Dopaminergic modulation of long-lasting direct current-induced cortical excitability changes in the human motor cortex.
Dopaminergic mechanisms participate in N-methyl-D-aspartate (NMDA) receptor-dependent neuroplasticity, as animal experiments have shown. This may be similar in humans, where dopamine influences learning and memory. We tested the role of dopamine in human cortical neuroplasticity. Changes of excitability were induced by transcranial direct current stimulation (tDCS). D2 receptor blocking by sulpiride abolished the induction of after-effects nearly completely. D1 activation alone in the presence of D2 receptor blocking induced by co-administration of sulpiride and pergolide did not re-establish the excitability changes induced by tDCS. This suggests that D2 receptors play a major supporting role in inducing neuroplasticity in the human motor cortex. Enhancement of D2 and, to a lesser degree, D1 receptors by pergolide consolidated tDCS-generated excitability diminution until the morning after stimulation. The readiest explanation for this pattern of results is that D2 receptor activation has a consolidation-enhancing effect on tDCS-induced changes of excitability in the human cortex. The results of this study underscore the importance of the dopaminergic system for human neuroplasticity, suggest a first pharmacological add-on mechanism to prolong the excitability-diminishing effects of cathodal tDCS for up to 24 h after stimulation, and thus render the application of tDCS practicable in diseases displaying enhanced cortical excitability, e.g. migraine and epilepsy.


Neutral lipid storage disease with ichthyosis. Defective lamellar body contents and intracellular dispersion.
Although the link between epidermal lamellar body lipids and stratum corneum barrier function is well established, a role for lamellar body lipids in desquamation remains unproved. We examined skin biopsy material from three family members of a Palestinian kindred with a multisystem disorder of altered lipid metabolism, ichthyosis, and deposition of fat droplets in multiple tissues (Chanarin-Dorfman syndrome, neutral lipid storage disease). Thin-section and freeze-fracture ultrastructural studies revealed a distinctive lamellar body abnormality: multilaminated spherules that distorted and displaced the normal internal disk structure of these organelles. Whereas these spherules remained interspersed with secreted lamellar body contents within the intercellular spaces of the outer epidermis, at the stratum granulosum-stratum corneum interface they apparently dispersed into electron-lucent "slits." These studies therefore provide strong support for the concept that lamellar body-derived lipids influence stratum corneum desquamation and further suggest that abnormalities of neutral lipid-alkane metabolism influence normal epidermal shedding.


Peritonectomy and intraperitoneal chemotherapy in appendiceal and colorectal cancer.
Peritoneal spread of gastrointestinal malignancies has been regarded as an incurable disease, and treatment has been aimed at short-term palliation. The use of cytoreductive surgery, including peritonectomy procedures and intraperitoneal chemotherapy, has been proposed with the intention of prolonging survival, and perhaps curing patients with peritoneal carcinomatosis from appendiceal and possibly colon cancers. A series of eight patients who have undergone this procedure at St George Hospital is presented, and the results obtained by other groups are reviewed. Eight patients fitted the criteria for peritoneal carcinomatosis between January 1996 and November 1998. In seven patients this was secondary to appendiceal or colon cancer. and one patient had signet ring cancer of the uterus. The surgical treatment involved removing all macroscopic evidence of disease, and this was followed by early postoperative intraperitoneal chemotherapy. The eight patients (seven female, one male) ranged in age from 25 to 67 years. There were seven complications, including two patients with pelvic abscesses, and one patient who developed Tenchkoff catheter occlusion. There were three deaths, one due to pelvic sepsis after 30 days, and the other two were due to metastatic disease. Of the remaining five patients, two have developed recurrence and three remain disease-free. The results of peritonectomy and intraperitoneal chemotherapy for appendiceal tumours are encouraging. The role in colorectal cancer is less clear, although there are some reports that suggest a benefit.


The applicability of the tetraclass model to the management of the patient satisfaction in the pharmacies.
The objective of this work is to study the possibilities of the tetraclass model for the evaluation of the changes in the consumer satisfaction from the provided pharmacy services during the time. Within the same 4 months period in 2004 and 2006 were questioned at approximately 10 pharmacy consumers per working day. Every consumer evaluated the 34 service elements on a 5 points semantic-differential scale. The technique of the correspondence data analysis was used for the categorisation of the services. Most of the services have been categorized as basic ones. For the age group up to 40 years the access to pharmacy became a key element and external aspects became a secondary element in 2006 year. For the group of patients that are using the services of the pharmacy for more than 2 years, availability of phone connection, quality of answers and product prices move from plus to secondary element. The ratio quality/price moves from the group of basic to key services, visibility of the prices and hygiene became basic elements from secondary ones. During the two years period, all the service elements connected with the staff as availability, identification, good looking, confidence, dressing, advices, technical competence, explanation, and time spent with clients remain basic services. The confidentiality of the staff remains always a key element. Our study shows that the tetraclass model allows taking more informed managerial decisions in the pharmacies, as well as, is providing information for the concrete area of services and possible measures. In case of a development of a simple statistical program for quick processing of the inquiry data, the method will became applicable and affordable even for small pharmacies.


Effects of bilateral stimulation and stimulus redundancy on interhemispheric interaction.
Recent visual laterality studies have included trials in which critical stimulus information is presented simultaneously in both visual half-fields and, thereby, simultaneously to both cerebral hemispheres. To investigate interhemispheric interaction, researchers compare performance on bilateral redundant trials with performance on unilateral trials in which a single copy of the target is presented to one hemisphere or the other. The authors used the identification of nonword letter trigrams to examine the relationship between unilateral and bilateral performance when the 2 types of trials were equated for the number of locations stimulated (Experiment 1) and the number of redundant copies of the target (Experiment 2). Results suggest that when the number of stimulated locations is held constant, each of 2 copies of a target stimulus can be processed with the same efficiency and the same strategy as it would have been had it been the only copy.


Fasciola: kinetics and quality of humoral responses to fatty acid binding protein and cathepsin l following delivery as DNA vaccines in mice.
The humoral response to DNA vaccination of mice with two important Fasciola antigens has been investigated. Both F. gigantica fatty acid binding protein (FABP) and F. hepatica cathepsin L5 (FhCatL5) were shown to be expressed in COS 7 cells and induced a humoral response when delivered as secretory constructs in mice. FABP induced an IgGl dominant response, with significant IgE, IgG2a, and IgG2b responses also present, indicating a mixed Th1/Th2 response. The total Ig response peaked at 1:24,500 and antibody titers were sustained for at least 32 weeks. In contrast, the delivery of FABP as a nonsecreted construct did not result in the induction of a measurable humoral response. FhCatL5 was delivered as a secretory construct, with secretion mediated by the native F. hepatica signal sequence, which was shown to operate in COS 7 cells. The humoral response peaked at 1:2000 at week 8 and was sustained for at least 20 weeks. Antibody isotype analysis demonstrated a Th2-like response, which was qualitatively different from that obtained for FABP with an IgE dominant response, and lower titers to IgG1 and IgG3. The results demonstrate that Fasciola antigens can be delivered as DNA vaccines, but that the quality of the response varies between antigens and is influenced by the method of vaccine delivery.


Latent variable models of alcohol-related constructs.
This study examines the improvement in validity coefficients and structural relationships derived from formally modeling latent variables of adverse alcohol-related constructs. Results of a confirmatory factor analysis of responses from 8,755 participants in the 1988 National Household Survey of Drug Abuse support a three-factor model of alcohol abuse, dependence, and adverse consequences. A comparison of construct intercorrelations shows latent variables to be superior to measurement approaches using unweighted sums, quantity x frequency calculation, and single-item measurement.


The importance of normalisation in the construction of deprivation indices.
Measuring socio-economic deprivation is a major challenge usually addressed through the use of composite indices. This paper aims to clarify the technical details regarding composite index construction. The distribution of some variables, for example unemployment, varies over time, and these variations must be considered when composite indices are periodically re-evaluated. The process of normalisation is examined in detail and particular attention is paid to the importance of symmetry and skewness of the composite variable distributions. Four different solutions of the Townsend index of socioeconomic deprivation are compared to reveal the effects that differing transformation processes have on the meaning or interpretation of the final index values. Differences in the rank order and the relative separation between values are investigated. Constituent variables which have been transformed to yield a more symmetric distribution provide indices that behave similarly, irrespective of the actual transformation methods adopted. Normalisation is seen to be of less importance than the removal of variable skewness. Furthermore, the degree of success of the transformation in removing skewness has a major effect in determining the variation between the individual electoral ward scores. Constituent variables undergoing no transformation produce an index that is distorted by the inherent variable skewness, and this index is not consistent between re-evaluations, either temporally or spatially. Effective transformation of constituent variables should always be undertaken when generating a composite index. The most important aspect is the removal of variable skewness. There is no need for the transformed variables to be normally distributed, only symmetrically distributed, before standardisation. Even where additional parameter weights are to be applied, which significantly alter the final index, appropriate transformation procedures should be adopted for the purpose of consistency over time and between different geographical areas.


Dr. Lippes and his loop. Four decades in perspective.
Forty years ago Jack Lippes, M.D., hand made the first models of his "Double-S" intrauterine contraceptive device (IUD). Subsequently the Lippes Loop became the standard against which other IUDs came to be compared. Though millions of loops have been used, they have mostly been supplanted by copper-bearing, T-shaped devices. Due to the implant nature of IUDs, on occasion a patient presents well into menopause still bearing a Lippes Loop or other early IUD. Although there is no established causal evidence linking IUDs retained after menopause and cancer or other significant problems, such retention does confuse the diagnosis of post-menopausal bleeding and makes difficult such procedures as endometrial biopsy and ultrasonic endometrial evaluation. When contraception is no longer an issue, it is prudent to remove IUDs since they may cloud future necessary evaluations.


Low-Dose Stevia (Rebaudioside A) Consumption Perturbs Gut Microbiota and the Mesolimbic Dopamine Reward System.
Stevia is a natural low-calorie sweetener that is growing in popularity in food and beverage products. Despite its widespread use, little is understood of its impact on the gut microbiota, an important environmental factor that can mediate metabolism and subsequent obesity and disease risk. Furthermore, given previous reports of dysbiosis with some artificial low-calorie sweeteners, we wanted to understand whether prebiotic consumption could rescue potential stevia-mediated changes in gut microbiota. Three-week old male Sprague-Dawley rats were randomized to consume: (1) Water (CTR); (2) Rebaudioside A (STV); (3) prebiotic (PRE); (4) Rebaudioside A + prebiotic (SP) (n = 8/group) for 9 weeks. Rebaudioside was added to drinking water and prebiotic oligofructose-enriched inulin added to control diet (10%). Body weight and feces were collected weekly and food and fluid intake biweekly. Oral glucose and insulin tolerance tests, gut permeability tests, dual X-ray absorptiometry, and tissue harvest were performed at age 12 weeks. Rebaudioside A consumption alone did not alter weight gain or glucose tolerance compared to CTR. Rebaudioside A did, however, alter gut microbiota composition and reduce nucleus accumbens tyrosine hydroxylase and dopamine transporter mRNA levels compared to CTR. Prebiotic animals, alone or with Rebaudioside A, had reduced fat mass, food intake, and gut permeability and cecal SCFA concentration. Adding Rebaudioside A did not interfere with the benefits of the prebiotic except for a significant reduction in cecal weight. Long-term low-dose Rebaudioside A consumption had little effect on glucose metabolism and weight gain; however, its impact on gut microbial taxa should be further examined in populations exhibiting dysbiosis such as obesity.


Parental feeding practices and children's weight.
Global increases in childhood obesity rates demand that we tackle the problem from many directions. One promising avenue is to explore the impact of parental feeding practices, particularly those related to parental control over children's intake. In this paper, we review studies of parent feeding and child adiposity covering a range of research methodologies (case-control studies, high risk studies, cross-sectional community studies and longitudinal cohort studies). We also present results from a cross-sectional community study of pre-schoolers (n = 439) and a longitudinal study of twins from ages of 4 to 7 years (n = 3175 pairs). We conclude that parents are more likely to encourage leaner than heavier children to eat, but relationships between adiposity and other parental feeding strategies are unclear. We suggest that future research should: (i) explore the impact of a comprehensive range of authoritative and authoritarian parental feeding behaviours, preferably using the same validated scales consistently across studies; (ii) test the generalisation of existing findings to diverse socio-economic and ethnic groups and (iii) utilise experimental, prospective and genetic methodologies to explore the causal relationships between parental feeding and child weight. We describe current projects in our own group that are designed to take forward these recommendations.


Defining the protein interaction network of human malaria parasite Plasmodium falciparum.
Malaria, caused by the protozoan parasite Plasmodium falciparum, affects around 225 million people yearly and a huge international effort is directed towards combating this grave threat to world health and economic development. Considerable advances have been made in malaria research triggered by the sequencing of its genome in 2002, followed by several high-throughput studies defining the malaria transcriptome and proteome. A protein-protein interaction (PPI) network seeks to trace the dynamic interactions between proteins, thereby elucidating their local and global functional relationships. Experimentally derived PPI network from high-throughput methods such as yeast two hybrid (Y2H) screens are inherently noisy, but combining these independent datasets by computational methods tends to give a greater accuracy and coverage. This review aims to discuss the computational approaches used till date to construct a malaria protein interaction network and to catalog the functional predictions and biological inferences made from analysis of the PPI network.


Effect of Time Lapse on the Diagnostic Accuracy of Cone Beam Computed Tomography for Detection of Vertical Root Fractures.
Accurate and early diagnosis of vertical root fractures (VRFs) is imperative to prevent extensive bone loss and unnecessary endodontic and prosthodontic treatments. The aim of this study was to assess the effect of time lapse on the diagnostic accuracy of cone beam computed tomography (CBCT) for VRFs in endodontically treated dog's teeth. Forty-eight incisors and premolars of three adult male dogs underwent root canal therapy. The teeth were assigned to two groups: VRFs were artificially induced in the first group (n=24) while the teeth in the second group remained intact (n=24). The CBCT scans were obtained by NewTom 3G unit immediately after inducing VRFs and after one, two, three, four, eight, 12 and 16 weeks. Three oral and maxillofacial radiologists blinded to the date of radiographs assessed the presence/absence of VRFs on CBCT scans. The sensitivity, specificity and accuracy values were calculated and data were analyzed using SPSS v.16 software and ANOVA. The total accuracy of detection of VRFs immediately after surgery, one, two, three, four, eight, 12 and 16 weeks was 67.3%, 68.7%, 66.6%, 64.6%, 64.5%, 69.4%, 68.7%, 68% respectively. The effect of time lapse on detection of VRFs was not significant (p>0.05). Overall sensitivity, specificity and accuracy of CBCT for detection of VRFs were 74.3%, 62.2%, 67.2% respectively. Cone beam computed tomography is a valuable tool for detection of VRFs. Time lapse (four months) had no effect on detection of VRFs on CBCT scans.


Anesthetic management. Historical, present, future.
This article deals with specific agents that either have been or are being employed for the production of general anesthesia or sedative states for the control of pain or anxiety in the dental setting. Change, progress, trends, and contributions to the field of dental anesthesia made by dentists are stressed. In addition, a brief synopsis of the most popular present-day techniques and agents is discussed. Finally, the future of the field of dental anesthesia and the role to be played by dentists is considered.


Unicameral bone cyst of the tibia complicated by genu valgum.
Progressive tibia valga occurred in an adolescent girl after curettage and allografting of a large unicameral bone cyst of the tibia. The valgus deformity was corrected by a closing-wedge osteotomy, which resulted in a good functional and cosmetic result. The progressive valgus deformity might have been caused by stimulation of overgrowth of the medial tibial metaphysis.


Suboptimal light conditions negatively affect the heterotrophy of Planktothrix rubescens but are beneficial for accompanying Limnohabitans spp.
We examined the effect of light on the heterotrophic activity of the filamentous cyanobacterium Planktothrix rubescens and on its relationship with the accompanying bacteria. In situ leucine uptake by bacteria and cyanobacteria was determined in a subalpine mesotrophic lake, and natural assemblages from the zone of maximal P. rubescens abundances were incubated for 2 days at contrasting light regimes (ambient, 100× increased, dark). Planktothrix rubescens from the photic zone of the lake incorporated substantially more leucine, but some heterotrophic activity was maintained in filaments from the hypolimnion. Exposure of cyanobacteria to increased irradiance or darkness resulted in significantly lower leucine incorporation than at ambient light conditions. Highest abundances and leucine uptake of Betaproteobacteria from the genus Limnohabitans were found in the accompanying microflora at suboptimal irradiance levels for P. rubescens or in dark incubations. Therefore, two Limnohabitans strains (representing different species) were co-cultured with axenic P. rubescens at different light conditions. The abundances and leucine incorporation rates of both strains most strongly increased at elevated irradiance levels, in parallel to a decrease of photosynthetic pigment fluorescence and the fragmentation of cyanobacterial filaments. Our results suggest that Limnohabitans spp. in lakes might profit from the presence of physiologically stressed P. rubescens.


Restricted variation in plant barcoding markers limits identification in closely related bryophyte species.
Species-level identification and delimitation of bryophytes using the proposed general barcode markers for land plants has been challenging. Bryophyta (mosses) is the second most species-rich group of land plants after angiosperms, and it is thus of great importance to find useful barcoding regions also for this group of plants. We investigated how the plastid regions atpF-atpH, rbcL and trnH-psbA and the nuclear ITS2 region performed as barcode markers on closely related bryophyte taxa of selected moss (Bartramia, Distichium, Fissidens, Meesia and Syntrichia) and liverwort (Blepharostoma) genera from boreal and arctic regions. We also evaluated how sequencing success of herbarium specimens is related to length of the sequenced fragment, specimen age and taxonomic group. Sequencing success was higher for shorter fragments and younger herbarium specimens, but was lower than expected in the genera Distichium and Fissidens, indicating imperfect universality of the primers used. None of the studied DNA barcode regions showed a consistent barcode gap across the studied genera. As a single locus, the region atpF-atpH performed slightly better than rbcL and ITS2 and much better than trnH-psbA in terms of grouping conspecific sequences in monophyletic groups. This marker also gave a higher percentage of correct hits when conducting blast searches on a local database of identified sequences. Concatenated data sets of two and three markers grouped more conspecific sequences in monophyletic groups, but the improvement was not great compared with atpF-atpH alone. A discussion of recent studies testing barcode regions for bryophytes is given. We conclude that atpF-atpH, rbcL and ITS2 are to be the most promising barcode markers for mosses.


Potential Mechanisms of Cancer-Related Hypercoagulability.
The association between cancer and thrombosis has been known for over a century and a half. However, the mechanisms that underlie this correlation are not fully characterized. Hypercoagulability in cancer patients can be classified into two main categories: Type I and Type II. Type I occurs when the balance of endogenous heparin production and degradation is disturbed, with increased degradation of endogenous heparin by tumor-secreted heparanase. Type II hypercoagulability includes all the other etiologies, with factors related to the patient, the tumor, and/or the treatment. Patients with poor performance status are at higher risk of venous thromboembolism (VTE). Tumors can result in VTE through direct pressure on blood vessels, resulting in stasis. Several medications for cancer are correlated with a high risk of thrombosis. These include hormonal therapy (e.g., tamoxifen), chemotherapy (e.g., cisplatin, thalidomide and asparaginase), molecular targeted therapy (e.g., lenvatinib, osimertinib), and anti-angiogenesis monoclonal antibodies (e.g., bevacizumab and ramucirumab).


The Impact of COVID-19 Lockdown on Patients with Lymphedema.
Background: The coronavirus disease 2019 (COVID-19) pandemic poses a challenge to management of lymphedema. The aim of this study was to assess general health conditions and evaluate the problems and concerns of lymphedema patients with regard to access to care and provision of management and control follow-ups during the lockdown period between March and June 2020. Methods: A web-based online survey, which included questions about demographic and clinical properties, compliance with restrictions and self-management, complications, needs, and difficulties in accessing health care, as well as the presence of psychological symptoms, was applied. Results: Two hundred three patients (190 female and 13 male) replied. Majority of them (73.4%) were between 30 and 60 years old and had high school/university education (67%). The duration of lymphedema was more than 3 years and sites were commonly extremities with mild to moderate intensity in 70.5% patients. Majority of them adhered to stay home warnings (88.7%). Weight gain was a common problem and self-care methods were generally skipped (81.8%). Seventeen percent of them had wounds and/or cellulitis. Forty percent of patients needed to apply to health centers to renew the pressure garment, but could not reach it. More than 70% of patients had sleep disorders and anxiety/stress. Majority of patients used television and social media to get information related to COVID-19 and the exposure time was commonly 2 to 6 hours. Conclusions: The COVID-19 lockdown had a great impact on lymphedema patients' health care not only from medical but also from psychosocial aspects. All these implications have to be identified and dealt with properly to avoid concerns and consequences of future pandemic lockdowns. Lymphedema services should be well prepared to be delivered virtually, enable effective care, and share knowledge to meet the needs of patients suffering from lymphedema.


[Magnetic resonance tomographic results in bone changes associated with sclerosis].
We have compared the value of MRI with conventional radiography and CT in 40 predominantly sclerotic skeletal lesions. We have found that sclerosis and other changes in the bone structure can be demonstrated by MRI in much the same way as with conventional radiography and CT. Using high resolution surface coils, it is possible to demonstrate small areas of new bone formation such as periosteal new bone or the calcification within the nidus of an osteoid osteoma. MRI is particularly appropriate if it is necessary to show soft tissue changes within an area of sclerosis, which may be responsible for the new bone formation and which may be masked on radiographs and CT by the surrounding sclerosis.


Medical Cannabis Use Patterns and Adverse Effects in Inflammatory Bowel Disease.
To investigate medical cannabis (MC) use patterns and adverse effects in patients with inflammatory bowel disease (IBD). MC is now legal in many states. Although previous studies suggest improvement in disease activity among IBD patients using MC, use patterns and adverse effects are unclear. A cross-sectional anonymous survey was conducted (October 23, 2020 to January 24, 2021) among patients accessing MC dispensaries in New York and Minnesota. Eligibility criteria: age 18 years or older, selfreported IBD diagnosis, MC dispensary purchase. Survey questions included IBD characteristics, MC and healthcare utilization, and MC effects/adverse events. Participant characteristics were analyzed with descriptive statistics. Utilization patterns and symptoms before and after MC use were compared using the Stuart Maxwell test. Of 236 respondents, overall IBD disease activity was mild-to-moderate. Most respondents (61.0%) took a biological. Median frequency of MC use was at least once within the past week. Most respondents used products with high Δ9-tetrahydrocannabinol content (87.5%) through vape pens/cartridges (78.6%). Respondents reported fewer emergency room visits in the 12 months after versus before MC use (35.2 vs 41.5%, P <0.01) and less impact of symptoms on daily life. Most respondents reported euphoria with MC use (75.4%). The other common side effects were feeling drowsy, groggy, or with memory lapses (4.2%), dry mouth/eyes (3.4%), and anxiety/depression or paranoia (3.4%). Few respondents reported MC diversion (1.3%). MC users with IBD perceive symptom benefits and report decreased emergency room visits without serious adverse effects. Further studies are needed to confirm these results with objective measures of healthcare utilization and disease activity.


Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA.
Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.


Fracture and fracture toughness of nanopolycrystalline metals produced by severe plastic deformation.
The knowledge of the fracture of bulk metallic materials developed in the last 50 years is mostly based on materials having grain sizes, d, in the range of some micrometres up to several hundred micrometres regarding the possibilities of classical metallurgical methods. Nowadays, novel techniques provide access to much smaller grain sizes, where severe plastic deformation (SPD) is one of the most significant techniques. This opens the door to extend basic research in fracture mechanics to the nanocrystalline (NC) grain size regime. From the technological point of view, there is also the necessity to evaluate standard fracture mechanics data of these new materials, such as the fracture toughness, in order to allow their implementation in engineering applications. Here, an overview of recent results on the fracture behaviour of several different ultrafine-grained (d<1 μm) and NC (d<100 nm) metals and alloys covering examples of body- and face-centred cubic structures produced by SPD will be given.


Potential of different AM fungi (native from As-contaminated and uncontaminated soils) for supporting Leucaena leucocephala growth in As-contaminated soil.
Arbuscular mycorrhizal (AM) fungi inoculation is considered a potential biotechnological tool for an eco-friendly remediation of hazardous contaminants. However, the mechanisms explaining how AM fungi attenuate the phytotoxicity of metal(oid)s, in particular arsenic (As), are still not fully understood. The influence of As on plant growth and the antioxidant system was studied in Leucaena leucocephala plants inoculated with different isolates of AM fungi and exposed to increasing concentrations of As (0, 35, and 75 mg dm-3) in a Typic Quartzipsamment soil. The study was conducted under greenhouse conditions using isolates of AM fungi selected from uncontaminated soils (Acaulospora morrowiae, Rhizophagus clarus, Gigaspora albida; and a mixed inoculum derived from combining these isolates, named AMF Mix) as well as a mix of three isolates from an As-contaminated soil (A. morrowiae, R. clarus, and Paraglomus occultum). After 21 weeks, the activities of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and glutathione reductase (GR) were determined in the shoots in addition to measuring plant height and mineral contents. In general, AM fungi have shown multiple beneficial effects on L. leucocephala growth. Although the activity of most of the stress-related enzymes increased in plants associated with AM fungi, the percentage increase caused by adding As to the soil was even greater for non-mycorrhizal plants when compared to AM-fungi inoculated ones, which highlights the phytoprotective effect provided by the AM symbiosis. The highest P/As ratio observed in AM-fungi plants, compared to non-mycorrhizal ones, can be considered a good indicator that the AM fungi alter the pattern of As(V) uptake from As-contaminated soil. Our results underline the role of AM fungi in increasing the tolerance of L. leucocephala to As stress and emphasize the potential of the symbiosis L. leucocephala-R. clarus for As-phytostabilization at moderately As-contaminated soils.


Stability and dynamics of polycomb target sites in Drosophila development.
Polycomb-group (PcG) and Trithorax-group proteins together form a maintenance machinery that is responsible for stable heritable states of gene activity. While the best-studied target genes are the Hox genes of the Antennapedia and Bithorax complexes, a large number of key developmental genes are also Polycomb (Pc) targets, indicating a widespread role for this maintenance machinery in cell fate determination. We have studied the linkage between the binding of PcG proteins and the developmental regulation of gene expression using whole-genome mapping to identify sites bound by the PcG proteins, Pc and Pleiohomeotic (Pho), in the Drosophila embryo and in a more restricted tissue, the imaginal discs of the third thoracic segment. Our data provide support for the idea that Pho is a general component of the maintenance machinery, since the majority of Pc targets are also associated with Pho binding. We find, in general, considerable developmental stability of Pc and Pho binding at target genes and observe that Pc/Pho binding can be associated with both expressed and inactive genes. In particular, at the Hox complexes, both active and inactive genes have significant Pc and Pho binding. However, in comparison to inactive genes, the active Hox genes show reduced and altered binding profiles. During development, Pc target genes are not simply constantly associated with Pc/Pho binding, and we identify sets of genes with clear differential binding between embryo and imaginal disc. Using existing datasets, we show that for specific fate-determining genes of the haemocyte lineage, the active state is characterised by lack of Pc binding. Overall, our analysis suggests a dynamic relationship between Pc/Pho binding and gene transcription. Pc/Pho binding does not preclude transcription, but levels of Pc/Pho binding change during development, and loss of Pc/Pho binding can be associated with both stable gene activity and inactivity.


Cyclooxygenase-2 expression and inhibition in atherothrombosis.
Arachidonic acid metabolism plays an important role in acute ischemic syndromes affecting the coronary or cerebrovascular territory, as reflected by biochemical measurements of eicosanoid biosynthesis and the results of inhibitor trials in these settings. Two cyclooxygenase (COX)-isozymes have been characterized, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression, tissue distribution, substrate specificity, preferential coupling to upstream and downstream enzymes, and susceptibility to inhibition by the extremely heterogeneous class of COX-inhibitors. Although the role of platelet COX-1 in acute coronary syndromes and ischemic stroke is firmly established through approximately 20 years of thromboxane metabolite measurements and aspirin trials, the role of COX-2 expression and inhibition in atherothrombosis is substantially uncertain, because the enzyme was first characterized in 1991 and selective COX-2 inhibitors became commercially available only in 1998. In this review, we discuss the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque "vulnerability," and the clinical consequences of COX-2 inhibition. Recent studies from our group suggest that variable expression of upstream and downstream enzymes in the prostanoid biosynthetic cascade may represent important determinants of the functional consequences of COX-2 expression and inhibition in different clinical settings.


Interface superconductor with gap behaviour like a high-temperature superconductor.
The physics of the superconducting state in two-dimensional (2D) electron systems is relevant to understanding the high-transition-temperature copper oxide superconductors and for the development of future superconductors based on interface electron systems. But it is not yet understood how fundamental superconducting parameters, such as the spectral density of states, change when these superconducting electron systems are depleted of charge carriers. Here we use tunnel spectroscopy with planar junctions to measure the behaviour of the electronic spectral density of states as a function of carrier density, clarifying this issue experimentally. We chose the conducting LaAlO3-SrTiO3 interface as the 2D superconductor, because this electron system can be tuned continuously with an electric gate field. We observed an energy gap of the order of 40 microelectronvolts in the density of states, whose shape is well described by the Bardeen-Cooper-Schrieffer superconducting gap function. In contrast to the dome-shaped dependence of the critical temperature, the gap increases with charge carrier depletion in both the underdoped region and the overdoped region. These results are analogous to the pseudogap behaviour of the high-transition-temperature copper oxide superconductors and imply that the smooth continuation of the superconducting gap into pseudogap-like behaviour could be a general property of 2D superconductivity.


Experimental autoimmune dacryoadenitis. II. Harderian gland disease in the rat.
Experimental autoimmune dacryoadenitis was induced in 100% of Lewis rats by immunization with a KCl extract of Harderian gland in complete Freund's adjuvant (CFA), providing that the animals had received simultaneously i.v. injection of killed Bordetella pertussis. No significant pathological changes in the Harderian gland were observed in control animals immunized with KCl extracts of lacrimal or salivary glands. Gel filtration of the KCl extract on Sephacryl S-300 column yielded three protein fractions. Fraction II (MW = 50-100K) induced severe Harderian gland disease following a single injection of 2.0 mg protein in CFA plus pertussis. The initial lesions consisted of multiple focal infiltrates of mononuclear cells. Later, the inflammatory process assumed a more granulomatous form, with significant contribution by epithelioid and giant cells. In contrast, Lewis rats immunized with Harderian gland fractions I or III proteins, or with extracts of lacrimal or salivary gland, showed little or no inflammatory lesions. These data suggest that Harderian gland contains unique tissue-specific autoantigen(s) capable of inducing autoimmune granulomatous dacryoadenitis in the rat.


Saturable, high-avidity monocyte receptors for monomeric IgG and Fc fragments increase in SLE and lyme disease.
We have devised an assay for quantifying high-avidity Fc receptors for monomeric IgG on peripheral blood monocytes. In the development of a radiolabelled ligand for the assay, we found that Fc fragments offer several advantages over 7S-IgG. Compared to the latter ligand, the fragments interacted more cleanly with a single high-avidity binding site, appeared to have easier access to this site, and, since they showed no binding to Millipore filters, their use made possible a wash procedure that was convenient and rapid, thus minimizing loss of specifically bound ligand. Application of the assay to a study of ten normal controls, five patients with SLE, and three patients with Lyme disease demonstrated that normal monocytes bear approximately 10,000 high-avidity binding sites per cell. In contrast, patient monocytes bore significantly more Fc receptors; on average their cells had about 40,000 such sites per cell (P = 0.01) and sometimes as many as 100,000 sites per cell. Both normal and patient monocytes bound IgG or Fc fragments with an apparent association constant (KA) of approximately 10(8) M-1. The majority of patients with active SLE and Lyme disease had serum C1q-binding material compatible with the presence of circulating immune complexes. This study shows that these putative circulating immune complexes do not necessarily lead to a reduction in the number of Fc receptors on peripheral blood monocytes. Rather, the data suggest that in the course of immune mediated diseases, either monocytes are activated in vivo to express greater numbers of Fc receptors, or a subset of monocytes bearing more Fc receptors is expanded.


A novel homozygous mutation in RASGRP1 that predisposes to immune dysregulation and immunodeficiency associated with uncontrolled Epstein-Barr virus-induced B cell proliferation.
RASGRP1-deficiency results in an immune dysregulation and immunodeficiency that manifest as autoimmunity, lymphoproliferation, lymphopenia, defective T cell function, and increased incidence of Epstein-Bar Virus infections and lymphomas. To investigate the mechanism of autoimmune hemolytic anemia and infections in a male patient of consanguineous parents from Lebanon. Genetic diagnosis was obtained using next generation and Sanger sequencing. Protein expression and phosphorylation were determined by immunoblotting. T and B cell development and function were studied by flow cytometry. Cytokine and immunoglobulin secretions were quantified by enzyme-linked immunosorbent assay. The patient suffered from severe lymphopenia especially affecting the T cell compartment. Genetic analysis revealed a homozygous insertion of adenine at position 1396_1397 in RASGRP1 that abolished protein expression and downstream Ras signaling. T cells from the patient showed severe activation defects resulting in uncontrolled Epstein-Bar Virus-induced B cell proliferation. B cells from the patient were normal. This report expands the spectrum of mutations in patients with RasGRP1 deficiency, and provides evidence for the important role RasGRP1 plays in the ability of T cells to control Epstein-Bar Virus-induced B cell proliferation. Following diagnosis, the patient will be maintained on oral valganciclovir and monitored regularly for Epstein-Bar Virus infections to avoid the development of Epstein-Bar Virus- induced B cell lymphoma. He is also candidate for hematopoietic stem cell transplantation.


Functional MRI measurement of language lateralization in Wada-tested patients.
In this study the use of functional MRI (fMRI) for measuring language lateralization non-invasively was examined. The subjects were seven patients with histories of temporal lobe epilepsy who had undergone Wada testing for pre-surgical evaluation. Four patients were left-hemisphere-dominant and three were right-hemisphere-dominant for language. They received fMRI scans while they made semantic or perceptual judgments about visually presented words. Regions of the inferior frontal gyrus (pars triangularis and pars orbitalis) and neighbouring orbital cortex, corresponding to portions of Brodmann areas 45, 46 and 47, exhibited significant increases in activation during semantic relative to perceptual judgments. Lateralization of the increases in activation were consistent with the Wada test assessments of hemispheric language dominance in each of the seven patients. These results suggest that, in addition to providing a tool for investigating human cognitive processes, fMRI has significant clinical potential as a non-invasive measure of language lateralization.


Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids.
Phospholipid-binding modules such as PH, C1, and C2 domains play crucial roles in location-dependent regulation of many protein kinases. Here, we identify the KA1 domain (kinase associated-1 domain), found at the C terminus of yeast septin-associated kinases (Kcc4p, Gin4p, and Hsl1p) and human MARK/PAR1 kinases, as a membrane association domain that binds acidic phospholipids. Membrane localization of isolated KA1 domains depends on phosphatidylserine. Using X-ray crystallography, we identified a structurally conserved binding site for anionic phospholipids in KA1 domains from Kcc4p and MARK1. Mutating this site impairs membrane association of both KA1 domains and intact proteins and reveals the importance of phosphatidylserine for bud neck localization of yeast Kcc4p. Our data suggest that KA1 domains contribute to "coincidence detection," allowing kinases to bind other regulators (such as septins) only at the membrane surface. These findings have important implications for understanding MARK/PAR1 kinases, which are implicated in Alzheimer's disease, cancer, and autism.


A novel rapid measurement method of cervical sagittal parameters based on the integrated inclinometer of a smartphone: a validity and reliability study.
Objectives: A new method was introduced using a smartphone's integrated inclinometer for rapid measurement of sagittal cervical parameters. The present study aims to compare the validity and reliability of the proposed method.Methods: We retrospectively reviewed 120 patients with cervical spondylosis treated at our hospital. The C0-2 Cobb angle, C2-7 Cobb angle, T1-slope (T1S), and neck tilt (NT) were selected as representative sagittal angles for this study. Two methods, the smartphone's integrated inclinometer and picture archiving and communication system (PACS), were used to measure these four representative angles. Validity, reliability, and measurement times were recorded and compared.Results: The representative parameters (C0-2 Cobb angle, C2-7 Cobb angle, T1S, and NT), the ICC was 0.957 (0.939-0.970), 0.971 (0.958-0.979), 0.974 (0.963-0.982) and 0.949 (0.927-0.964) for validity respectively. For the aforementioned representative parameters, the ICC values were 0.972 (0.960-0.980), 0.979 (0.969-0.985), 0.972 (0.959-0.980), 0.942 (0.917-0.959) for intraobserver reliability respectively. For the representative parameters mentioned above, the ICC values were 0.947 (0.926-0.963), 0.964 (0.949-0.975), 0.956 (0.938-0.969), 0.916 (0.881-0.940) for interobserver reliability respectively. For the validity of the representative parameters mentioned above, the Bland-Altman plot displayed a mean difference of 0.2, 0.1, 0.1, and 0.4°with a 95% CI of 4.3, 4.5, 3.4, and 4.1°, respectively. The measurement by smartphone's integrated inclinometer (46.31 ± 3.99 s) was significantly quicker than that by PACS (69.48 ± 3.25 s) according to independent-samples T test (p < 0.001).Conclusion: This novel smartphone measurement based on the integrated inclinometer is accurate and reliable for measuring cervical sagittal parameters rapidly and conveniently.


Diffusion properties of molecules at the blood-brain interface: potential contributions of astrocyte endfeet to diffusion barrier functions.
Molecular diffusion in the extracellular space (ECS) plays a key role in determining tissue physiology and pharmacology. The blood-brain barrier regulates the exchange of substances between the brain and the blood, but the diffusion properties of molecules at this blood-brain interface, particularly around the astrocyte endfeet, are poorly characterized. In this study, we used 2-photon microscopy and acute brain slices of mouse neocortex and directly assessed the diffusion patterns of fluorescent molecules. By observing the diffusion of unconjugated and 10-kDa dextran-conjugated Alexa Fluor 488 from the ECS of the brain parenchyma to the blood vessels, we find various degrees of diffusion barriers at the endfeet: Some allow the invasion of dye inside the endfoot network while others completely block it. Detailed analyses of the time course for dye clearance support the existence of a tight endfoot network capable of acting as a diffusion barrier. Finally, we show that this diffusion pattern collapses under pathological conditions. These data demonstrate the heterogeneous nature of molecular diffusion dynamics around the endfeet and suggest that these structures can serve as the diffusion barrier. Therefore, astrocyte endfeet may add another layer of regulation to the exchange of molecules between blood vessels and brain parenchyma.


Prevalence and Risk Factors of Blindness Among Primary Angle Closure Glaucoma Patients in the United States: An IRIS® Registry Analysis.
To assess the prevalence and risk factors of blindness among patients newly diagnosed with primary angle closure glaucoma (PACG) in the United States (US). Retrospective cross-sectional study. Eligible patients from the American Academy of Ophthalmology (AAO) IRIS® Registry (Intelligent Research in Sight) had newly diagnosed PACG, defined as: 1) observable during a 24-month lookback period from index date of PACG diagnosis; 2) no prior history of eye drops, laser, or cataract surgery unless preceded by a diagnosis of anatomical narrow angle (ANA); 3) no prior history of glaucoma surgery. Logistic regression models were developed to identify risk factors for any (one or both eyes) or bilateral (both eyes) blindness (visual acuity ≤ 20/200) at first diagnosis of PACG. Among 43,901 eligible patients, overall prevalence of any and bilateral blindness were 11.5% and 1.8%, respectively. Black and Hispanic patients were at higher risk of any (OR=1.42 and 1.21, respectively; p<0.001) and bilateral (OR=2.04 and 1.53, respectively; p<0.001) blindness compared to non-Hispanic White patients adjusted for ocular comorbidities. Age <50 or >80 years, male sex, Medicaid or Medicare insurance product, and Southern or Western practice region also conferred higher risk of blindness (OR>1.28; p≤0.01). Blindness affects 1 out of 9 patients with newly diagnosed PACG in the IRIS® Registry. Black and Hispanic patients and Medicaid and Medicare recipients are at significantly higher risk. These findings highlight the severe ocular morbidity among PACG patients and the need for improved disease awareness and detection methods.


[Radiosurgery in the treatment of cerebral arteriovenous malformations].
Stereotactic radiosurgery is one of the principle treatment options for small cerebral arteriovenous malformations, even in eloquent locations. Complete obliteration mainly depends on the applied single dose and treatment volume, although other potential factors may interfere. The risk of intracranial hemorrhage after radiosurgery is related to the obliteration status and depends on the size and volume of cerebral arteriovenous malformations. Radiosurgery has shown to be effective with minimum morbidity. According to appropriate criteria as far as characteristics of cerebral arteriovenous malformations are concerned, and, balancing dose prescription and optimum planning, radiosurgery results are undeniably encouraging.


Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients.
The purpose is to investigate the clinical relevance of altered patterns of p27 and Skp2 expression in African-American patients with localized prostate cancer. The abundance of p27, an inhibitor of cell proliferation, is controlled by Skp2-dependent proteolysis. A well-characterized cohort of 162 African-Americans who underwent radical prostatectomy at the Veterans Affairs Medical Center of New York between 1990 and 2000 was studied. We analyzed p27 and Skp2 expression by immunohistochemistry. Altered expression of p27 (defined as <40% tumor cells expressing the protein) and Skp2 (defined as > or ==" BORDER="0">20% tumor cells expressing the protein) were correlated with clinicopathological parameters and time to prostate-specific antigen (PSA) recurrence. Altered expression of p27 and Skp2 was observed in 112 of 162 (69.1%) and 93 of 162 (57.4%) cases, respectively. Inverse patterns of Skp2 and p27 protein expression were seen in 87 of 162 (53.7%) cases. A marginally significant association was found between Skp2 overexpression and extracapsular extension (P = 0.065). Moreover, patients with Skp2 overexpression had a 2.77 years decreased median time to PSA recurrence compared with patients with low Skp2 expression; however, the difference was not statistically significant. In multivariate analysis, only tumor grade and stage independently predicted PSA recurrence in this cohort. Our data suggest a role for Skp2 overexpression in prostate cancer pathogenesis that might not be exclusively related to p27 degradation. More studies are needed to determine the mechanistic role of Skp2 in prostate cancer.


Do patients with active RA have differences in disease activity and perceptions if anti-TNF naïve versus anti-TNF experienced? Baseline results of the optimization of adalimumab trial.
The chance of a good response in RA is attenuated in previous anti-TNF users who start new anti-TNF therapy compared to biologic naïve patients. In active RA, those with previous anti-TNF exposure compared to anti-TNF naïve may have different baseline disease activity and patient perceptions when starting a new anti-TNF treatment that could explain the observed response differences. The aim of this study was a post hoc analysis of baseline characteristics of patients enrolled in the Optimization of Adalimumab study that was a treat to target vs. routine care study in patients initiating adalimumab. As per the protocol, a maximum of 20% anti-TNF experienced patients were enrolled in the 300 patient trial. Twelve (4.0%) were excluded who previously used other biologics. Baseline characteristics including age, gender, tender and swollen joint counts, disease activity (DAS28), function (HAQ-DI), patient global assessment, patient satisfaction with current treatment, and inflammatory markers (CRP, ESR), were compared between previously anti-TNF experienced [etanercept or infliximab (EXP)], and anti-TNF naïve patients (NAÏVE). The mean (SD) age was 54.8 (13.3) years; 81.0% were female, and 237 (79.0%) were anti-TNF naïve while 51 (17.0%) patients were anti-TNF experienced (29 with etanercept, 16 with infliximab, and 6 for both). The mean (SD) baseline in EXP versus NAÏVE groups respectively was: CRP=21.7(32.9) vs. 17.5(20.7); ESR=28.7(22.5) vs. 29.8(20.4); SJC=10.5(6.0) vs. 10.7(5.6); TJC=12.8(7.1) vs. 12.3(7.3); and DAS28=6.0(1.2) vs. 5.8(1.1). None of the between-group differences were statistically significant, however, the HAQ-DI in EXP was 1.7(0.6) compared to 1.5(0.7) for the NAÏVE (P=0.021). Additionally, EXP patients had a higher patient global score [71.3(26.1) vs. 61.9(26.2), P=0.021]. Although anti-TNF naïve and experienced patients who initiated adalimumab were similar, with respect to several baseline characteristics, significant differences in subjective measures were observed, which may indicate more severe patient measures (function and global disease activity) in anti-TNF experienced patients.


Coupled electron transfer and proton hopping in the final step of CYP19-catalyzed androgen aromatization.
Aromatase (CYP19) catalyzes the terminal step in estrogen biosynthesis, which requires three separate oxidation reactions, culminating in an enigmatic aromatization that converts an androgen to an estrogen. A stable ferric peroxo (Fe(3+)O(2)(2-)) intermediate is seen by electron paramagnetic resonance, but its role in this complex reaction remains controversial. Combining molecular dynamics simulation and hybrid quantum mechanics/molecular mechanics, we show that ferric peroxo addition to the 19-aldehyde initiates the reaction. Stepwise cleavage of the C10-C19 and O-O bonds of the peroxohemiacetal extrudes formate and yields Compound II, which in turn desaturates the steroid through successive abstraction of the 1β-hydrogen atom and deprotonation of the 2β-position. Throughout the transformation, a proton is cyclically relayed between D309 and the substrate to stabilize reaction intermediates. This mechanism invokes novel oxygen intermediates and provides a unifying interpretation of past experimental mechanistic studies.


Development and reliability of two core stability field tests.
Because of the recognized link between core stability and back and lower extremity injury in sport, additional field tests that assess the strength and power component of core stability are needed to identify athletes at risk of such injury. To that end, we developed and tested the reliability of the front and side abdominal power tests (FAPT and SAPT), which were adapted from plyometric medicine ball exercises. The FAPT and SAPT were performed by explosively contracting the core musculature using the arms as a lever to project a medicine ball. Twenty-four untrained young women (aged 20.9 +/- 1.1 year) completed three trials each of the FAPT and SAPT on separate nonconsecutive days. The average distance the medicine ball was projected on each day was recorded; power was inferred from this measure. There was an approximately 3% increase in the mean distance between the testing sessions for the FAPT and SAPT; this was not significant and indicates there was no learning effect in the measurement protocol. Heteroscedasticity was present in the SAPT data but not the FAPT data. For the FAPT, the intraclass correlation coefficient was 0.95, standard error of measurement was 24 cm, and random error using the limits of agreement method was 67.5 cm. For the SAPT, the intraclass correlation coefficient was 0.93, mean coefficient of variation was 9.8%, and the limits of agreement ratio was 36.8%. The FAPT and SAPT displayed excellent test-retest reliability, as well as acceptable measurement error. These findings suggest the FAPT and SAPT are reliable tests and may be used to assess the power component of core stability in young women.


Gene silencing in Fucus embryos: developmental consequences of RNAi-mediated cytoskeletal disruption.
Brown algae (Phaeophyceae) are an important algal class that play a range of key ecological roles. They are often important components of rocky shore communities. A number of members of the Fucales and Ectocarpales have provided models for the study of multicellular evolution, reproductive biology and polarized development. Indeed the fucoid algae exhibit the unusual feature of inducible embryo polarization, allowing many classical studies of polarity induction. The potential of further studies of brown algae in these important areas has been increasingly hindered by the absence of tools for manipulation of gene expression that would facilitate further mechanistic analysis and gene function studies at a molecular level. The aim of this study was to establish a method that would allow the analysis of gene function through RNAi-mediated gene knockdown. We show that injection of double-stranded RNA (dsRNA) corresponding to an α-tubulin gene into Fucus serratus Linnaeus zygotes induces the loss of a large proportion of the microtubule cytoskeleton, leading to growth arrest and disruption of cell division. Injection of dsRNA targeting β-actin led to reduced rhizoid growth, enlarged cells and the failure to develop apical hair cells. The silencing effect on actin expression was maintained for 3 months. These results indicate that the Fucus embryo possesses a functional RNA interference system that can be exploited to investigate gene function during embryogenesis.


Susceptibility variation to the main pathogens of Crassostrea gigas at the larval, spat and juvenile stages using unselected and selected oysters to OsHV-1 and/or V. aestuarianus.
French commercial hatcheries are massively producing Crassostrea gigas selected for their higher resistance to OsHV-1, and soon should also implement selection for increasing resistance to Vibrio aestuarianus. The first objective of this study was to optimize the breeding programs for dual resistance to OsHV-1 and V. aestuarianus to determine the earliest life stage for which oysters are able to develop disease resistance. Wild stocks and selected families were tested using experimental infections by both pathogens at the larval, spat and juvenile stages. Oyster families could be evaluated for OsHV-1 as soon as the larval stage by a bath method, but this only highlighted the most resistant families; those that showed the highest resistance to V. aestuarianus could be determined using the cohabitation method at the juvenile stage. The second objective of this study was to determine if selection to increase/decrease the resistance to OsHV-1 and V. aestuarianus could have an impact on other major pathogens currently detected in hatchery at the larval stage, and in nursery and field at the spat/juveniles stages (V. coralliilyticus, V. crassostreae, V. tasmaniensis, V. neptunius, V. europaeus, V. harveyi, V. chagasi). No relationship was found between mortality caused by V. aestuarianus/OsHV-1 and the mortality caused by the other virulent bacterial strains tested regardless the stages, except between OsHV-1 and V. tasmaniensis at the juvenile stage. Finally, miscellaneous findings were evidenced such as (1) bath for bacterial challenges was not adapted for spat, (2) the main pathogens at the larval stage were OsHV-1 and V. coralliilyticus using bath, while it was V. coralliilyticus, V. europaeus, and V. neptunius at the juvenile stage by injection, and (4) variation in mortality was observed among families/wild controls for all pathogens at larval and juvenile stages, except for V. harveyi for larvae.


Immunological changes in primary HIV-1 infection.
Homosexual men with symptomatic primary HIV-1 infection displayed a pronounced lymphopaenia with significantly depressed numbers of CD3+, CD4+ and CD8+ cells and B cells during the first week of illness. Subsequently, the CD8+ cell counts rose in parallel with numbers of CD3+ cells, atypical lymphocytes and activated (CD38+ and HLA-Dr+) cells to attain maximal levels about a month following onset of illness. In contrast CD4+ and B cell numbers remained low for an extended period of time. Early signs of a host response included a transient appearance of interferon-alpha in the blood and raised levels of neopterin and beta 2-microglobulin (beta 2-M). Neither CD4+/CD8+ cell ratio nor beta 2-M resumed completely normal values during a follow-up period of 2 years. These findings shed some light on pathogenetic events during early HIV-1 infection and suggest that the infection, following the acute symptomatic stage, usually enters a stage of chronic active rather than latent infection.


Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis.
Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-Kras(G12D/+); Trp53(fl/fl) murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α-deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination. Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifi cally the collagen-modifying enzyme PLOD2.


What Is New in the Treatment of Smoldering Multiple Myeloma?
Smoldering multiple myeloma (SMM), an asymptomatic plasma cell neoplasm, is currently diagnosed according to the updated IMWG criteria, which reflect an intermediate tumor mass between monoclonal gammopathy of undetermined significance (MGUS) and active MM. However, SMM is a heterogeneous entity and individual case may go from an "MGUS-like" behavior to "early MM" with rapid transformation into symptomatic disease. This wide range of clinical outcomes poses challenges for prognostication and management of individual patients. However, initial studies showed a benefit in terms of progression or even survival for early treatment of high-risk SMM patients. While outside of clinical trials the conventional approach to SMM generally remains that of close observation, these studies raised the question of whether early treatment should be offered in high-risk patients, prompting evaluation of several different therapeutic approaches with different goals. While delay of progression to MM with a non-toxic treatment is clearly achievable by early treatment, a convincing survival benefit still needs to be proven by independent studies. Furthermore, if SMM is to be considered less biologically complex than MM, early treatment may offer the chance of cure that is currently not within reach of any active MM treatment. In this paper, we present updated results of completed or ongoing clinical trials in SMM treatment, highlighting areas of uncertainty and critical issues that will need to be addressed in the near future before the "watch and wait" paradigm in SMM is abandoned in favor of early treatment.


Purification and localization of human carbonic anhydrase. III. Typing of skeletal muscle fibers in paraffin embedded sections.
Three different isoenzymes of human carbonic anhydrase are now well characterized. Carbonic anhydrase I and II have been known for several years and are located in high amounts in red blood cells as well as in many other tissues. Carbonic anhydrase III, a protein showing CO2 hydratase and p-nitrophenylphosphatase activity was isolated from skeletal muscle some years ago. Earlier observations based on enzyme activity and radioimmunoassay studies have suggested that this protein is present in greater quantities in red skeletal muscles than in white ones. We have purified CA III from human soleus muscle and using obtained monospecific polyclonal antibody localized this protein in the same muscle fibers which show acid resistant ATPase activity. Using this protein as a marker for type I muscle fibers, fiber classification into type I and II could now be done also from paraffin embedded sections.


Characterising molecules for fundamental physics: an accurate spectroscopic model of methyltrioxorhenium derived from new infrared and millimetre-wave measurements.
Precise spectroscopic analysis of polyatomic molecules enables many striking advances in physical chemistry and fundamental physics. We use several new high-resolution spectroscopic devices to improve our understanding of the rotational and rovibrational structure of methyltrioxorhenium (MTO), the achiral parent of a family of large oxorhenium compounds that are ideal candidate species for a planned measurement of parity violation in chiral molecules. Using millimetre-wave and infrared spectroscopy in a pulsed supersonic jet, a cryogenic buffer gas cell, and room temperature absorption cells, we probe the ground state and the Re[double bond, length as m-dash]O antisymmetric and symmetric stretching excited states of both CH3187ReO3 and CH3185ReO3 isotopologues in the gas phase with unprecedented precision. By extending the rotational spectra to the 150-300 GHz range, we characterize the ground state rotational and hyperfine structure up to J = 43 and K = 41, resulting in refinements to the rotational, quartic and hyperfine parameters, and the determination of sextic parameters and a centrifugal distortion correction to the quadrupolar hyperfine constant. We obtain rovibrational data for temperatures between 6 and 300 K in the 970-1015 cm-1 range, at resolutions down to 8 MHz and accuracies of 30 MHz. We use these data to determine more precise excited-state rotational, Coriolis and quartic parameters, as well as the ground-state centrifugal distortion parameter DK of the 187Re isotopologue. We also account for hyperfine structure in the rovibrational transitions and hence determine the upper state rhenium atom quadrupole coupling constant eQq'.


[Prevalence of mycelial fungi in hematological hospital].
To study prevalence, quantity and species of mycelial fungi in the air of a hematological hospital. Air samples in the hematological departments were taken monthly by PU-1B device in the volume 250 l/min. Seeding and identification of mycelial fungi were made on the Chapeck medium. Tests for mycelial fungi in the air was 95%. Dominating species were the following: Penicillium spp., Cladosporium spp., Aspergillus spp. The fungal contamination was seasonal. Maximal isolation of Penicillium spp was seen in winter and autumn. Aspergillus spp. is represented with 13 species of which most frequent were A.versicolor, A. niger, A. fumigatus, A. ochraceus, A. flavus. Pathological material from 19 patients contained Aspergillus spp.: A. fumigatus, A. flavus, A. niger. The isolation peak was in autumn-winter and coincided with maximal isolation of fungal spores from the air. The analysis of air samples taken in the wards where patients had Aspergillus spp. in biomaterials showed that concentration of spores Aspergillus spp. was higher than in nearby wards and corridor: 45.6 CFU/M3 vs 18.8 CFU/m3 and 24.7 CFU/M3, respectively. However, morphologically identical strains (patient-air) were recognized only in 4 cases from the nearby wards and corridor. None of the air samples taken in the ward of the patient contained identical species. Minimal amount of the spores of micromycetes was registered in the wards furnished with ventilation with laminar air flow. Most contaminated was the air of 4 bed wards in the old building. Mycological monitoring of the air in hematological departments determined the structure of mycelial fungi complexes. Though ambient air in the wards is full of fungi, detection of morphologically identical strains causing invasive mycosis in immunocompromised patients is rare. Further studies are necessary.


Electroconvulsive Shock, but Not Transcranial Magnetic Stimulation, Transiently Elevates Cell Proliferation in the Adult Mouse Hippocampus.
Hippocampal plasticity is hypothesized to play a role in the etiopathogenesis of depression and the antidepressant effect of medications. One form of plasticity that is unique to the hippocampus and is involved in depression-related behaviors in animal models is adult neurogenesis. While chronic electroconvulsive shock (ECS) strongly promotes neurogenesis, less is known about its acute effects and little is known about the neurogenic effects of other forms of stimulation therapy, such as repetitive transcranial magnetic stimulation (rTMS). Here, we investigated the time course of acute ECS and rTMS effects on markers of cell proliferation and neurogenesis in the adult hippocampus. Mice were subjected to a single session of ECS, 10 Hz rTMS (10-rTMS), or intermittent theta burst stimulation (iTBS). Mice in both TMS groups were injected with BrdU 2 days before stimulation to label immature cells. One, 3, or 7 days later, hippocampi were collected and immunostained for BrdU + cells, actively proliferating PCNA + cells, and immature DCX + neurons. Following ECS, mice displayed a transient increase in cell proliferation at 3 days post-stimulation. At 7 days post-stimulation there was an elevation in the number of proliferating neuronal precursor cells (PCNA + DCX +), specifically in the ventral hippocampus. iTBS and rTMS did not alter the number of BrdU + cells, proliferating cells, or immature neurons at any of the post-stimulation time points. Our results suggest that neurostimulation treatments exert different effects on hippocampal neurogenesis, where ECS may have greater neurogenic potential than iTBS and 10-rTMS.


Development and evaluation of the MiCheck test for aggressive prostate cancer.
A clinical need exists for a biomarker test to accurately delineate aggressive prostate cancer (AgCaP), and thus better assist clinicians and patients decision-making on whether to proceed to prostate biopsy. To develop a blood test for AgCaP and compare to PSA, %free PSA, proPSA, and prostate health index (PHI) tests. Patient samples from the MiCheck-01 trial were used for development of the MiCheck test. Serum analyte concentrations for cellular growth factors were determined using a custom-made Luminex-based R&D Systems multianalyte kit. Bayesian model averaging and random forest approaches were used to identify clinical factors and growth factors able to distinguish between men with AgCaP (Gleason Score [GS] ≥3+4) from those with non-AgCaP (GS 3+3). Logistic regression and Monte Carlo cross-validation identified variable combinations in order to able to maximize differentiation of AgCaP from non-AgCaP. The MiCheck logistic regression model was developed and comprises the following variables: serum prostate-specific antigen (PSA), patient age, Digital Rectal Exam (DRE) status, Leptin, IL-7, vascular endothelial growth factor, and Glypican-1. The model differentiated AgCaP from non-AgCaP with an area under the curve of 0.83 and was superior to PSA, %free PSA and PHI in all patient groups, regardless of PSA range. Applying the MiCheck test to all evaluable biopsy patients from the MiCheck-01 study demonstrated that up to 30% of biopsies could be avoided while delaying diagnosis of only 6.8% of GS ≥3+4 cancers, 5% of GS ≥4+3 cancers and no cancers of GS 8 or higher. The MiCheck test outperforms PSA, %free PSA and PHI tests in differentiating AgCaP vs. non-AgCaP patients. The MiCheck test could result in a significant number of biopsies being avoided with a low number of patients experiencing a delayed diagnosis.


Management of Bacteriuria in Veterans Affairs Hospitals.
Bacteriuria contributes to antibiotic overuse through treatment of asymptomatic bacteriuria (ASB) and long durations of therapy for symptomatic urinary tract infections (UTIs), yet large-scale evaluations of bacteriuria management among inpatients are lacking. Inpatients with bacteriuria were classified as asymptomatic or symptomatic based on established criteria applied to data collected by manual chart review. We examined frequency of treatment of ASB, factors associated with treatment of ASB, durations of therapy, and frequency of complications including Clostridium difficile infection, readmission, and all-cause mortality within 28 days of discharge. Among 2225 episodes of bacteriuria, 64% were classified as ASB. After excluding patients with non-UTI indications for antibiotics, 72% of patients with ASB received antibiotics. When evaluating only patients not meeting SIRS criteria, 68% of patients with ASB received antibiotics. The mean (±SD) days of antibiotic therapy for ASB, cystitis, CA-UTI and pyelonephritis were 10.0 (4.5), 11.4 (4.7), 12.0 (6.1), and 13.6 (5.3), respectively. In sum, 14% of patients with ASB were treated for greater than 14 days, and fluoroquinolones were the most commonly used empiric antibiotic for ASB [245/691 (35%)]. Complications were rare but more common among patients with ASB treated with antibiotics. The majority of bacteriuria among inpatient veterans is due to ASB with high rates of treatment of ASB and prolonged durations of therapy for ASB and symptomatic UTIs.


A SLC24A2 Gene Variant Uncovered in Pancreatic Ductal Adenocarcinoma by Whole Exome Sequencing.
Pancreatic ductal adenocarcinoma (PDAC) presents as an aggressive malignancy caused by environmental and genetic factors. In order to identify causal genes for PDAC, we performed whole exome sequencing (WES) to detect gene mutations in seven pairs of PDAC tissue and adjacent non-tumor tissue samples. Finally, we found a new nonsynonymous single nucleotide variant (nsSNV) in solute carrier 24 family member 2 (SLC24A2) gene resulting in the substitution of native glutamic acid (E) into aspartic acid (D) at position of 287 amino acid (E287D) in SLC24A2 protein, and confirmed this variant by Sanger gene sequencing. SLC24A2 is a potassium-dependent sodium-calcium exchanger and can transport metal ion across cell membrane. Multiple in silico variants' effects analyses methods including SIFT, PolyPhen, PROVEAN, and PANTHER demonstrated this variant had probably damaging effects, which was consistent with the results obtained from Mutation Taster software analysis with a probability of 0.99999997 to be "disease causing." The three dimension (3D) structure analysis results suggested this variant had little effects on the solubility and hydrophobicity of the protein; but it could decrease the protein stability by increasing the total protein structure energy (-8874.33 kJ/mol for the mutant and -8963.54 kJ/mol for the native) and by causing the mutant protein decreasing three stabilizing residues. Less stability of the mutant 287D protein than the native E287 protein was also supported by I-Mutant and Western-blotting analysis results. Overall, a new mutation in SLC24A2 gene was identified to decrease the stability of SLC24A2, which may have potential clinical usages.


Probing the ligand binding domain of the GluR2 receptor by proteolysis and deletion mutagenesis defines domain boundaries and yields a crystallizable construct.
Ionotropic glutamate receptors constitute an important family of ligand-gated ion channels for which there is little biochemical or structural data. Here we probe the domain structure and boundaries of the ligand binding domain of the AMPA-sensitive GluR2 receptor by limited proteolysis and deletion mutagenesis. To identify the proteolytic fragments, Maldi mass spectrometry and N-terminal amino acid sequencing were employed. Trypsin digestion of HS1S2 (Chen GQ, Gouaux E. 1997. Proc Natl Acad Sci USA 94:13431-13436) in the presence and absence of glutamate showed that the ligand stabilized the S1 and S2 fragments against complete digestion. Using limited proteolysis and multiple sequence alignments of glutamate receptors as guides, nine constructs were made, folded, and screened for ligand binding activity. From this screen, the S1S21 construct proved to be trypsin- and chymotrypsin-resistant, stable to storage at 4 degrees C, and amenable to three-dimensional crystal formation. The HS1S21 variant was readily prepared on a large scale, the His tag was easily removed by trypsin, and crystals were produced that diffracted to beyond 1.5 A resolution. These experiments, for the first time, pave the way to economical overproduction of the ligand binding domains of glutamate receptors and more accurately map the boundaries of the ligand binding domain.


Acute coordinative exercise ameliorates general and food-cue related cognitive function in obese adolescents.
Whether the acute coordinative exercise could affect the inhibitory control and food-cue related attention in obese adolescents remains understudied. Therefore, this study used the Stroop test and the food-cue related Stroop test to explore the impacts of 20 min of acute coordinative exercise on the cognitive tests involving inhibitory control and attentional bias towards food-cue related stimuli, respectively, in obese adolescents. Thirty-eight obese adolescents (mean age = 14.63 ± 0.69 years) were equally divided into exercise and control groups. The cognitive tests (i.e., the Stroop test and the food-cue related Stroop test) and hunger scores were conducted and assessed before and after an intervention. The exercise group had significantly larger negative pre-post response time difference in the congruent (-1.04 ± 0.29 ms) and incongruent (-5.76 ± 1.66 ms) conditions of the Stroop test than the control group (ps < 0.01), and a smaller post-interference (1.13 ± 0.14) than the pre-interference (1.31 ± 0.14, p = 0.04). Moreover, a significantly larger negative pre-post response time difference on the food-cue related Stroop test was observed in the exercise group (-4.42 ± 7.20 ms) than the control group (1.76 ± 8.37 ms, p = 0.02). Collectively, an acute coordinative exercise session could induce superior inhibitory control and less attentional bias towards food-cue related stimuli in obese adolescents.


Effects of phosphodiesterase inhibitors on normal and chemically-skinned isolated airway smooth muscle.
1. The effects of three phosphodiesterase inhibitors (papaverine, isobutyl methyl xanthine (IBMX) and SKF 94120) were examined on tension responses and cyclic nucleotide content (both cyclic AMP and cyclic GMP) of normal and Triton X-100 skinned isolated trachealis of the guinea-pig. 2. The three inhibitors were approximately equipotent in eliciting concentration-dependent relaxation of histamine-induced contractions of the trachealis. 3. Papaverine-induced relaxation was associated with concentration-related increases in the levels of both cyclic nucleotides. 4. IBMX at low concentrations (1 mumol l-1) produced significant relaxation (36%) of histamine-contracted trachealis without changing cyclic nucleotide levels. At a ten fold higher concentration IBMX-induced relaxation (95%) was associated with a selective increase in tissue cyclic GMP levels. Only at the highest concentration tested (100 mumol l-1) did IBMX increase cyclic AMP levels significantly. 5. SKF 94120 (1 mumol l-1) elicited a 23% relaxation of the contracted trachealis without altering the tissue content of either cyclic nucleotide. At the two higher concentrations tested (10 and 100 mumol l-1), SKF 94120-induced relaxation was accompanied by a selective increase in the levels of cyclic AMP. 6. In the skinned trachealis Ca2+ (10 and 20 mumol l-1)-induced contractions were significantly inhibited by the calmodulin antagonist calmidazolium (10 mumol l-1) and by cyclic AMP (10 mumol l-1), the catalytic subunit of cyclic AMP-dependent protein kinase (0.1 mumol l-1) and cyclic GMP (10 mumol l-1). 7. Papaverine (100 mumol l-1) significantly inhibited (31 +/- 6%) the Ca2+-induced contractions of the skinned trachealis. Both IBMX and SKF 94120 were without effect. It is concluded that cyclic nucleotide-dependent mechanisms have an inhibitory action on the biochemical processes that lead to contraction of the guinea-pig trachealis. The results suggest that a functional sarcoplasmic reticular and/or plasma membrane is essential for the expression of IBMXand SKF 94120-induced relaxation. This is not the case for papaverine. The results also highlight the fact that significant relaxant responses of airway smooth muscle can be produced by phosphodiesterase- inhibiting drugs without concomitant elevations in tissue cyclic nucleotide content.


Interferon-gamma suppresses T-cell proliferation to mitogen via the nitric oxide pathway during experimental acute graft-versus-host disease.
The development of graft-versus-host disease (GVHD) is associated with long-lasting and profound deficits in immune function that lead to increased morbidity and mortality after bone marrow transplantation (BMT). We investigated a mechanism of T-cell immunodeficiency in response to mitogen or alloantigen in an experimental model of acute GVHD by analyzing the roles of two immunosuppressive moieties: interferon gamma (IFN-gamma) and nitric oxide (NO). Splenocytes from mice with GVHD did not proliferate either to the T-cell mitogen, concanavalin A (Con A), or to host alloantigens, but only mitogen-activated cultures produced increased levels of NO. The abrogation of NO synthesis with LG-mono-methyl-arginine (NMMA) restored mitogen-induced proliferation but not the response to host antigens. The mechanism of impared proliferation to mitogen was dependent on IFN-gamma because blockade of this cytokine in culture inhibited NO production and restored proliferation to Con A to levels similar to those in transplanted control mice without GVHD. NMMA did not substantially reduce IFN-gamma levels, demonstrating that NO acted distally to IFN-gamma in the pathway of immunosuppression in response to mitogen. Furthermore, the prevention of IFN-gamma production in vivo after allogeneic BMT, by transplantation of polarized type 2 donor T cells (secreting interleukin-4 but not IFN-gamma), also prevented NO production and restored splenocyte responses to mitogen. Our data demonstrate the existence of NO-dependent and NO-independent pathways involved in suppression of T-cell proliferation during acute GVHD. Excess NO synthesis appears to be one mechanism by which IFN-gamma induces immunodeficiency after allogeneic BMT.


Microwave amplification with nanomechanical resonators.
The sensitive measurement of electrical signals is at the heart of modern technology. According to the principles of quantum mechanics, any detector or amplifier necessarily adds a certain amount of noise to the signal, equal to at least the noise added by quantum fluctuations. This quantum limit of added noise has nearly been reached in superconducting devices that take advantage of nonlinearities in Josephson junctions. Here we introduce the concept of the amplification of microwave signals using mechanical oscillation, which seems likely to enable quantum-limited operation. We drive a nanomechanical resonator with a radiation pressure force, and provide an experimental demonstration and an analytical description of how a signal input to a microwave cavity induces coherent stimulated emission and, consequently, signal amplification. This generic scheme, which is based on two linear oscillators, has the advantage of being conceptually and practically simpler than the Josephson junction devices. In our device, we achieve signal amplification of 25 decibels with the addition of 20 quanta of noise, which is consistent with the expected amount of added noise. The generality of the model allows for realization in other physical systems as well, and we anticipate that near-quantum-limited mechanical microwave amplification will soon be feasible in various applications involving integrated electrical circuits.


Favorable control of rapidly progressive retroperitoneal pleomorphic leiomyosarcoma with multimodality therapy: a case report.
Retroperitoneal sarcomas (RPS), such as pleomorphic leiomyosarcoma, often invade or displace vital organs in the abdominal cavity and exhibit an aggressive clinical course. Complete surgical resection of the tumor and preoperative radiotherapy and chemotherapies can be used for non-metastatic RPS. However, in case of huge retroperitoneal sarcoma fully occupying the abdominal cavity, surgical resection tends to be insufficient, resulting in poor outcomes. This report describes a case of rapidly progressive retroperitoneal pleomorphic leiomyosarcoma that was favorably controlled by debulking surgery followed by combination chemotherapy and radiotherapy. A 65-year-old Japanese woman developed abdominal discomfort due to a huge retroperitoneal tumor fully occupying the abdominal cavity. The immunohistochemical diagnosis was pleomorphic leiomyosarcoma with high-grade malignancy and aggressive proliferative features. Debulking surgery could be performed, but the small residual tumor had rapidly grown to an approximately 22 cm in length on the major axis within 38 days after the operation. The patient's general condition progressively declined. Combination chemotherapy, consisting of doxorubicin and ifosfamide, was successfully administered for six cycles while maintaining dose intensity. The best objective response was a partial response, and the chemotherapy was well tolerated. Approximately 50 Gy of radiotherapy was delivered to the remaining tumor. This multimodal strategy resulted in progression-free survival for more than 17 months and achieved sustained symptomatic relief. Multimodal therapy with debulking surgery, combination chemotherapy and radiotherapy controlled a rapidly progressive retroperitoneal pleomorphic leiomyosarcoma. Maintaining dose intensity of the chemotherapy and radiotherapy might contribute to overall tumor control.


Are the deficits in navigational abilities present in the Williams syndrome related to deficits in the backward inhibition?
Williams syndrome (WS) is associated with a distinct profile of relatively proficient skills within the verbal domain compared to the severe impairment of visuo-spatial processing. Abnormalities in executive functions and deficits in planning ability and spatial working memory have been described. However, to date little is known about the influence of executive function deficits on navigational abilities in WS. This study aimed at analyzing in WS individuals a specific executive function, the backward inhibition (BI) that allows individuals to flexibly adapt to continuously changing environments. A group of WS individuals and a mental age- and gender-matched group of typically developing children were subjected to three task-switching experiments requiring visuospatial or verbal material to be processed. Results showed that WS individuals exhibited clear BI deficits during visuospatial task-switching paradigms and normal BI effect during verbal task-switching paradigm. Overall, the present results suggest that the BI involvement in updating environment representations during navigation may influence WS navigational abilities.


Anxiolytic- and antidepressant-like effects of group III metabotropic glutamate agonist (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) in rats.
We examined the anxiolytic-like activity of (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) using the Vogel conflict drinking test, while antidepressant-like effects of this compound were evaluated using Porsolt's test. ACPT-I, a selective group III mGlu receptor agonist, produced a dose-dependent anticonflict effect after intrahippocampal injections and antidepressant-like effect in rats after intraventricular injections. These data suggest that selective group III mGlu receptor agonists may become a new class of anxiolytics and/or antidepressants.


Personalised lung cancer risk stratification and lung cancer screening: do general practice electronic medical records have a role?
In the United Kingdom (UK), cancer screening invitations are based on general practice (GP) registrations. We hypothesize that GP electronic medical records (EMR) can be utilised to calculate a lung cancer risk score with good accuracy/clinical utility. The development cohort was Secure Anonymised Information Linkage-SAIL (2.3 million GP EMR) and the validation cohort was UK Biobank-UKB (N = 211,597 with GP-EMR availability). Fast backward method was applied for variable selection and area under the curve (AUC) evaluated discrimination. Age 55-75 were included (SAIL: N = 574,196; UKB: N = 137,918). Six-year lung cancer incidence was 1.1% (6430) in SAIL and 0.48% (656) in UKB. The final model included 17/56 variables in SAIL for the EMR-derived score: age, sex, socioeconomic status, smoking status, family history, body mass index (BMI), BMI:smoking interaction, alcohol misuse, chronic obstructive pulmonary disease, coronary heart disease, dementia, hypertension, painful condition, stroke, peripheral vascular disease and history of previous cancer and previous pneumonia. The GP-EMR-derived score had AUC of 80.4% in SAIL and 74.4% in UKB and outperformed ever-smoked criteria (currently the first step in UK lung cancer screening pilots). A GP-EMR-derived score may have a role in UK lung cancer screening by accurately targeting high-risk individuals without requiring patient contact.


Two new acyclic diterpene-gamma-lactones from Salix matsudan.
Two new phytane-type diterpene-gamma-lactones named hanliuine I (1) and hanliuine II (2), were isolated from leaves of Salix matsudana (chinese name "hanliu", Berberidaceae). Their structures were deduced from 1D and 2D NMR techniques.


Do polymorphisms in transcription factors LMX1A and LMX1B influence the risk for Parkinson's disease?
The key symptoms of Parkinson's disease (PD) are caused by degeneration of dopamine neurons originating in substantia nigra. Whereas, transcription factor LMX1A is crucial for the differentiation of mesencephalic dopamine neurons, LMX1B appears to be important for both the development and the survival of these cells. The aim of this study was to investigate if genetic variation in LMX1A and LMX1B differs between patients with PD (n = 357) and control subjects (n = 1428) by genotyping 33 single nucleotide polymorphisms (SNPs) in LMX1A and 11 SNPs in LMX1B. Three SNPs in LMX1A and one in LMX1B were associated with PD. After splitting for gender, six SNPs were associated with PD in women and four in men. The significances obtained did not survive correction for multiple testing, and our results should hence be interpreted with caution, but are partly in line with a previous report, and should thus be of sufficient interest to encourage further studies of these genes in PD.


The Comet Assay and its applications in the field of ecotoxicology: a mature tool that continues to expand its perspectives.
Since Singh and colleagues, in 1988, launched to the scientific community the alkaline Single Cell Gel Electrophoresis (SCGE) protocol, or Comet Assay, its uses and applications has been increasing. The thematic areas of its current employment in the evaluation of genetic toxicity are vast, either in vitro or in vivo, both in the laboratory and in the environment, terrestrial or aquatic. It has been applied to a wide range of experimental models: bacteria, fungi, cells culture, arthropods, fishes, amphibians, reptiles, mammals, and humans. This document is intended to be a comprehensive review of what has been published to date on the field of ecotoxicology, aiming at the following main aspects: (i) to show the most relevant experimental models used as bioindicators both in the laboratory and in the field. Fishes are clearly the most adopted group, reflecting their popularity as bioindicator models, as well as a primary concern over the aquatic environment health. Amphibians are among the most sensitive organisms to environmental changes, mainly due to an early aquatic-dependent development stage and a highly permeable skin. Moreover, in the terrestrial approach, earthworms, plants or mammalians are excellent organisms to be used as experimental models for genotoxic evaluation of pollutants, complex mix of pollutants and chemicals, in both laboratory and natural environment. (ii) To review the development and modifications of the protocols used and the cell types (or tissues) used. The most recent developments concern the adoption of the enzyme linked assay (digestion with lesion-specific repair endonucleases) and prediction of the ability to repair of oxidative DNA damage, which is becoming a widespread approach, albeit challenging. For practical/technical reasons, blood is the most common choice but tissues/cells like gills, sperm cells, early larval stages, coelomocytes, liver or kidney have been also used. (iii) To highlight correlations with other biomarkers. (iv) To build a constructive criticism and summarize the needs for protocol improvements for future test applications within the field of ecotoxicology. The Comet Assay is still developing and its potential is yet underexploited in experimental models, mesocosmos or natural ecosystems.


Risk Factors for Long-term Hip Osteoarthritis in Patients With Femoroacetabular Impingement Without Surgical Intervention.
Femoroacetabular impingement (FAI) is a common cause of hip pain and a known risk factor for hip osteoarthritis (OA) and total hip arthroplasty (THA) at a young age. Unfortunately, little is known about the specific factors associated with an increased risk of OA. To (1) report the overall rate of symptomatic hip OA and/or THA in patients with FAI without surgical intervention and (2) identify radiographic features and patient characteristics associated with hip OA. Case-control study; Level of evidence, 3. A geographic database was used to identify all patients with hip pain and radiographs between 2000 and 2016. Chart review was performed to identify patients with FAI. Patient medical records were reviewed to obtain demographic information, clinical history, physical examination findings, imaging details, and treatment details. Kaplan-Meier analysis was used to determine the rate of hip OA. Univariate and multivariate proportional hazard regression models were performed to determine risk factors for OA. The study included 952 patients (649 female; 303 male; 1104 total hips) with FAI. The majority of hips had mixed type (n = 785; 71.1%), 211 (19.1%) had pincer type, and 108 (9.8%) had cam type. Mean age at time of presentation was 27.6 ± 8.7 years. Mean follow-up time was 24.7 ± 12.5 years. The rate of OA was 13.5%. THA was performed in 4% of patients. Male sex, body mass index (BMI) greater than 29, and increased age were risk factors for OA (male sex: hazard ratio [HR], 2.28; P < .01; BMI >29: HR, 2.11; P < .01; per year of increased age: HR, 1.11; P < .01.). Smoking and diabetes mellitus were not significant risk factors. No radiographic morphological features were found to be significant risk factors for OA. At mean follow-up of 24.7 years, 14% of hips had symptomatic OA and 4% underwent THA. BMI greater than 29, male sex, and increased age at the time of presentation with hip pain were risk factors for hip OA. The cohort consisted of a large percentage of mixed-type FAI morphologies, and no specific radiographic risk factors for OA were identified.