correlation with the other two approaches, and is not recommended for such analysis. Overall, the sequential approach showed -14, +4, -32, and + 56% change, the parallel approach showed -46, -43, -43 and + 7% change, and the machine learning approach showed -47, -44, -38 and + 5% change in NOx, NO2, NO and PM10 concentrations, respectively. The pollution roses demonstrated that the UK received easterly polluted winds from the central and eastern Europe, promoting secondary particulates and O3 formation during the lockdown. Changes in pollutant concentrations vary both in space and time according to the approach used, environment type of the monitoring site and the data type (e.g., deweathered vs. raw data). Therefore, the reported results (here or elsewhere) should be viewed in light of these factors before making any conclusion.


Relevance feedback in content-based image retrieval: Bayesian framework, feature subspaces, and progressive learning.
Research has been devoted in the past few years to relevance feedback as an effective solution to improve performance of content-based image retrieval (CBIR). In this paper, we propose a new feedback approach with progressive learning capability combined with a novel method for the feature subspace extraction. The proposed approach is based on a Bayesian classifier and treats positive and negative feedback examples with different strategies. Positive examples are used to estimate a Gaussian distribution that represents the desired images for a given query; while the negative examples are used to modify the ranking of the retrieved candidates. In addition, feature subspace is extracted and updated during the feedback process using a principal component analysis (PCA) technique and based on user's feedback. That is, in addition to reducing the dimensionality of feature spaces, a proper subspace for each type of features is obtained in the feedback process to further improve the retrieval accuracy. Experiments demonstrate that the proposed method increases the retrieval speed, reduces the required memory and improves the retrieval accuracy significantly.


Identification of adducts formed in the reactions of 5'-acetoxy-N'-nitrosonornicotine with deoxyadenosine, thymidine, and DNA.
N'-Nitrosonornicotine (NNN) is the most prevalent of the carcinogenic tobacco-specific nitrosamines found in all tobacco products. Previous studies have demonstrated that cytochrome P450-mediated 5'-hydroxylation of NNN is a major metabolic pathway leading to mutagenic products, but to date, DNA adducts formed by this pathway have been only partially characterized, and there have been no studies reported on adducts formed with bases other than dGuo. Because adducts with dAdo and dThd have been identified in the DNA of the livers of rats treated with the structurally related carcinogen N-nitrosopyrrolidine, we investigated dAdo and dThd adduct formation from 5'-acetoxyNNN (3), a stable precursor to 5'-hydroxyNNN (2). Reaction of 3 with dAdo gave diastereomeric products, which were identified by their spectral properties and LC-ESI-MS/MS-SRM analysis as N(6)-[5-(3-pyridyl)tetrahydrofuran-2-yl]dAdo (9). This adduct was further characterized by NaBH(3)CN reduction to N(6)-[4-hydroxy-4-(3-pyridyl)but-1-yl]dAdo (17). A second dAdo adduct was identified, after NaBH(3)CN treatment, as 6-[2-(3-pyridyl)pyrrolidin-1-yl]purine-2'-deoxyriboside (18). Reaction of 3 with dThd, followed by NaBH(3)CN reduction, gave O(2)-[4-(3-pyridyl)-4-hydroxybut-1-yl]thymidine (11). Adducts 9, 11, 17, and 18 were all identified by LC-ESI-MS/MS-SRM comparison to synthetic standards. The reaction of 3 with calf thymus DNA was then investigated. The DNA was enzymatically hydrolyzed to deoxyribonucleosides, and the resulting mixture was treated with NaBH(3)CN and analyzed by LC-ESI-MS/MS-SRM. Adducts 11, 17, and 18, as well as the previously identified dGuo adducts, were identified. The results of this study provide a more comprehensive picture of DNA adduct formation by the quantitatively important 5'-hydroxylation pathway of NNN and will facilitate investigation of the presence of these adducts in laboratory animals treated with NNN or in people who use tobacco products.


Functional and Structural Findings in Infants Treated for Retinopathy of Prematurity Using Optical Coherence Tomography Angiography.
To assess the foveal microvascular structure of children with retinopathy of prematurity (ROP) treated with diode laser photocoagulation using optical coherence tomography angiography (OCTA). OCTA was performed at a tertiary medical center in 17 children (27 eyes) aged 4 to 16 years with a history of diode laser photocoagulation treated ROP. OCTA parameters were compared with those of 12 healthy age-matched controls (23 eyes) attending the orthoptics clinic and correlated with clinical factors. Compared with controls, the ROP group had a smaller foveal avascular zone area (P < .001), lower deep vascular plexus density (P < .001), lower flow density (P = .025), and greater central macular thickness (P < .001). High intraventricular hemorrhage grade correlated with smaller foveal avascular zone area (P = .008) and greater inner macular thickness (P = .047). There was no impact of gestational age, birth weight, or refractive status. OCTA can identify significant quantifiable long-term macular microvascular and structural changes in this patient population. [Ophthalmic Surg Lasers Imaging Retina. 2022;53(4):194-201.].


New-Onset Accelerated Idioventricular Rhythm During Dental Rehabilitation.
Accelerated idioventricular rhythm has been documented in several cases involving the induction of general anesthesia; however, it has not previously been known to occur during reversal of neuromuscular blockade with neostigmine and glycopyrrolate. The current understanding of the pathophysiology of accelerated idioventricular rhythm involves enhanced automaticity of ventricular myocardium in the setting of increased vagal tone suppressing sinoatrial node pace making. We present the case of an 8-year-old boy who developed accelerated idioventricular rhythm during dental rehabilitation. In this case, accelerated idioventricular rhythm developed immediately upon reversal of neuromuscular blockade with neostigmine and glycopyrrolate and recurred intermittently during his recovery in the postanesthesia care unit. This was a benign occurrence in our patient who remained asymptomatic and hemodynamically stable, and his arrhythmia eventually subsided without intervention after several hours of telemetry. This case suggests that reversal of neuromuscular blockade with neostigmine and glycopyrrolate may induce accelerated idioventricular rhythm in certain patients without known cardiovascular disease.


Methicillin-resistant Staphylococcus aureus control in the 21st century: beyond the acute care hospital.
To describe new trends in the epidemiology of methicillin-resistant Staphylococcus aureus in the community, among animals and in long-term care settings and to discuss potential infection control implications. Healthcare-associated methicillin-resistant S. aureus rates have decreased in several European countries. Community-associated methicillin-resistant S. aureus is spreading quickly in many parts of the world; however, its prevalence and molecular epidemiology varies considerably from continent to continent. Only few intervention studies have been published examining preventive strategies to control community-associated methicillin-resistant S. aureus transmission in the community. Although current North-American guidelines neither recommend contact tracing nor systematic decontamination with topical regimens, anecdotal evidence from several European countries suggests that these strategies could be useful in containing community-associated methicillin-resistant S. aureus. The spread of community-associated methicillin-resistant S. aureus in the healthcare setting is an emerging problem that needs early recognition and aggressive control measures, as proposed in several recent outbreak reports. Whether the increasing animal methicillin-resistant S. aureus reservoir also poses a threat to human health needs further investigation. The spectrum of methicillin-resistant S. aureus epidemiology is extending into new populations. The impact on healthcare of this worrisome development has been documented in several studies. Implications for long-term methicillin-resistant S. aureus control strategies are yet unclear and need further study.


Pathology of Plasmodium chabaudi chabaudi infection and mortality in interleukin-10-deficient mice are ameliorated by anti-tumor necrosis factor alpha and exacerbated by anti-transforming growth factor beta antibodies.
Interleukin-10 (IL-10)-deficient (IL-10(-/-)) mice infected with Plasmodium chabaudi (AS) suffer a more severe disease and exhibit a higher rate of mortality than control C57BL/6 mice. Here, we show that a drop in body temperature to below 28 degrees C and pronounced hypoglycemia of below 3 mM are reliable indicators of a lethal infection. Elevated inflammatory responses have been shown to accompany pathology in infected IL-10(-/-) mice. We show that neutralization of tumor necrosis factor alpha (TNF-alpha) in IL-10(-/-) mice abolishes mortality and ameliorates the hypothermia, weight loss, and anemia but does not affect the degree of hypoglycemia. These data suggest that TNF-alpha is involved in some of the pathology associated with a P. chabaudi infection in IL-10(-/-) mice but other factors play a role. IL-10(-/-) mice that survive a primary infection have been shown to control gamma interferon (IFN-gamma) and TNF-alpha production, indicating that other cytokines or mechanisms may be involved in their down-regulation. Significantly higher levels of transforming growth factor beta (TGF-beta), a cytokine with such properties, are present in the plasma of infected IL-10(-/-) mice at a time that coincides with the disappearance of IFN-gamma and TNF-alpha from the blood. Neutralization of TGF-beta in IL-10(-/-) mice resulted in higher circulating amounts of TNF-alpha and IFN-gamma, and all treated IL-10(-/-) mice died within 12 days with increased pathology but with no obvious increase in parasitemia. Our data suggest that a tight regulation of the balance between regulatory cytokines such as IL-10 and TGF-beta and inflammatory cytokines such as IFN-gamma and TNF-alpha is critical for survival in a mouse malaria infection.


[Optokinetic nystagmus studied through otoneurologic methods].
The horizontal optokinetic nystagmus (NOC) has been studied during 5,000 otoneurological investigations. In 16.25% of all our cases, the NOC was found to be either weakened in both directions, or only in one direction. There has been no constant relationship between intensity of the spontaneous nystagmus and NOC asymmetry in case of peripheral vestibular lesion. NOC asymmetry seems to be a reliable sign of the evolution of a lesion. Cases without peripheral hypofunction have been divided into three groups: ocular disturbances, brain stem lesions and hemispherical lesions. In these cases the value of the localization of the asymmetry in NOC and nystagmus induced by vestibular tests has been studied. In hemisperical lesions, when asymmetry affected exclusively the NOC, the direction of the weakened NOC was always towards the healthy side. When asymmetry affected not only NOC but even nystagmus induced by vestibular stimulations, this weakened side of the nystagmus was less significant.


Mechanisms of motivation-cognition interaction: challenges and opportunities.
Recent years have seen a rejuvenation of interest in studies of motivation-cognition interactions arising from many different areas of psychology and neuroscience. The present issue of Cognitive, Affective, & Behavioral Neuroscience provides a sampling of some of the latest research from a number of these different areas. In this introductory article, we provide an overview of the current state of the field, in terms of key research developments and candidate neural mechanisms receiving focused investigation as potential sources of motivation-cognition interaction. However, our primary goal is conceptual: to highlight the distinct perspectives taken by different research areas, in terms of how motivation is defined, the relevant dimensions and dissociations that are emphasized, and the theoretical questions being targeted. Together, these distinctions present both challenges and opportunities for efforts aiming toward a more unified and cross-disciplinary approach. We identify a set of pressing research questions calling for this sort of cross-disciplinary approach, with the explicit goal of encouraging integrative and collaborative investigations directed toward them.


Swine influenza virus infection dynamics in two pig farms; results of a longitudinal assessment.
In order to assess the dynamics of influenza virus infection in pigs, serological and virological follow-ups were conducted in two whole batches of pigs from two different farms (F1 and F2), from 3 weeks of age until market age. Anti-swine influenza virus (SIV) antibodies (measured by ELISA and hemagglutination inhibition) and nasal virus shedding (measured by RRT-PCR and isolation in embryonated chicken eggs and MDCK cells) were carried out periodically. SIV isolates were subtyped and hemagglutinin and neuraminidase genes were partially sequenced and analyzed phylogenetically. In F1, four waves of viral circulation were detected, and globally, 62/121 pigs (51.2%) were positive by RRT-PCR at least once. All F1 isolates corresponded to H1N1 subtype although hemagglutination inhibition results also revealed the presence of antibodies against H3N2. The first viral wave took place in the presence of colostral-derived antibodies. Nine pigs were positive in two non-consecutive sampling weeks, with two of the animals being positive with the same isolate. Phylogenetic analyses showed that different H1N1 variants circulated in that farm. In F2, only one isolate, H1N2, was detected and all infections were concentrated in a very short period of time, as assumed for a classic influenza outbreak. These findings led us to propose that influenza virus infection in pigs might present different patterns, from an epidemic outbreak to an endemic form with different waves of infections with a lower incidence.


The epidemiology of common late-life mental disorders in the community: themes for the new century.
The prevalence and incidence of the major mental disorders of late life that are common in the community and in primary health care are reviewed. Community-based studies in English that included older adults were identified through MEDLINE searches and were reviewed. As the population ages, dementia, depression, and other mental conditions of the aged will demand more attention from clinicians and investigators to minimize their effects on disability, the use of health care services, and the quality of life for older adults and caregivers. Up to 15 to 20 percent of older adults have significant depressive symptoms, and it is estimated that as many as 45 percent of persons age 85 years and older have significant cognitive impairment and dementia. Other mental-health-related conditions, such as anxiety disorders, alcohol abuse, and prescription medicine misuse, are also important considerations but have not been as well studied as depression and dementia. Because an increasing proportion of older adults are members of minority groups, clinicians need to increase their awareness of how cultural factors relate to risk for mental disorders in late life. Attention to three themes may help clinicians and investigators meet the challenge of treating the common mental disorders of later life: the effect of these disorders on functioning, prevention of the consequences of mental disorders, and integration of mental health care and primary health care services.


Vasa promotes Drosophila germline stem cell differentiation by activating mei-P26 translation by directly interacting with a (U)-rich motif in its 3' UTR.
Vasa (Vas) is a DEAD-box RNA-binding protein required in Drosophila at several steps of oogenesis and for primordial germ cell (PGC) specification. Vas associates with eukaryotic initiation factor 5B (eIF5B), and this interaction has been implicated in translational activation of gurken mRNA in the oocyte. Vas is expressed in all ovarian germline cells, and aspects of the vas-null phenotype suggest a function in regulating the balance between germline stem cells (GSCs) and their fate-restricted descendants. We used a biochemical approach to recover Vas-associated mRNAs and obtained mei-P26, whose product represses microRNA activity and promotes GSC differentiation. We found that vas and mei-P26 mutants interact, and that mei-P26 translation is substantially reduced in vas mutant cells. In vitro, Vas protein bound specifically to a (U)-rich motif in the mei-P26 3' untranslated region (UTR), and Vas-dependent regulation of GFP-mei-P26 transgenes in vivo was dependent on the same (U)-rich 3' UTR domain. The ability of Vas to activate mei-P26 expression in vivo was abrogated by a mutation that greatly reduces its interaction with eIF5B. Taken together, our data support the conclusion that Vas promotes germ cell differentiation by directly activating mei-P26 translation in early-stage committed cells.


Perspectives in the biological function and the technological application of polygalacturonases.
Polygalacturonases (PG) have evolved in the past years from a pectinase "simply" being used for food processing to an important parameter in plant-fungal interaction. PG-inhibiting proteins (PGIP) that are synthesised in plants as a specific response to PGs of pathogenic fungi, have become a focus as a possible target in resistance breeding, and PGIPs are also a concern as an inhibiting factor in food processing. Plant PGs have been identified as a major factor in fruit ripening, and PG-deficient transgenic plants have been bred. Mainly fungal PGs are used in industrial processes for juice clarification and the range of enzymes is being extended through new recombinant and non-recombinant fungal strains. Finally, novel fields of application can be envisaged for PGs in the production of oligogalacturonides as functional food components. Here we aim to highlight the various fields where PGs are encountered and where they are of biological or technological importance.


Left atrial remodeling: assessment of size and shape to detect vulnerability to atrial fibrillation.
The ellipse formula often underestimates left atrial (LA) dilation. Complete echocardiographic analysis of LA shape in relation to electrical remodeling has not been performed. To analyze the relation between LA shape/surface and vulnerability to atrial fibrillation (AF). We studied 112 patients aged 43 +/- 16 years, and referred for electrophysiological study. LA surface (LAS) was measured at end-systole (maximal). Trapezoidal LA shape was defined if the transverse dimension was less than the basal dimension. Decremental index (DI) was calculated as the maximal percentage prolongation of interatrial conduction time during atrial extrastimulation. The LA was considered vulnerable if AF was inducible. DI > 50%, repetitive atrial activity, and fragmented electrograms defined susceptibility to vulnerability. LAS ranged between 10.5 and 36.6 cm(2); 77 patients had a trapezoidal LA. By simple regression analysis LAS correlated with DI (r(2) = 0.38, P = 0.0001). LAS predicted susceptibility to vulnerability better than vulnerability to AF (area under the ROC curve: 0.93 vs 0.81). The best cut-off value for LAS as predictor of susceptibility to vulnerability was 19.5 cm(2) (sensitivity: 89%; specificity: 90.5%; positive predictive value: 93.4%; negative predictive value: 84.4%). Using LAS > 25 cm(2) as a cut-off value, LA vulnerability to AF was detected with a sensitivity of 56.2% and a specificity of 95% (positive predictive value: 81.8%; negative predictive value: 83.3%). LA shape was trapezoidal in 72% patients with LAS > 25 cm(2) and in 30% patients with LAS < 19.5 cm(2) (P < 0.0001). LA dilation and electrical remodeling are related. Progressive LA dilation is accompanied by shape remodeling. Appropriate characterization of LA remodeling should therefore include LAS measurement and LA shape assessment.


Limited Stress Response to Transplantation in the Mediterranean Macroalga Ericaria amentacea, a Key Species for Marine Forest Restoration.
In the Mediterranean Sea, brown macroalgae represent the dominant species in intertidal and subtidal habitats. Despite conservation efforts, these canopy-forming species showed a dramatic decline, highlighting the urge for active intervention to regenerate self-sustaining populations. For this reason, the restoration of macroalgae forests through transplantation has been recognized as a promising approach. However, the potential stress caused by the handling of thalli has never been assessed. Here, we used a manipulative approach to assess the transplant-induced stress in the Mediterranean Ericaria amentacea, through the analysis of biochemical proxies, i.e., phenolic compounds, lipids, and fatty acids in both transplanted and natural macroalgae over time. The results showed that seasonal environmental variability had an important effect on the biochemical composition of macroalgae, suggesting the occurrence of acclimation responses to summer increased temperature and light irradiance. Transplant-induced stress appears to have only amplified the biochemical response, probably due to increased sensitivity of the macroalgae already subjected to mechanical and osmotic stress (e.g., handling, wounding, desiccation). The ability of E. amentacea to cope with both environmental and transplant-induced stress highlights the high plasticity of the species studied, as well as the suitability of transplantation of adult thalli to restore E. amentacea beds.


A worldwide survey of neonicotinoids in honey.
Growing evidence for global pollinator decline is causing concern for biodiversity conservation and ecosystem services maintenance. Neonicotinoid pesticides have been identified or suspected as a key factor responsible for this decline. We assessed the global exposure of pollinators to neonicotinoids by analyzing 198 honey samples from across the world. We found at least one of five tested compounds (acetamiprid, clothianidin, imidacloprid, thiacloprid, and thiamethoxam) in 75% of all samples, 45% of samples contained two or more of these compounds, and 10% contained four or five. Our results confirm the exposure of bees to neonicotinoids in their food throughout the world. The coexistence of neonicotinoids and other pesticides may increase harm to pollinators. However, the concentrations detected are below the maximum residue level authorized for human consumption (average ± standard error for positive samples: 1.8 ± 0.56 nanograms per gram).


Microvascular anastomoses for bone grafts in the treatment of massive defects in bone.
Six patients with large defects in bone are described in whom we performed microvascular anastomoses of grafted fibular vessels (arteries and veins) to vessels in the recipient site. Two other patients, with massive loss of bone and skin, were treated by grafting of osteocutaneous composites also using microvascular anastomoses. All but one defect healed successfully. There is a wide potential for applications of these two techniques in the treatment of large segmental bone defects secondary to trauma or following tumor resection.


Homoplasy in the evolution of modern human-like joint proportions in Australopithecus afarensis.
The evolution of bipedalism and reduced reliance on arboreality in hominins resulted in larger lower limb joints relative to the joints of the upper limb. The pattern and timing of this transition, however, remains unresolved. Here, we find the limb joint proportions of Australopithecus afarensis, Homo erectus, and Homo naledi to resemble those of modern humans, whereas those of A. africanus, Australopithecus sediba, Paranthropus robustus, Paranthropus boisei, Homo habilis, and Homo floresiensis are more ape-like. The homology of limb joint proportions in A. afarensis and modern humans can only be explained by a series of evolutionary reversals irrespective of differing phylogenetic hypotheses. Thus, the independent evolution of modern human-like limb joint proportions in A. afarensis is a more parsimonious explanation. Overall, these results support an emerging perspective in hominin paleobiology that A. afarensis was the most terrestrially adapted australopith despite the importance of arboreality throughout much of early hominin evolution.


Association between low-sodium salt intervention and long-term blood pressure changes is modified by ENaC genetic variation: a gene-diet interaction analysis in a randomized controlled trial.
Background: Hypertension is closely associated with excessive sodium intake, and low-sodium salt has been shown to lower blood pressure. However, whether low-sodium salt interacts with genetic variation related to salt sensitivity of blood pressure is unclear. Methods: A total of 259 hypertensive patients who completed the previous 3 years of a low-sodium salt vs. normal salt intervention were included in our study. Genetic risk scores (GRSs) of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were respectively built for each participant. A general linear regression model and a generalized mixed model were applied to identify the interaction effects between low-sodium salt intervention and ENaC genetic variation on SBP/DBP changes and trajectories over 3 years. Findings: during the 3-year intervention, both SBP and DBP levels showed a significant decline in the low-sodium salt intervention group than those in the normal salt intervention group over 3 years (Psalt intervention group = 0.001 for SBP and Psalt intervention group = 0.006 for DBP). Furthermore, a gene-diet interaction was found for the SBP change trajectory over 3 years (PSBP-GRS×salt intervention group = 0.011); specifically, significant SBP reductions were found between salt intervention groups in the high SBP-GRS group (-18.77 vs. -9.58 mmHg, Psalt intervention group = 0.001), but not in the low SBP-GRS group (-15.71 vs. -14.62 mmHg, Psalt intervention group = 0.791). No interaction effect between low-sodium salt intervention and genetic variation of ENaC was found for changes in DBP. Conclusions: Higher ENaC genetic variation is associated with a greater reduction in SBP in response to a low-sodium salt intervention. Hypertensive patients with higher ENaC genetic variation may experience a greater benefit in SBP reductions by consuming low-sodium salt. (Trial registration: chiCTR-TRC-09000538, https://www.chictr.org.cn).


Long-term safety, tolerability and efficacy of aliskiren in combination with valsartan in patients with hypertension: a 6-month interim analysis.
Renin-angiotensin system (RAS) blockade with ACE inhibitor and/or angiotensin receptor blocker therapy can lead to increased potassium levels, hence the need to assess dual blockade involving a direct renin inhibitor. Here we report the results of a pre-planned 6-month interim analysis of a long-term, open-label study examining the safety, tolerability and efficacy of the aliskiren/valsartan 300/320-mg combination in patients with hypertension. A total of 601 patients with hypertension (msDBP > or = 90 and < 110 mmHg) received a combination of aliskiren/valsartan 150/160 mg for 2 weeks followed by forced titration to aliskiren/valsartan 300/320 mg once daily for a targeted duration of 52 weeks. Optional hydrochlorothiazide (HCTZ) addition was allowed from week 8 for inadequate BP control (> or = 140/90 mmHg). The primary objective was to assess the safety of combination therapy; potassium elevations were a predefined safety outcome. BP was measured at regular intervals during the study. At the 6-month cut-off date, 512 patients (85.2%) were still ongoing with study treatment, and 192 patients had received at least one dose of HCTZ add-on during this period. Combination therapy was generally well-tolerated; the most commonly reported adverse events were headache (7.5%), dizziness (7.3%) and nasopharyngitis (7.2%). Ten patients (2.5%) receiving aliskiren/valsartan and two patients (1.0%) receiving aliskiren/valsartan/HCTZ had serum potassium elevations > 5.5 mmol/L. Only one patient (0.2%) exhibited potassium levels > or = 6.0 mmol/L during this period and the patient was treated with aliskiren/valsartan. Mean msSBP/DBP reductions of 22.3/14.4 mmHg were observed at 6-month endpoint (LOCF analysis) and 73.4% of patients achieved BP control (< 140/90 mmHg; LOCF). Although lack of an active comparator group is a limitation of the study, our findings show that long-term treatment with the aliskiren/valsartan 300/320-mg combination provided clinically significant BP lowering, was well-tolerated and was associated with a very low rate of potassium elevations in patients with hypertension.


NK cells as effectors of acquired immune responses: effector CD4+ T cell-dependent activation of NK cells following vaccination.
We characterized vaccine-induced cellular responses to rabies virus in naive adult volunteers. Contrary to current paradigms, we observed potent and prolonged in vitro NK cell cytokine production and degranulation responses after restimulation of PBMCs with inactivated rabies virus in vaccinated, but not in unvaccinated, individuals. This "recall" NK cell response was absolutely dependent on Ag-specific IL-2 from CD45RO(+) CD4(+) T cells as well as IL-12 and IL-18 from accessory cells. Importantly, NK cells represented over 70% of all IFN-gamma-secreting and degranulating cells in the first 12-18 h after virus rechallenge indicating they may be required for rapid control of infection after vaccination. Activation of NK cells may be a critical function of IL-2-secreting effector memory T cells. Although IL-2-dependent postvaccination NK cell activation has been reported previously, this is the first time the magnitude of this effect and its contribution to the overall vaccine-induced response has been appreciated and the mechanisms of NK activation postvaccination have been elucidated. Our data will allow standard protocols for evaluating vaccine-induced immunity to be adapted to assess NK cell effector responses.


Sociodemographic and clinical characteristics of patients with dissociative disorders in an Arabian society.
The aim of the study was to determine the sociodemographic and clinical characteristics of patients with dissociative disorders among psychiatric patients in the population of the United Arab Emirates. Six hundred inpatients with dissociative disorders were approached during the period 1997-2003, and 468 agreed to participate in the study. These patients were recruited from Al-Ain and Tawam Teaching Hospitals and Al-Jahili Primary Health Care Centers in Al-Ain, United Arab Emirates. The study is based on a questionnaire that included sociodemographic and clinical variables. Dissociative disorders were diagnosed according to the classification set forth in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the International Classification of Diseases (ICD-10) of the World Health Organization. Of the 468 patients studied, the majority (67.9%) were young, under the age of 25 years; 55% were UAE nationals, 59.4% female and 40.6% male. Disorganized movement was significantly lower among females (34.2%) than males (44.2%, p < 0.03). Disapproving of the key relative behaviour was higher in females (24.1%) compared to males (13.2%); comorbid anxiety was higher in females (37.4%) vs. males (25.3%). Disturbed relationships were more common in females (40.3%) while precipitating factors, such as intolerable stressful events, were significantly higher in males (42.6%, p < 0.01). Furthermore, males (20.5%) had a significantly higher history of similar episodes and other psychiatric illnesses (7.5%) than females. Finally, females (41%) showed more statistically significant improvements compared to males (29.5%, p < 0.001). Patients under 25 years of age suffered more from dissociative disorders with no correlation to educational level as a predisposing factor. The most common symptoms were fits or unorganized movements.


Properties of ubiquinol oxidase reconstituted from ubiquinol-cytochrome c reductase, cytochrome c and cytochrome c oxidase.
Ubiquinol-cytochrome c reductase (Complex III), cytochrome c and cytochrome c oxidase can be combined to reconstitute antimycin-sensitive ubiquinol oxidase activity. In 25 mM-acetate/Tris, pH 7.8, cytochrome c binds at high-affinity sites (KD = 0.1 microM) and low-affinity sites (KD approx. 10 microM). Quinol oxidase activity is 50% of maximal activity when cytochrome c is bound to only 25% of the high affinity sites. The other 50% of activity seems to be due to cytochrome c bound at low-affinity sites. Reconstitution in the presence of soya-bean phospholipids prevents aggregation of cytochrome c oxidase and gives rise to much higher rates of quinol oxidase. The cytochrome c dependence was unaltered. Antimycin curves have the same shape regardless of lipid/protein ratio, Complex III/cytochrome c oxidase ratio or cytochrome c concentration. Proposals on the nature of the interaction between Complex III, cytochrome c and cytochrome c oxidase are considered in the light of these results.


Non-septicemic melioidosis presenting as cardiac tamponade.
Melioidosis is endemic in Taiwan. It is caused by infection with Burkholderia pseudomallei. A prolonged course of oral eradication therapy to avoid relapse after an intensive intravenous therapy is recommended to treat melioidosis. Melioidosis with cardiac involvement is rare and is often combined with septicemia, for which the mortality rate is 20-60%. The initial clinical presentations of melioidosis mimic Mycobacterium tuberculosis infection, which is the most common etiology of bacterial pericarditis in Taiwan. We present a case of non-septicemic melioidosis that presented as non-suppurative cardiac tamponade and left subcarinal lymphadenopathy. Underlying diseases included hepatitis B-related liver cirrhosis and hepatocellular carcinoma. The patient was successfully treated with 2 weeks of intravenous ceftazidime and 12 weeks of oral doxycycline, trimethoprim-sulfamethoxazole, and amoxicillin/clavulanate. Melioidosis-related pericarditis should be considered in the differential diagnoses of bacterial pericarditis in Taiwan.


A Portable Low-Cost Respiration Rate Measurement System for Sleep Apnea Detection.
Continuous monitoring of breathing activity is vital in detecting respiratory-based diseases such as obstructive sleep apnea (OSA) and hypopnea. Sleep apnea (SA) is a potentially dangerous sleep problem that occurs when a person's breathing stops and begins periodically while they sleep. In addition, SA interrupts sleep, causing significant daytime sleepiness, weirdness, and irritability. This study aims to design a single inertial measurement unit (IMU) sensor-based system to analyze the respiratory rate of humans. The results of the developed system is validated with the Equivital Wireless Physiological Systems for different activities. Further, the experiment has been designed to identify the optimal sensor placement location for efficient respiration rate estimation during different activities. The performance of the developed model has been quantified using breathing rate estimation accuracy (% BREA) and mean absolute error (MAE). Among all sensor placement locations and activities combinations, a window size of 30sec resulted in the worst performance, whereas a window size ≥ 60sec resulted in a better performance (p-value<0.05). In addition, the performance of the model has been found consistent for window size ≥ 60sec (p-value>0.05). For activity 3 (lying straight), comparably similar performance, 0.52±0.24 and 0.52±0.12 (p-value>0.05) have been depicted by the sensor placement position 3 (Abdomen) and position 1 (chest), respectively. Further, for the other two activities, activity 1 (sitting and working) and activity 2 (sitting straight), the best performance has been depicted as 0.32±0.18, 0.49±0.21 respectively (p-value<0.05), by the sensor placement position 2 (left ribs). This research presents a reliable, cost-effective, portable respiration monitoring system that could detect SA during sleep.


Efficient mid-infrared Cr:ZnSe channel waveguide laser operating at 2486 nm.
We report a Cr:ZnSe channel waveguide laser operating at 2486 nm. A maximum power output of 285 mW is achieved and slope efficiencies as high as 45% are demonstrated. Ultrafast laser inscription is used to fabricate the depressed cladding waveguide in a polycrystalline Cr:ZnSe sample. Waveguide structures are proposed as a compact and robust solution to the thermal lensing problem that has so far limited power scaling of transition metal doped II-VI lasers.


Composite hip prosthesis design. II. Simulation.
An investigation was performed to study the mechanical performance of fiber-reinforced composite hip prostheses. In Part I of the study, a three-dimensional finite element code was developed for analyzing a composite hip prosthesis in a femur. The material properties of the composite were treated as anisotropic and inhomogeneous while the properties of the femoral bone were treated as anisotropic and homogeneous. All the materials were assumed to behave linear-elastically. Thermoplastic graphite/PEEK material was selected for the study. No slippage was assumed at the interface between the implant and the surrounding femoral bone. In Part II, numerical simulations were performed using the code to study the performance of a composite prosthesis in the femur. The stress/strain distributions, micromotions, and strain energy density of the surrounding femoral bone were evaluated and found to be related to initial fixation and long-term stability of the prosthesis in the femur. Numerous fiber orientations were studied, and the results of the calculations were compared with those generated from a prosthesis made of cobalt chrome and Ti-6Al-4V titanium alloys. Based on the analysis, it was shown that compared to conventional metallic implants more favorable stresses and deformations could be generated in the femur using composite implants. In addition, by changing fiber orientations according to femoral loads, a composite implant could be designed specifically for the left or the right femur.


A simple method of plaque rupture induction in apolipoprotein E-deficient mice.
The development of a murine model of atherosclerotic plaque rupture. The left common carotid arteries of male apolipoprotein E (apoE)-deficient mice (9 weeks old) were ligated just proximal to their bifurcations. After 4 weeks on a standard diet, the mice received polyethylene cuff placement just proximal to the ligated site, and the animals were then processed for morphological studies at specific time points. Ligation of the carotid artery in apoE-deficient mice for 4 weeks induced marked intimal hyperplasia, which is a lipid- and collagen-rich lesion that contains a number of macrophages, T lymphocytes, and smooth muscle cells. Subsequently, the cuff placement evoked intraplaque hemorrhage and plaque rupture with fibrin(ogen)-positive luminal thrombus in this region accompanying a decrease in collagen content as well as an increase in apoptotic cells in the intima within a few days after cuff placement. We demonstrated the murine model of human plaque rupture, which is simple, fast, and highly efficient. This model would help us not only to understand the mechanism of human plaque rupture but also to assess various already-known and as-yet-unknown agents in the future.


Revisiting 30 years of biofunctionalization and surface chemistry of inorganic nanoparticles for nanomedicine.
In the last 30 years we have assisted to a massive advance of nanomaterials in material science. Nanomaterials and structures, in addition to their small size, have properties that differ from those of larger bulk materials, making them ideal for a host of novel applications. The spread of nanotechnology in the last years has been due to the improvement of synthesis and characterization methods on the nanoscale, a field rich in new physical phenomena and synthetic opportunities. In fact, the development of functional nanoparticles has progressed exponentially over the past two decades. This work aims to extensively review 30 years of different strategies of surface modification and functionalization of noble metal (gold) nanoparticles, magnetic nanocrystals and semiconductor nanoparticles, such as quantum dots. The aim of this review is not only to provide in-depth insights into the different biofunctionalization and characterization methods, but also to give an overview of possibilities and limitations of the available nanoparticles.


Further studies on irreversible inhibition of dopamine-beta-hydroxylase by cysteine.
In the process of studying the inhibition of dopamine-beta-hydroxylase by cysteine, we observed an interesting relationship between cysteine and catalase. This suggests that two different patterns of the inhibition of dopamine-beta-hydroxylase exist; the one is reversible inhibition, the other is irreversible inhibition. In the present experiments, we have particularly investigated the irreversible inhibition of dopamine-beta-hydroxylase by cysteine, and the following conclusions were drawn: (a) The rate of the inhibitory effect of cysteine pretreatment on dopamine-beta-hydroxylase is independent of a function of the temperature, while at temperature above 20 degrees C the extent of the reversibility of cysteine inhibition by N-ethylmaleimide is temperature dependent. (b) The rate of inhibitory effect is dependent on the time of cysteine pretreatment at 37 degrees C, and the ability of N-ethylmaleimide to reverse the cystine-induced inhibition is gradually diminished by increasing the time of cysteine pretreatment. (c) The inhibitory effect of cysteine pretreatment (37 degrees C, 10 min) is not reversed by the addition of Cu++. (d) In the presence of higher concentrations of catalase, the cystein-induced inhibition is recovered after the addition of equimolar concentration of N-ethylmaleimide. (e) Both inhibitions of cysteine on dopamine-beta-hydroxylase with and without pretreatment were the noncompetitive type to the substrate, tyramine.


Mapping information exposure on social media to explain differences in HPV vaccine coverage in the United States.
Together with access, acceptance of vaccines affects human papillomavirus (HPV) vaccine coverage, yet little is known about media's role. Our aim was to determine whether measures of information exposure derived from Twitter could be used to explain differences in coverage in the United States. We conducted an analysis of exposure to information about HPV vaccines on Twitter, derived from 273.8 million exposures to 258,418 tweets posted between 1 October 2013 and 30 October 2015. Tweets were classified by topic using machine learning methods. Proportional exposure to each topic was used to construct multivariable models for predicting state-level HPV vaccine coverage, and compared to multivariable models constructed using socioeconomic factors: poverty, education, and insurance. Outcome measures included correlations between coverage and the individual topics and socioeconomic factors; and differences in the predictive performance of the multivariable models. Topics corresponding to media controversies were most closely correlated with coverage (both positively and negatively); education and insurance were highest among socioeconomic indicators. Measures of information exposure explained 68% of the variance in one dose 2015 HPV vaccine coverage in females (males: 63%). In comparison, models based on socioeconomic factors explained 42% of the variance in females (males: 40%). Measures of information exposure derived from Twitter explained differences in coverage that were not explained by socioeconomic factors. Vaccine coverage was lower in states where safety concerns, misinformation, and conspiracies made up higher proportions of exposures, suggesting that negative representations of vaccines in the media may reflect or influence vaccine acceptance.


Does Mitral Valve Calcium in Patients Undergoing Mitral Valve Replacement Portend Worse Survival?
Mitral annular calcification (MAC) is associated with worse outcomes after mitral valve replacement (MVR). With limited data available on long-term outcomes, we reviewed our experience of MVR in presence of MAC. A retrospective review of 1,710 consecutive patients who underwent MVR between January 2000 and December 2015 was performed. Patients with isolated primary MVR (n = 496) were included, whereas patients with concomitant cardiac surgery (n = 1,068), previous MVR (n = 110), and mitral valve (MV) endocarditis (n = 36) were excluded. MV calcification was classified as MAC present in anterior/posterior annulus and vertically at the level of leaflets/subvalvular apparatus. A conservative approach towards annular debridement was followed. Our sample's mean age was 64.4 ± 14.1 years, and included 279 (56%) women. MV calcification was observed in 169 (34%) patients with MAC in 115 (23%). Older age, higher ejection fraction, peripheral vascular disease, diabetes, dialysis, and previous aortic valve surgery were associated with increased prevalence of MAC. Patients with MV calcification had higher stroke rate (p = 0.040), patients with anterior leaflet and commissural calcification had higher pacemaker implantation (p = 0.010, p = 0.001, respectively), and patients with circumferential MAC had higher postoperative dialysis (p = 0.006). Operative mortality was not significantly different (p = 0.466) between MAC (n = 1, 1%) and non-MAC (n = 9, 2%) patients. MAC was associated with late mortality (unadjusted hazard ratio, 1.62; 95% confidence interval, 1.20 to 2.18), though on multivariable analysis age, diabetes, dialysis, hypertension, previous aortic valve surgery, previous coronary artery bypass grafting, and MVR with a bioprosthetic valve were found to be independent risk factors for mortality whereas MAC was not. A conservative approach to treat MAC achieves satisfactory results. Patients with MAC have significant comorbidities contributing to a worse survival, though MAC in itself is not a risk factor for mortality.


Uptake of human pharmaceuticals by plants grown under hydroponic conditions.
Cabbage (Brassica rapa var. pekinensis) and Wisconsin Fast Plants (Brassica rapa) were chosen for a proof of concept study to determine the potential uptake and accumulation of human pharmaceuticals by plants. These plants were grown hydroponically under high-pressure sodium lamps in one of two groups including a control and test group exposed to pharmaceuticals. The control plants were irrigated with a recirculating Hoagland's nutrient solution while the test plants were irrigated with a Hoagland's nutrient solution fortified with the pharmaceuticals carbamazepine, salbutamol, sulfamethoxazole, and trimethoprim at 232.5 microg L(-1). When plants reached maturity, nine entire plants of each species were separated into components such as roots, leaves, stems, and seedpods where applicable. An analytical method for quantifying pharmaceuticals and personal care products was developed using pressurized liquid extraction and liquid chromatography electrospray ionization mass spectrometry (LC/ESI/MS) in positive and negative ion modes using single ion monitoring. The method detection limits ranged from 3.13 ng g(-1) to 29.78 ng g(-1) with recoveries ranging from 66.83% to 113.62% from plant matrices. All four of the pharmaceuticals were detected in the roots and leaves of the cabbage. The maximum wet weight concentrations of the pharmaceuticals were detected in the root structure of the cabbage plants at 98.87 ng g(-1) carbamazepine, 114.72 ng g(-1) salbutamol, 138.26 ng g(-1) sulfamethoxazole, and 91.33 ng g(-1) trimethoprim. Carbamazepine and salbutamol were detected in the seedpods of the Wisconsin Fast Plants while all four of the pharmaceuticals were detected in the leaf/stem/root of the Wisconsin Fast Plants. Phloroglucinol staining of root cross-sections was used to verify the existence of an intact endodermis, suggesting that pharmaceuticals found in the leaf and seedpods of the plants were transported symplastically.


Phase I clinical trials with fludarabine phosphate.
There have been six different phase I trials of Fludara I.V. (fludarabine phosphate) in patients with solid tumors and three different phase I trials of Fludara I.V. in patients with acute leukemia. In addition, one trial of the agent given intraperitoneally has also been published. In patients with solid tumors, the two most often used schedules are a daily bolus schedule of 18 to 25 mg/m2/d for 5 days repeated every 28 days, and a 20 mg/m2 loading dose followed by a 48-hour continuous infusion of the agent at a dose of 25 to 30 mg/m2/d. The dose-limiting toxicity in these studies has been myelosuppression. No dosage or schedule could be recommended for patients with acute leukemia because of the severe neurotoxicity (progressive dementia with blindness leading to coma) noted with doses greater than or equal to 96 mg/m2/d for 5 to 7 days. Other toxicities noted in phase I trials have included somnolence, mild to moderate nausea and vomiting, and a rare and reversible interstitial pneumonitis. Of greatest interest is that a profound lymphopenia has been noted as a side effect of Fludara I.V. That toxicity has proven to be of benefit for patients with chronic lymphocytic leukemia, low-grade lymphoma, and mycosis fungoides, all of which are responsive to Fludara I.V. therapy.


The effect of 40-m repeated sprint training on maximum sprinting speed, repeated sprint speed endurance, vertical jump, and aerobic capacity in young elite male soccer players.
The purpose of this study was to examine the effect of 10 weeks' 40-m repeated sprint training program that does not involve strength training on sprinting speed and repeated sprint speed on young elite soccer players. Twenty young well-trained elite male soccer players of age (±SD) 16.4 (±0.9) years, body mass 67.2 (±9.1) kg, and stature 176.3 (±7.4) cm volunteered to participate in this study. All participants were tested on 40-m running speed, 10 × 40-m repeated sprint speed, 20-m acceleration speed, 20-m top speed, countermovement jump (CMJ), and aerobic endurance (beep test). Participants were divided into training group (TG) (n = 10) and control group (CG) (n = 10). The study was conducted in the precompetition phase of the training program for the participants and ended 13 weeks before the start of the season; the duration of the precompetition period was 26 weeks. The TG followed a Periodized repeated sprint training program once a week. The training program consisted of running 40 m with different intensities and duration from week to week. Within-group results indicate that TG had a statistically marked improvement in their performance from pre to posttest in 40-m maximum sprint (-0.06 seconds), 10 × 40-m repeated sprint speed (-0.12 seconds), 20- to 40-m top speed (-0.05 seconds), and CMJ (2.7 cm). The CG showed only a statistically notable improvement from pre to posttest in 10 × 40-m repeated sprint speed (-0.06 seconds). Between-group differences showed a statistically marked improvement for the TG over the CG in 10 × 40-m repeated sprint speed (-0.07 seconds) and 20- to 40-m top speed (-0.05 seconds), but the effect of the improvement was moderate. The results further indicate that a weekly training with repeated sprint gave a moderate but not statistically marked improvement in 40-m sprinting, CMJ, and beep test. The results of this study indicate that the repeated sprint program had a positive effect on several of the parameters tested. However, because the sample size in this study is 20 participants, the results are valid only for those who took part in this study. Therefore, we advice to use repeated sprint training similar to the one in this study only in periods where the players have no speed training included in their program. Furthermore, the participants in this study should probably trained strength, however, benefits were observed even without strength training is most likely to be caused by the training specificity.


An analysis of the impact of diverse forms of childhood psychological maltreatment on emotional adjustment in early adulthood.
Recent research has documented the long-term mental health consequences of childhood psychological maltreatment; however, this research is limited in that it typically fails to recognize the qualitative differences of the various behaviors labeled as psychological maltreatment. This study examines the predictive ability of caregiver terrorizing, degradation, ignoring, and isolating during childhood on the self-reported occurrence of anxiety, depression, somatic complaints, and features of borderline personality disorder (BPD) in a sample of 256 university students between the ages of 18 and 22. Witnessing violence and childhood physical abuse are included in the analyses. Simultaneous regression analyses reveal that different forms of maltreatment emerge as predictors of the variables of emotional adjustment. Terrorizing predicted anxiety and somatic concerns, ignoring predicted scores of depression and features of BPD, and degradation predicted BPD features only. Findings suggest psychological maltreatment is a multifaceted construct requiring further research to investigate the long-term impact of various subtypes.


Subjective and objective parameters in the evaluation of radiofrequency ablation of the inferior turbinate do not correlate: A pilot study.
Inferior turbinate hypertrophy is a common cause of nasal obstruction. We conducted a prospective study to correlate subjective and objective parameters in assessing the effectiveness of radiofrequency ablation (RFA). Our initial study population was made up of 10 patients who presented with nasal obstruction; 1 patient was lost to follow-up, leaving us with 7 women and 2 men, aged 26 to 65 years (mean: 37.9 ± 12.8), and 16 turbinates (7 bilateral, 1 right, and 1 left). Visual analogue scale (VAS) scores, Nasal Obstruction and Symptom Evaluation (NOSE) questionnaire scores, rhinomanometry results, and CT- and MRI-based volumetry were obtained before RFA and 6 months afterward. For the subjective parameters, the mean pre- and postoperative VAS scores for the 16 turbinates were 6.6 ± 1.6 and 2.8 ± 2.0 (p < 0.001), respectively, and the mean pre- and postoperative NOSE scores in the 9 patients were 15.3 ± 3.1 and 5.8 ± 5.4 (p = 0.003). For the objective parameters, the mean pre- and postoperative rhinomanometry values at 150 Pa were 241.0 ± 141.3 and 265.4 ± 157.3 ml/sec (p = 0.403), and the mean pre- and postoperative volumetry values were 5.3 ± 2.5 and 5.0 ± 2.1 cm(3) (p = 0.551). Note that only the differences in the subjective parameters reached statistical significance. RFA of the inferior turbinates as a treatment for nasal obstruction is safe and easy. However, our study found a discrepancy between the subjective and objective outcomes parameters, as the former showed highly significant improvement and the latter showed only a slight improvement that did not reach statistical significance.


[Genetic susceptibility to infectious diseases: immunogenetical approaches to mycobacterial infections and subacute sclerosing panencephalitis].
Genetic susceptibility to infectious diseases can be explained by nucleotide alteration (mutation, polymorphism, etc.) of genes encoding molecules involved in the entry of or the immune response to microorganisms. We have conducted studies on host genetic factors for the development of mycobacterial infections and subacute sclerosing panencephalitis (SSPE) in the past decade. First, we identified autosomal dominant IFN-gamma receptor deficiency as a predominant genetic basis of patients with bacille Calmette-Guérin osteomyelitis in Japan. Second, by gene-based association analysis of 21 candidate genes, it was suggested that genetic variants of IL-12 receptor beta1 gene (IL12RB1) confer genetic susceptibility to tuberculosis, and are associated with the progression of the disease in Japanese. Third, we demonstrated that variants of several genes encoding molecules associated with innate immunity (MxA and TLR3 genes) and acquired immunity (IL4 and programmed cell death 1 [PD1] genes) were associated with the development of SSPE. Immunogenetical approaches to infectious diseases would help us to evaluate the risk for disease development and progression, individualize prevention and treatment strategies, and create new therapies.


Quantification of Rotavirus Diarrheal Risk Due to Hydroclimatic Extremes Over South Asia: Prospects of Satellite-Based Observations in Detecting Outbreaks.
Rotavirus is the most common cause of diarrheal disease among children under 5. Especially in South Asia, rotavirus remains the leading cause of mortality in children due to diarrhea. As climatic extremes and safe water availability significantly influence diarrheal disease impacts in human populations, hydroclimatic information can be a potential tool for disease preparedness. In this study, we conducted a multivariate temporal and spatial assessment of 34 climate indices calculated from ground and satellite Earth observations to examine the role of temperature and rainfall extremes on the seasonality of rotavirus transmission in Bangladesh. We extracted rainfall data from the Global Precipitation Measurement and temperature data from the Moderate Resolution Imaging Spectroradiometer sensors to validate the analyses and explore the potential of a satellite-based seasonal forecasting model. Our analyses found that the number of rainy days and nighttime temperature range from 16°C to 21°C are particularly influential on the winter transmission cycle of rotavirus. The lower number of wet days with suitable cold temperatures for an extended time accelerates the onset and intensity of the outbreaks. Temporal analysis over Dhaka also suggested that water logging during monsoon precipitation influences rotavirus outbreaks during a summer transmission cycle. The proposed model shows lag components, which allowed us to forecast the disease outbreaks 1 to 2 months in advance. The satellite data-driven forecasts also effectively captured the increased vulnerability of dry-cold regions of the country, compared to the wet-warm regions.


Scoping review of patient-centered care approaches in healthcare.
The purpose of this scoping review was to describe how three tenants of patient-centered care provision: communication, partnership, and health promotion are addressed in patient-centered care models/frameworks across the literature. A scoping review of literature published in English since 1990 was conducted using Medline, CINAHL, and EMBASE. A key term search strategy was employed using "patient-centered care", "client-centered care", "framework" and "model" to identify relevant studies. Application of the search strategy resulted in a hit total of 101 articles. Nineteen articles met inclusion criteria, of which 12 were review articles; 5 were qualitative research papers; one was a randomized control trial; and one was a prospective study. From these articles, 25 different patient-centered care frameworks/models were identified. The fact that all identified approaches to patient-centered care incorporated strategies to achieve effective communication, partnership, and health promotion indicates that clinicians can select a patient-centered approach from the literature that best suits their patient's needs, and be confident that it will satisfy the three core elements of patient-centered care provision. While empirical literature on specific patient-centric frameworks and models was limited, much empiric evidence was sourced for the most consistently defined component of patient-centered care, communication.


Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice.
This study investigated the hypoglycemic, hypolipidemic, and antioxidant effects of dietary quercetin in an animal model of type 2 diabetes mellitus. Four-week-old C57BL/KsJ-db/db mice (n = 18) were offered an AIN-93G diet or a diet containing quercetin at 0.04% (low quercetin, LQE) or 0.08% of the diet (high quercetin, HQE) for 6 weeks after 1 week of adaptation. Plasma glucose, insulin, adiponectin, and lipid profiles, and lipid peroxidation of the liver were determined. Plasma glucose levels were significantly lower in the LQE group than in the control group, and those in the HQE group were even further reduced compared with the LQE group. The homeostasis model assessment for insulin resistance (HOMA-IR) showed lower values for LQE and HQE than for the control group without significant influence on insulin levels. High quercetin increased plasma adiponectin compared with the control group. Plasma triglycerides in the LQE and HQE groups were lower than those in the control group. Supplementation with high quercetin decreased plasma total cholesterol and increased HDL-cholesterol compared with the control group. Consumption of low and high quercetin reduced thiobarbituric acid reactive substances (TBARS) levels and elevated activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the liver. Thus, quercetin could be effective in improving hyperglycemia, dyslipidemia, and antioxidant status in type 2 diabetes.


Descriptive Analysis of Mortality Predictors in H1n1 Influenza in South Indian Patients.
H1N1 (hemagglutinin-H-neuroaminidase-N) influenza infection is associated with high morbidity and mortality because of associated complications and related factors. Predictors of mortality in H1N1 patients are studied with very few without seasonal/pandemic declaration. This study was carried out to describe the clinical features, complications and different risk factors that affect the outcome in the patients with confirmed H1N1influenza infection. A retrospective study was done in Kasturba Medical College Hospital, Manipal, India by analyzing the medical records of 141 patients admitted from January, 2011 to June, 2015. Of the 141 patients in the study, 51.1% of the patients were female with a mean age of 32±16.2 years. Fever with headache was observed in 92.9% patients while cough in 78.7% patients and breathlessness in 54.6% patients. On the basis of disease severity, 53.2% of the patients were put on mechanical ventilation. For all the patients, treatment for influenza management began with oseltemivir. Diuretics, antianxiety and corticosteroids were given as supportive and symptomatic care which contributed to high mortality in hospitalized patients. Mean hospitalization period was 8.5 days. During the hospitalization, patients developed different complications i.e. 31.20% patients developed respiratory tract infections, while 17.7% patients developed ARDS and 14.4% patients developed sepsis. The mortality rate of this study population was found to be 29.1 %. It was observed that low oxygen saturation during admission, high blood urea level, use of diuretics, corticosteroids, anti-anxiety drugs and complications like ARDS, sepsis influence the mortality rate of patients with H1N1 infection.


AT-RvD1 Promotes Resolution of Inflammation in NOD/ShiLtJ mice.
Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease characterized by diminished secretory function of the exocrine glands. Treatments for hyposalivation are limited to the use of saliva substitutes and medications that provide only temporary relief. In light of the high degree of need and the limitations of current therapies, development of alternative treatments to restore functioning is essential. Resolvins (Rv), which are highly potent lipid mediators, offer a viable alternative for better treating inflammatory diseases such as SS. The goal of this study was to determine whether systemic preventive treatment with Aspirin-triggered RvD1 (AT-RvD1) reduces inflammation and preserves secretory functioning in NOD/ShiLtJ SS-like mice. Our results indicate that systemic treatment with AT-RvD1 diminishes the progression of the disease in salivary epithelium from female mice as follows: (a) improves secretory function, (b) reduces pro-inflammatory molecule gene expression, (c) increases anti-inflammatory molecule gene expression and (d) induces M2 macrophage polarization. Finally, AT-RvD1 decreases lymphocytic infiltration into the salivary glands when used with small doses of the steroid, dexamethasone, and promotes the tissue healing process.


Implants outcome inserted in different sites.
Oral rehabilitation by means dental implants has high standards of success. Recently, a new type of two-pieces spiral implants has been introduced in the market. Since few reports focus of the efficacy of this medical device as a reliable tool for oral rehabilitation, here a retrospective study is reported. In the period June-December 2017 one hundred and two spiral fixtures were inserted, half in females and 51 in males. The median age was 56 ± 8 (min-max 36-73 years). Forty-eight implants were inserted in upper jawbone and 54 in mandible. Two implants were lost and thus survival rate (SVR) is 99.9%. Then peri-implant bone resorption was used to investigate the clinical success (success rate, SCR) over time. No implants have a crestal bone resorption greater than 1.5 mm in the first year follow up. No studied variable has an effect on clinical outcome. In conclusion the studied implants have high SCR and SVR so that they are good tools for oral rehabilitation.


COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1.
Endothelial cell (EC) identity is in part genetically predetermined. Transcription factor NR2F2 (also known as chicken ovalbumin upstream promoter transcription factor II, COUP-TFII) plays a key role in EC fate decision making; however, many of the underlying mechanisms remain enigmatic. In the present study, we demonstrate that NR2F2 differentially regulates gene expression of venous versus lymphatic ECs (LECs) and document a novel paradigm whereby NR2F2 homodimers induce a venous EC fate, while heterodimers with the LEC-specific transcription factor PROX1 instruct LEC lineage specification. NR2F2 homodimers inhibit arterial differentiation in venous ECs through direct binding to the promoter regions of the Notch target genes HEY1 and HEY2 (HEY1/2), whereas NR2F2/PROX1 heterodimers lack this inhibitory effect, resulting at least in part in non-canonical HEY1/2 expression in LECs. Furthermore, NR2F2/PROX1 heterodimers actively induce or are permissive for the expression of a major subset of LEC-specific genes. In addition to NR2F2/PROX1 heterodimerisation, the expression of HEY1 and some of these LEC-specific genes is dependent on PROX1 DNA binding. Thus, NR2F2 homodimers in venous ECs and NR2F2/PROX1 heterodimers in LECs differentially regulate EC subtype-specific genes and pathways, most prominently the Notch target genes HEY1/2. This novel mechanistic insight could pave the way for new therapeutic interventions for vascular-bed-specific disorders.


Salivary proteome modifications associated with periodontitis in obese patients.
To identify changes in the salivary protein/peptide profiles by differential proteomics in obese patients with or without periodontitis. Periodontal examinations and whole saliva samples were obtained from 38 obese patients (mean age: 45.1 ± 7.3 years, mean BMI: 49.3 ± 9 kg/m(2) ) including 13 periodontitis and 25 non-periodontitis subjects, and 19 healthy controls (mean age: 44.2 ± 6.4 years, mean BMI: 21.5 ± 2.1 kg/m(2) ). Surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS) was used to compare the whole saliva polypeptide profiles. The SELDI-TOF-MS analysis detected eight putative markers. Six of them were increased and identified in obese subjects versus controls (albumin, α and β haemoglobin chains, α-defensins 1, 2 and 3). Alpha-defensins were less abundant in saliva of periodontitis obese patients (36.47 ± 19.84 μA) versus non-periodontitis obese patients (43.44 ± 30.34 μA), whereas α-defensins were more abundant in obese patients (40.99 ± 26.66 μA) versus controls (27.1 ± 23.98 μA). Periodontal status modifies the salivary proteome in obese patients. Alpha-defensins may play a role in gingival inflammation, and be involved in the higher susceptibility of obese patients to periodontal diseases.


Serum C-reactive protein distribution in minimally invasive total knee arthroplasty do not differ with distribution in conventional total knee arthroplasty.
Minimally invasive total knee arthroplasty (MITKA) has been developed to reduce surgical trauma and facilitate rehabilitation after arthroplasty. A plausible hypothesis is that this reduced trauma results in lower concentrations of circulating inflammatory biomarkers, such as C-reactive protein (CRP). In this study, we compared CRP concentrations in patients undergoing MITKA to those undergoing conventional TKA (CTKA). Eight hundred and seven patients undergoing MITKA were prospectively recruited. CRP was measured before operation and on days 2, 4, 21, and 42 after operation. Two hundred and forty-seven patients who had CTKA were collected retrospectively, with the same inclusion and exclusion criteria as those who had MITKA. We found in both groups, that CRP values rose abruptly after operation, with peak values reached on day 2 or 4. Values then declined so that by days 21 and 42 they were only modestly above baseline values. Throughout the entire study period, mean CRP in MITKA patients did not differ significantly from those in CTKA patients. However, a significantly higher proportion of CTKA patients than of MITKA patients had peak CRP values at day 4 rather than at day 2 (76.8% vs 42.5%), a difference that was more pronounced in women. Also, by day 42, CRP values were still above baseline in 18.5% of MITKA patients and 28.8% of CTKA patients without known complications. In conclusion, CRP distribution pattern was similar in patients who received MITKA or CTKA,. CRP values remained slightly elevated in both MITKA and CTKA patients for as long 42 days after operation. These findings suggest that MITKA is no less traumatic than CTKA, as determined by CRP values, and the patterns of postoperative CRP may be useful in the management of TKA patients.


[Improvement in the method of cultivated corneal epithelial sheet generation].
Stromal cells and/or soluble factors such as growth factors have been considered until now as the main niche of corneal epithelial stem cells. We found that cultivated epithelial cells had epithelial clusters when cultured, maintaining the sheet structure. Therefore, we hypothesized that the epithelial cells themselves might be a niche of the stem cells, and the cell clusters could be maintained during the gentle enzymatic digestion of the limbal epithelial sheets. The main methods of generating cultivated limbal epithelial sheet for clinical application are, the cell suspension method (complete enzymatic digestion of limbal epithelia), and the explant method (cells grown from limbal explants). For cell suspension, it is good to expand cells and generating sheets quickly, but it is not clear wheather these sheets maintain the normal homeostatic levels of the progenitor cells. Explants maintain homeostatic levels more similar to in vivo homeostasis, but the low proliferative speed of epithelial expansion and reproducibility are the problem. In this review, we hypothesize that to generate cultivated epithelial sheets while maintaining a corneal epithelial stem cells' niche is a better way to proceed as it includes the advantages of both the cell suspension and explant methods. The growth potential, colony-forming efficiency of p63-positive cell clusters, and immunostaining by differentiation/ undifferentiation markers, demonstrated that progenitor cells could be maintained by these gentle enzymatic digestion maintaining cell clusters.


Cardiovascular effects of a novel enkephalin analogue, 443C81, in humans.
The cardiovascular effects of a novel enkephalin analogue, 443C81 (Tyr-D-Arg-Gly-Phe(4NO2)-Pro.NH2), were studied in healthy volunteers. According to a double-blind, cross-over, randomised, balanced design, six men received two different doses of 443C81 or saline as intravenous (i.v.) infusions on three occasions. Mean +/- SD plasma concentrations achieved at steady state were 0.46 +/- 0.11 microgram/ml after low-dose 443C81 and 1.0 +/- 0.2 microgram/ml after high-dose 443C81. In the supine position, low and high doses produced mean transient increases in diastolic blood pressure (DBP) of 5 and 4 mm Hg and heart rate (HR) of 5 and 12 beats/min, respectively. With the higher dose, these changes were followed by a mean decrease in DBP of 8 mm Hg while HR returned to control values. When the subjects were tilted, the pressor effect was not observed, and hypotension occurred earlier and was more pronounced. Both doses reduced forearm and systemic vascular resistance, and there was a dose-related increase in supine forearm venous capacitance; venoconstriction associated with tilting was unaffected by 443C81. Plasma renin activity and elevation of epinephrine concentrations on tilting were increased by the enkephalin, which also caused a diuresis through an increase in free water clearance.


Dermagraft: Use in the Treatment of Chronic Wounds.
Lower limb ulceration is a common problem in clinical practice. A variety of metabolic and physical causes can lead to a diversity of chronic ulcer types, including diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs). A wide variety of technologies have been developed to treat chronic wounds, with varying levels of success. Depending upon the type and severity of the wound being treated, treatments may include systemic or local antibiotic therapy, application of fillers such as collagen sponges, use of negative wound pressure, hyperbaric oxygen therapy, application of select growth factors, advanced wound dressings, and more recently, the use of cell-based tissue-engineered products. Dermagraft® is a sterile, cryopreserved, human fibroblast-derived dermal substitute generated by the culture of neonatal dermal fibroblasts onto a bioabsorbable polyglactin mesh scaffold. During the product-manufacturing process, the human fibroblasts proliferate to fill the interstices of this scaffold and secrete collagen, other extracellular matrix proteins, growth factors, and cytokines, creating a three-dimensional human tissue containing metabolically active living cells. Dermagraft has been approved for marketing in the United States for the treatment of DFUs. In addition, the product is in active development for the treatment of VLUs and has been clinically used in a variety of other indications to stimulate wound healing. When treating DFUs, Dermagraft should be used in conjunction with standard wound care regimens and in patients who have adequate blood supply to the involved foot.


Computational Prediction and Validation of Tumor-Associated Neoantigens.
Tumor progression is typically accompanied by an accumulation of driver and passenger somatic mutations. A handful of those mutations occur in protein coding genes which introduce non-synonymous polymorphisms. Certain substitutions may give rise to novel, tumor-associated antigens or neoantigens, presentable by cancer cells to the host adaptive immune system. As antigen recognition is the core of an effective immune response, the identification of patient tumor specific antigens derived from transformed cells is of importance for immunotherapeutic approaches. Recent technological advances in DNA sequencing of tumor genomes, advances in gene expression analysis, algorithm development for antigen predictions and methods for T-cell receptor (TCR) repertoire sequencing have facilitated the selection of candidate immunogenic neoantigens. In this regard, multiple research groups have reported encouraging results of neoantigen-based cancer vaccines that generate tumor antigen specific immune responses, both in mouse models and clinical trials. Additionally, both the quantity and quality of neoantigens has been shown to have predictive value for clinical outcomes in checkpoint-blockade immunotherapy in certain tumor types. Neoantigen recognition by vaccination or through adoptive T cell therapy may have unprecedented potential to advance cancer immunotherapy in combination with other approaches. In our review we discuss three parameters regarding neoantigens: computational methods for epitope prediction, experimental methods for epitope immunogenicity validation and future directions for improvement of those methods. Within each section, we will describe the advantages and limitations of existing methods as well as highlight pressing fundamental problems to be addressed.


[Determination of leukocyte sensitization to tumor and embryonic tissue antigens in cancer of the large intestine].
Aqueous-saline extracts of autologous rectal tumor tissue inhibited leukocyte migration in 7 out of 10 patients with rectal tumors in autoplasm-containing medium, and in 5 out of 11 patients-in control serum. Antigens of allogenic rectal tumors inhibited leukocyte migration (LMI) in 4 out of 5 patients (stage II), in 15 out of 21 patients (stage III), and in 5 out of 10 patients (stage IV) in control serum medium, and in non of control patients. Leukocyte sensitization to mucosal antigen was established only in 8% of patients (stage II-IV), in control serum medium. LMI in medium containing autoplasm and control serum was observed in 24 out of 36 patients. Extracts obtained from human embryonal liver inhibited leukocyte migration in 14 out of 27 patients (stage II-IV), including 3 cases in which leukocytes did not respond to tumor-associated antigen. LMI by carcinoembryonic antigen was registered in a total of 31 out of 36 cases (86%). In 5 cases out of 7, unresponsive leukocytes of patients with rectal tumors did respond to tumor-associated antigen by inhibiting leukocyte migration, after re-incubation at low temperature, in a medium free from autologous blood plasma.


[Working methods of ambulatory psychiatric emergency services in the Netherlands].
No recent information is available concerning the working methods of the ambulatory psychiatric emergency services in The Netherlands.
 To obtain insight into the working methods of the ambulatory psychiatric emergency services.
 We performed a descriptive research.
 Twenty of the 28 ambulatory psychiatric emergency services participated in our study (more than 71 %). The study revealed that some of the ambulatory psychiatric emergency services used differing procedures. However, all the services had a common target: they dealt with young people, adults and the elderly. In half of the organisations it was the community mental health nurse who initially went alone to visit a prospective patient. There are large differences in the number of face-to-face contacts made by emergency services and in the type of medication provided before the patient was taken by ambulance to a psychiatric hospital.
 In our study we describe the working methods used by several of the ambulatory psychiatric emergency services in the Netherlands. However, our investigation produced only limited information because participating institutions were often unable to provide the information we requested and/or they did not record the methods they had used. More attention needs to be given to the best way of dealing with patients who already have an official 'emergency card'; in addition, more information is required about whether the medication used by the emergency services influenced the subsequent course of the treatment that a patient received. In view of the current situation certain important features of the emergency services such as the quality of care they provided remains underexposed.


Chabazite Synthesis and Its Exchange with Ti, Zn, Cu, Ag and Au for Efficient Photocatalytic Degradation of Methylene Blue Dye.
A chabazite-type zeolite was prepared by the hydrothermal method. Before ion exchange, the chabazite was activated with ammonium chloride (NH4Cl). The ion exchange process was carried out at a controlled temperature and constant stirring to obtain ion-exchanged chabazites of Ti4+ chabazite (TiCHA), Zn2+ chabazite (ZnCHA), Cu2+ chabazite (CuCHA), Ag+ chabazite (AgCHA) and Au3+ chabazite (AuCHA). Modified chabazite samples were characterized by X-ray diffraction (XRD), scanning electron microscope equipped with energy-dispersive spectroscopy (SEM-EDS), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), N2 adsorption methods and UV-visible diffuse reflectance spectroscopy (DRS). XRD results revealed that the chabazite structure did not undergo any modification during the exchange treatments. The photocatalytic activity of chabazite samples was evaluated by the degradation of methylene blue (MB) in the presence of H2O2 under ultraviolet (UV) light illumination. The photodegradation results showed a higher degradation efficiency of modified chabazites, compared to the synthesized chabazite. CuCHA showed an efficiency of 98.92% in MB degradation, with a constant of k = 0.0266 min-1 following a first-order kinetic mechanism. Then, it was demonstrated that the modified chabazites could be used for the photodegradation of dyes.


Promoting macrophage survival delays progression of pre-existing atherosclerotic lesions through macrophage-derived apoE.
Macrophage apoptosis is a prominent feature of atherosclerosis, yet whether cell death-protected macrophages would favour the resolution of already established atherosclerotic lesions, and thus hold therapeutic potential, remains unknown. We irradiated then transplanted into Apoe(-/-) or LDLr(-/-) recipient mice harbouring established atherosclerotic lesions, bone marrow cells from mice displaying enhanced macrophage survival through overexpression of the antiapoptotic gene hBcl-2 (Mø-hBcl2 Apoe(-/-) or Mø-hBcl2 Apoe(+/+) LDLr(-/-)). Both recipient mice exhibited decreased lesional apoptotic cell content and reduced necrotic areas when repopulated with Mø-hBcl2 mouse-derived bone marrow cells. In contrast, only LDLr(-/-) recipients showed a reduction in plasma cholesterol levels and in atherosclerotic lesions. The absence of significant reduction of plasma cholesterol levels in the context of apoE deficiency highlighted macrophage-derived apoE as key in both the regulation of plasma and tissue cholesterol levels and the progression of pre-existing lesion. Accordingly, hBcl2 expression in macrophages was associated with larger pools of Kupffer cells and Ly-6C(low) monocytes, both high producers of apoE. Additionally, increased Kupffer cells population was associated with improved clearance of apoptotic cells and modified lipoproteins. Collectively, these data show that promoting macrophage survival provides a supplemental source of apoE, which hinders pre-existing plaque progression.