Homoepitaxy of Crystalline Rubrene Thin Films.
The smooth surface of crystalline rubrene films formed through an abrupt heating process provides a valuable platform to study organic homoepitaxy. By varying growth rate and substrate temperature, we are able to manipulate the onset of a transition from layer-by-layer to island growth modes, while the crystalline thin films maintain a remarkably smooth surface (less than 2.3 nm root-mean-square roughness) even with thick (80 nm) adlayers. We also uncover evidence of point and line defect formation in these films, indicating that homoepitaxy under our conditions is not at equilibrium or strain-free. Point defects that are resolved as screw dislocations can be eliminated under closer-to-equilibrium conditions, whereas we are not able to eliminate the formation of line defects within our experimental constraints at adlayer thicknesses above ∼25 nm. We are, however, able to eliminate these line defects by growing on a bulk single crystal of rubrene, indicating that the line defects are a result of strain built into the thin film template. We utilize electron backscatter diffraction, which is a first for organics, to investigate the origin of these line defects and find that they preferentially occur parallel to the (002) plane, which is in agreement with expectations based on calculated surface energies of various rubrene crystal facets. By combining the benefits of crystallinity, low surface roughness, and thickness-tunability, this system provides an important study of attributes valuable to high-performance organic electronic devices.


Comparison of standard and double reading and computer-aided detection (CAD) of interval cancers at prior negative screening mammograms: blind review.
The study evaluates the role of computer-aided detection (CAD) in improving the detection of interval cancers as compared to conventional single (CONV) or double reading (DOUBLE). With this purpose, a set of 89 negative cases was seeded with 31 mammograms reported as negative and developing interval cancer in the following 2-year interval (false negative (FN)=11, minimal signs (MS)=20). A total of radiologists read the set with CONV and then with CAD. Overall, there were 589 cancer and 1691 noncancer readings with both CONV and CAD. Double reading was simulated by combining conventional readings in all 171 possible combinations of 19 radiologists, resulting in a total of 5301 cancer and 15 219 noncancer readings. Conventional single, DOUBLE and CAD readings were compared in terms of sensitivity and recall rate. Considering all 19 readings, cancer was identified in 190 or 248 of 589 readings (32.2 vs 42.1%, chi(2)=11.80, df=1, P<0.01) and recalls were 287 or 405 of 1691 readings (16.9 vs 23.9%, chi(2)=24.87, df=1, P<0.01) at CONV or CAD, respectively. When considering FN and MS cases separately, sensitivity at CONV or CAD was 50.2 or 62.6% (chi(2)=6.98, df=1, P=0.01) for FN and 22.3 or 30.7% (chi(2)=6.47, df=1, P=0.01) for MS cases, respectively. Computer-aided detection (average of 19 readings) was slightly and not significantly less sensitive (sensitivity: 42.1 vs 46.1%, chi(2)=3.24, df=1, P=0.07) but more specific (recall rate 23.9 vs 26.1%, chi(2)=3.8, df=1, P=0.04) as compared to DOUBLE (average of 171 readings). Average sensitivity for FN cases only was 62.6% for CAD and 64.8% for DOUBLE (chi(2)=0.32, df=1, P=0.58). Corresponding values for MS cases were 30.7% for CAD and 35.7% for DOUBLE (chi(2)=3.53, df=1, P=0.06). Compared to CONV, CAD allowed for improved sensitivity, though with reduced specificity, both effects being statistically significant. Computer-aided detection was almost as sensitive as DOUBLE but significantly more specific. Computer-aided detection might be used in the current practice to improve sensitivity of conventional single reading. Based on estimates of screening sensitivity and FN/MS interval cancer expected frequency, the absolute increase of screening sensitivity expected by introducing CAD-assisted reading may be estimated around 0.9%. The use of CAD as a possible surrogate to conventional DOUBLE needs to be confirmed by further studies, which should include a cost-effective analysis.


Epidermal mosaicism and Blaschko's lines.
To test the hypothesis that epidermal rather than dermal mosaicism determines Blaschko's lines in hypomelanosis of Ito (HI), we studied the distribution of chromosomal mosaicism in four patients. In two, mosaicism had not been detected in lymphocytes or dermal fibroblasts, but was clearly shown in epidermal keratinocytes; furthermore, the abnormal cell line was confirmed to the hypopigmented epidermis and the normal epidermis contained only normal cells. Negative findings in the other two patients might be because of mosaicism which was undetected either because it was submicroscopic or because it was present in melanocytes, which have not yet been studied. These preliminary results support the ideas that (1) Blaschko's lines represent single clones of epidermal cells; (2) in patients with HI and severe neurological involvement mosaicism, if detectable, is best shown in keratinocytes; and (3) the cytogenetic defect in epidermal cells may be directly responsible for the failure of pigmentation in HI.


Phylogeny of the Trichogramma endosymbiont Wolbachia, an alpha-proteobacteria (Rickettsiae).
Wolbachia (Hertig) endosymbionts are extensively studied in a wide range of organisms and are known to be transmitted through the egg cytoplasm to the offsping. Wolbachia may cause several types of reproductive modifications in arthropods. In Trichogramma species, parthenogenesis-inducing Wolbachia bacteria allow females wasps to produce daughters from unfertilized eggs and these bacteria are present in at least 9% of all Trichogramma species. Phylogenetic studies have led to the subdivision of the Wolbachia clade in five supergroups (A, B, C, D and E) and Wolbachia from Trichogramma belong to supergroup B. Here, using the wsp gene, four groups of Wolbachia that infect Trichogramma species were distinguished and the addition of a new group "Ato" was suggested due to the addition of Wolbachia from Trichogramma atopovirilia (Oatman and Platner). Specific primers were designed and tested for the "Ato" group. Seventy-five percent of all evaluated Wolbachia strains from Trichogramma fell within "Sib" group.


Trends in survival based on treatment modality for esophageal cancer: a population-based study.
The primary objective was to examine the trends in treatment modalities and the respective survival rates for esophageal cancer in the province of Ontario, Canada. This is a population-based study of all esophageal cancer cases diagnosed in Ontario between 2007 and 2015, including squamous cell carcinoma and adenocarcinoma, with known disease stage. Other characteristics include sex, age, date of diagnosis, and treatment modalities. Treatment modalities were classified as no-treatment, radiation only or chemotherapy only, chemoradiation, and surgical resection. In total, 2572 patients were identified with esophageal cancer from 2007 to 2015, of which 2014 (78.3%) were male. The mean age at diagnosis was 66.6 (SD = 11.7) years. Survival rate increased over time in patients who underwent chemoradiation or surgical resection but remained unchanged for the radiation-only or chemotherapy-only group and decreased for the no-treatment group. Survival considerably improved (15-20%) for patients with stages I-III disease. The positive trends in the survival rate for esophageal patients could be due to adoption of multimodal therapy. Despite a lower proportion of advanced disease among patients over 80, they received less curative treatments compared with other age groups. Further studies are required to identify strategies to maximize survival for patients with stage IV disease, and patients 80 years and older.


The Stereotype Content Model: The Role Played by Competence in Inferring Group Status.
In the context of the Stereotype Content Model, we investigate the "backward" inferential process that leads from the competence stereotype to the structural attribute of status. Three hypotheses were tested: (1) Perceived competence affects attributions of status; (2) the less competent group is perceived as warmer (compensation effect); (3) membership leads to ingroup status enhancement. Two minimal groups were created; groups' competence and membership were manipulated. Findings supported the hypotheses: Group status was rated higher when the target group was described as competent; groups were rated warmer when lower in competence; group status was rated higher by members than non-members.


On-line assessment of comprehension processes.
In this paper we describe a new version of a former paper-and-pencil standardized comprehension test called Test of Comprehension Processes (Vidal-Abarca, Gilabert, Martínez, & Sellés, 2007). The new version has been adapted to a computer-based environment based on the moving window technique. It can be used to assess comprehension strategies of students from fifth to tenth grades (11- to 16-years-old). Comprehension strategies are registered on-line using reading times and visits to relevant sections of the text during the question-answering process. Data show that the computer-based version draws similar results to those provided by the paper-and-pencil version. In addition, we identify the particular strategies deployed during the question-answering process by high, medium and low comprehenders.


Neural tube defects in the sample of genetic counselling.
This study was conducted to evaluate the major demographic details, diagnostical and clinical features, as well as the risk of recurrence of cases with the major types of neural tube defects (NTD). We also examined the efficiency of ultrasonography based on autopsy examinations during 26 years. The investigations were made into the sample of 743 NTD diagnosed between 1 January 1976 and 31 December 2002. A computerized database was used to sum up the available information about the individual cases; in addition to surveying the couples' major demographic details, we also had the opportunity to collect detailed information about the history, diagnostics (ultrasound) and outcome of the pregnancies as well as the results of the autopsies during the investigation. In the 743 cases of NTD, maternal and paternal median ages turned out to be 23.7 years (+/-5.22 years) and 28.7 years (+/-5.81 years), respectively. The male:female ratio was 0.78. Comparable samples of anencephaly and spina bifida allowed for the conclusion that a positive genetic history was equally often found while a positive obstetrical history was almost twice as common in anencephaly. The sensitivity of the maternal serum-alpha fetoprotein (AFP) screening test is the highest in anencephaly and lowest in encephalocele. While the majority of cases of anencephaly were diagnosed before the 24th gestational week, examples of diagnosing spina bifida and encephalocele at a later time could also be found. Among the associated malformations other than those of the central nervous system special mentioning should be made of fetal pyelectasia, cleft palate as well as diaphragmatic herniation. No pathological karyotypes were found in association with encephalocele or spina bifida, but anencephaly was accompanied with trisomy 21 and trisomy 18 in one case each. Anencephaly was found to have the highest risk of recurrence in both nervous system malformations and malformations other than those of the nervous system. Sonography proved to be the most reliable method in cases of enecephalocele. The respective median values of maternal and paternal age show that aetas has no role in the occurrence of NTDs. NTDs are more common among girls. Positive genetic, obstetrical and medical findings are of great importance in the incidence of NTDs. Although reliable to only a limited extent, maternal serum-AFP tests are considered to be useful and necessary in screening NTDs, while sonography is the gold standard method in recognizing these frequent malformations. The knowledge of the eventual associated malformations is mainly important in certain cases of spina bifida, which may also yield a good post-natal prognosis. Our data obtained from the sample of 26 years also confirm that the periconceptional administration of folic acid reduces the incidence and risk of recurrence of NTDs.


Suspension cultures of bone-marrow-derived mesenchymal stem cells: effects of donor age and glucose level.
Both ageing and diabetes are associated with reduced numbers and functional viability of mesenchymal stem cells (MSCs) in vivo which in turn lead to degenerative pathologies of the musculoskeletal system. The overall aim of this study was to elucidate the effects of age and raised glucose levels on the proliferation and self-renewal of rat nonadherent bone marrow MSCs (Na-BM-MSCs) in suspension cultures. MSC cultures isolated from 3- and 12-month-old rats were maintained using the "pour-off" method for up to 14 days in media containing different glucose levels and the phenotype, growth characteristics, colony forming unit-fibroblastic (CFU-f) numbers, and pluripotency characteristics of these cells were determined. This study indicates that rat adult bone marrow harbors pluripotent Na-BM-MSCs that seem to be unaffected by ageing during in vitro expansion. The Na-BM-MSCs express the pluripotency markers Oct4, Sox2, and Nanog. It was found that culture in high-glucose-containing medium had a negative effect on colony formation and differentiation. In contrast to classical MSC cultures, the generation of colonies by Na-BM-MSCs in suspension culture was not reduced in the older animals. The Na-BM-MSCs were found to express the pluripotency markers Oct4, Sox2, and Nanog, suggesting a more primitive stage of differentiation as compared with adherent MSCs. These data indicate that rat adult bone marrow harbors a population of pluripotent Na-BM-MSCs that appear to be relatively unaffected by ageing during in vitro expansion in suspension.


Cyclosporine and the reversibility of chronic vascular rejection.
A model of chronic vascular rejection of cardiac allografts has been developed in inbred rats using the WF.1L/Gut congenic strain as donor into LEW recipients. The hearts beat for more than 200 days without the need for exogenous immunosuppression. The histopathology is characterized by cellular rejection, vasculitis, and myointimal arterial wall thickening, and by day 60 posttransplant, there are widespread occlusive vascular changes similar to those seen in human cardiac allografts. CsA, at a dose of 15 mg/kg/d, is effective in preventing as well as reversing the vasculopathy. These data (1) confirm other studies of ours on the reliability of the experimental model using this strain combination, (2) establish the time window of days 40 to 60 whereby mechanisms of lesion regression can be studied, (3) prove the MHC class I and class II antigen incompatibility are not a necessary condition for the generation of the vascular lesions, (4) show that CsA is a useful probe for study of the vasculopathy, and (5) suggest that the model is a useful probe of the mechanism of action of CsA.


EPR spectroscopy of MRI-related Gd(III) complexes: simultaneous analysis of multiple frequency and temperature spectra, including static and transient crystal field effects.
For the first time, a very general theoretical method is proposed to interpret the full electron paramagnetic resonance (EPR) spectra at multiple temperatures and frequencies in the important case of S-state metal ions complexed in liquid solution. This method is illustrated by a careful analysis of the measured spectra of two Gd3+ (S = 7/2) complexes. It is shown that the electronic relaxation mechanisms at the origin of the EPR line shape arise from the combined effects of the modulation of the static crystal field by the random Brownian rotation of the complex and of the transient zero-field splitting. A detailed study of the static crystal field mechanism shows that, contrarily to the usual global models involving only second-order terms, the fourth and sixth order terms can play a non-negligible role. The obtained parameters are well interpreted in the framework of the physics of the various underlying relaxation processes. A better understanding of these mechanisms is highly valuable since they partly control the efficiency of paramagnetic metal ions in contrast agents for medical magnetic resonance imaging (MRI).


Pigs in Toxicology: Breed Differences in Metabolism and Background Findings.
Both a rodent and a nonrodent species are required for evaluation in nonclinical safety studies conducted to support human clinical trials. Historically, dogs and nonhuman primates have been the nonrodent species of choice. Swine, especially the miniature swine or minipigs, are increasingly being used in preclinical safety as an alternate nonrodent species. The pig is an appropriate option for these toxicology studies based on metabolic pathways utilized in xenobiotic biotransformation. Both similarities and differences exist in phase I and phase II biotransformation pathways between humans and pigs. There are numerous breeds of pigs, yet only a few of these breeds are characterized with regard to both xenobiotic-metabolizing enzymes and background pathology findings. Some specific differences in these enzymes based on breed and sex are known. Although swine have been used extensively in biomedical research, there is also a paucity of information in the current literature detailing the incidence of background lesions and differences between commonly used breeds. Here, the xenobiotic-metabolizing enzymes are compared between humans and pigs, and minipig background pathology changes are reviewed with emphasis on breed differences.


Scanning moiré method and automatic measurement of 3-D shapes.
A new type of moiré and its application to topography are discussed. moiré fringes are generated by observing a grating projected on an object under test with a scanning imaging device. The general equations of the projection-type moiré topography are given. By controlling the phase, the pitch, or the direction of the virtual grating corresponding to the scanning lines of the imaging device, the automatic sign determination of the contour lines is accomplished. By the use of a high precision flying spot scanner with CRT(DD-tube) and a minicomputer system, an experimental measurement system is developed. Very significant is the fact that a contour line system and a sectional shape of the object are automatically reconstructed and displayed on a color TV monitor.


Evaluating the Impact of Uncertainties in Clearance and Exposure When Prioritizing Chemicals Screened in High-Throughput Assays.
The toxicity-testing paradigm has evolved to include high-throughput (HT) methods for addressing the increasing need to screen hundreds to thousands of chemicals rapidly. Approaches that involve in vitro screening assays, in silico predictions of exposure concentrations, and pharmacokinetic (PK) characteristics provide the foundation for HT risk prioritization. Underlying uncertainties in predicted exposure concentrations or PK behaviors can significantly influence the prioritization of chemicals, though the impact of such influences is unclear. In the current study, a framework was developed to incorporate absorbed doses, PK properties, and in vitro dose-response data into a PK/pharmacodynamic (PD) model to allow for placement of chemicals into discrete priority bins. Literature-reported or predicted values for clearance rates and absorbed doses were used in the PK/PD model to evaluate the impact of their uncertainties on chemical prioritization. Scenarios using predicted absorbed doses resulted in a larger number of bin misassignments than those scenarios using predicted clearance rates, when comparing to bin placement using literature-reported values. Sensitivity of parameters on the model output of toxicological activity was examined across possible ranges for those parameters to provide insight into how uncertainty in their predicted values might impact uncertainty in activity.


Reconstructing population exposures from dose biomarkers: inhalation of trichloroethylene (TCE) as a case study.
Physiologically based pharmacokinetic (PBPK) modeling is a well-established toxicological tool designed to relate exposure to a target tissue dose. The emergence of federal and state programs for environmental health tracking and the availability of exposure monitoring through biomarkers creates the opportunity to apply PBPK models to estimate exposures to environmental contaminants from urine, blood, and tissue samples. However, reconstructing exposures for large populations is complicated by often having too few biomarker samples, large uncertainties about exposures, and large interindividual variability. In this paper, we use an illustrative case study to identify some of these difficulties, and for a process for confronting them by reconstructing population-scale exposures using Bayesian inference. The application consists of interpreting biomarker data from eight adult males with controlled exposures to trichloroethylene (TCE) as if the biomarkers were random samples from a large population with unknown exposure conditions. The TCE concentrations in blood from the individuals fell into two distinctly different groups even though the individuals were simultaneously in a single exposure chamber. We successfully reconstructed the exposure scenarios for both subgroups - although the reconstruction of one subgroup is different than what is believed to be the true experimental conditions. We were however unable to predict with high certainty the concentration of TCE in air.


Open valvotomy for critical aortic stenosis in infancy.
Over a 5 year period open valvotomy was performed on 13 patients under the age of one year with critical aortic stenosis. All 13 survived operation. There were two late deaths--one 38 days after operation, associated with an unrelated neurosurgical procedure and the other 2 years 6 months after when aortic root enlargement and replacement of the aortic valve were performed. During this period two other infants presented with aortic stenosis. One, who was very ill before transfer, died before operation could be performed. The second patient had a hypoplastic left ventricle with a small mitral valve ring and was, therefore, considered to be part of a different subgroup. All the surviving children have been followed up (median length of follow up 2 years and 11 months, range 7 months-5 years). Left ventricular function, in terms of percentage systolic wall thickening, was shown to be significantly impaired in all age groups. Peak diastolic thinning was abnormal in those children aged from 3 to 5. The aortic valve gradient, as assessed by peak instantaneous continuous wave Doppler, was less than 40 mm Hg in five patients and between 40 and 70 mm Hg in seven patients. One patient, with appreciable restenosis, has undergone successful percutaneous balloon dilatation of the aortic valve.


A 2-year clinical evaluation of fluoride-containing pit and fissure sealants placed with an invasive technique.
The aim of this study was to clinically evaluate fluoride-containing sealants in teeth subjected to minimal enamel reduction (preventive resin restorations). Two hundred fourteen sealants (109 FluroShield and 105 Delton Fluor) were applied in 153 teeth of 32 subjects. The sealants were evaluated for superficial irregularities, marginal adaptation, retention, and caries after 6, 12, 18, and 24 months. After 6, 12, and 18 months, the attendance at recall was 100.00%. After 24 months, 93.75% of subjects returned for reevaluation. Although total or partial loss of sealant occurred in a few instances, no occlusal caries was found in any tooth at any recall. No statistically significant differences in the results of the clinical evaluation were found between sealant in the maxillary and mandibular dentitions.


Order parameter fluctuations at a buried quantum critical point.
Quantum criticality is a central concept in condensed matter physics, but the direct observation of quantum critical fluctuations has remained elusive. Here we present an X-ray diffraction study of the charge density wave (CDW) in 2H-NbSe(2) at high pressure and low temperature, where we observe a broad regime of order parameter fluctuations that are controlled by proximity to a quantum critical point. X-rays can track the CDW despite the fact that the quantum critical regime is shrouded inside a superconducting phase; and in contrast to transport probes, allow direct measurement of the critical fluctuations of the charge order. Concurrent measurements of the crystal lattice point to a critical transition that is continuous in nature. Our results confirm the long-standing expectations of enhanced quantum fluctuations in low-dimensional systems, and may help to constrain theories of the quantum critical Fermi surface.


Opportunities and challenges in applying genomics to the study of oogenesis and folliculogenesis in farm animals.
Ovarian oogenesis and folliculogenesis are complex and coordinated biological processes which require a series of events that induce morphological and functional changes within the follicle, leading to cell differentiation and oocyte development. In this context, the challenge of the researchers is to describe the dynamics of gene expression in the different compartments and their interactions during the follicular programme. In recent years, high-throughput arrays have become a powerful tool with which to compare the whole population of transcripts in a single experiment. Here, we review the challenges of applying genomics to this model in farm animal species. The first limitation lies in limited the availability of biological material, which makes the study of the follicle compartments (oocyte, granulosa cells and thecal cells) or early embryo much more difficult. The concept of observing all transcripts at once is very attractive but despite progress in sequencing, the genome annotation remains very incomplete in non-model species. Particularly, oogenesis and early embryo development relate to the high proportion of unknown expressed sequence tags. Then, it is important to consider post-transcriptional and translational regulation to understand the role of these genes. Ultimately, these new inferred insights will still have to be validated by functional approaches. In addition to in vitro or ex vivo functional approaches, both 'natural mutant' ewe models and RNA interference represent, at the moment, the best hope for functional genomics. Advances in our understanding of reproductive physiology should be facilitated by gene expression data exchange and translation into a better understanding of the underlying biological phenomena.


Guidelines for field triage of injured patients: recommendations of the National Expert Panel on Field Triage, 2011.
In the United States, injury is the leading cause of death for persons aged 1-44 years. In 2008, approximately 30 million injuries were serious enough to require the injured person to visit a hospital emergency department (ED); 5.4 million (18%) of these injured patients were transported by Emergency Medical Services (EMS). On arrival at the scene of an injury, the EMS provider must determine the severity of injury, initiate management of the patient's injuries, and decide the most appropriate destination hospital for the individual patient. These destination decisions are made through a process known as "field triage," which involves an assessment not only of the physiology and anatomy of injury but also of the mechanism of the injury and special patient and system considerations. Since 1986, the American College of Surgeons Committee on Trauma (ACS-COT) has provided guidance for the field triage process through its "Field Triage Decision Scheme." This guidance was updated with each version of the decision scheme (published in 1986, 1990, 1993, and 1999). In 2005, CDC, with financial support from the National Highway Traffic Safety Administration, collaborated with ACS-COT to convene the initial meetings of the National Expert Panel on Field Triage (the Panel) to revise the decision scheme; the revised version was published in 2006 by ACS-COT (American College of Surgeons. Resources for the optimal care of the injured patient: 2006. Chicago, IL: American College of Surgeons; 2006). In 2009, CDC published a detailed description of the scientific rationale for revising the field triage criteria (CDC. Guidelines for field triage of injured patients: recommendations of the National Expert Panel on Field Triage. MMWR 2009;58[No. RR-1]). In 2011, CDC reconvened the Panel to review the 2006 Guidelines in the context of recently published literature, assess the experiences of states and local communities working to implement the Guidelines, and recommend any needed changes or modifications to the Guidelines. This report describes the dissemination and impact of the 2006 Guidelines; outlines the methodology used by the Panel for its 2011 review; explains the revisions and modifications to the physiologic, anatomic, mechanism-of-injury, and special considerations criteria; updates the schematic of the 2006 Guidelines; and provides the rationale used by the Panel for these changes. This report is intended to help prehospital-care providers in their daily duties recognize individual injured patients who are most likely to benefit from specialized trauma center resources and is not intended as a mass casualty or disaster triage tool. The Panel anticipates a review of these Guidelines approximately every 5 years.


Prevalence of obesity in Canada.
Excess weight represents a critical and common health problem in Canada. The last survey of a national representative sample based on measured anthropometrics has been conducted in 1992. According to surveys using measured data, the prevalence of obesity (body mass index, BMI = 30.0 kg m(-2)) between 1970 and 1992 for those aged 20-69 years increased from 8% to 13% in men and 13% to 15% in women. The proportion of Canadians displaying a BMI > or =25.0 kg m(-2) increased from 47% to 58% in men and from 34% to 41% in women in the same period. The most recent prevalence estimates from self-reported data in a national representative sample indicated that 15% of the adult population (> or =18 years) was affected by obesity, while an additional 33% was classified in the overweight category (BMI 25.0-29.9 kg m(-2)) in 2003. However, it has been suggested that self-reported height and weight underestimate the prevalence of obesity by approximately 10%. Canadian children, aboriginal populations, and immigrants are some of the vulnerable groups particularly at risk of excess weight or for which the increase in the recent decades has been greater than the national increase. The increases in overweight and obesity over the past 30 years among Canadians have been dramatic. It will be possible to precisely analyse the current situation and its evolution in the last 10 years when data based on measured height and weight will be released, that is, in 2005 and after.


Excreted Cytoplasmic Proteins Contribute to Pathogenicity in Staphylococcus aureus.
Excretion of cytoplasmic proteins in pro- and eukaryotes, also referred to as "nonclassical protein export," is a well-known phenomenon. However, comparatively little is known about the role of the excreted proteins in relation to pathogenicity. Here, the impact of two excreted glycolytic enzymes, aldolase (FbaA) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), on pathogenicity was investigated in Staphylococcus aureus Both enzymes bound to certain host matrix proteins and enhanced adherence of the bacterial cells to host cells but caused a decrease in host cell invasion. FbaA and GAPDH also bound to the cell surfaces of staphylococcal cells by interaction with the major autolysin, Atl, that is involved in host cell internalization. Surprisingly, FbaA showed high cytotoxicity to both MonoMac 6 (MM6) and HaCaT cells, while GAPDH was cytotoxic only for MM6 cells. Finally, the contribution of external FbaA and GAPDH to S. aureus pathogenicity was confirmed in an insect infection model.


Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.
Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 [37%]), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.


Post-transcriptional regulation of the content of spermidine/spermine N1-acetyltransferase by N1N12-bis(ethyl)spermine.
Spermidine/spermine N1-acetyltransferase (SSAT) is the rate-limiting enzyme for the degradation and excretion of polyamines in mammalian cells, and its activity is known to be increased enormously on exposure to polyamines and polyamine analogues. The mechanism by which such an analogue, BESM [N1N12-bis(ethyl)spermine], increases the content of SSAT was investigated by transfecting COS-7 cells with plasmids containing SSAT cDNA in the pEUK expression vector. Despite a large increase in mRNA production, there was only a very small increase in SSAT activity in the transfected cells. When BESM was added at 36 h after transfection, there was a large and very rapid increase in SSAT protein amounting to 380-fold in 12 h without any increase in the mRNA. SSAT protein turned over very rapidly, with a half-life of about 20 min. In the presence of BESM, this turnover was greatly reduced, and the half-life increased to more than 13 h. However, this increase was not sufficient to account for all of the increase in SSAT protein, suggesting that there is also regulation of the translation of the mRNA by BESM. Further evidence for such translation regulation was obtained by studying the polysomal distribution of the SSAT mRNA. In the absence of BESM, most of the mRNA was present in fractions which sedimented more slowly than the monoribosome peak. In BESM-treated cells, a significant proportion of the SSAT mRNA was moved into the small-polysome region of the gradient. The expression of SSAT and the effects of BESM on the polysomal distribution of SSAT mRNA were not affected by the 5'- or 3'-untranslated regions of the mRNA, since constructs which lacked all of these regions gave similar results to constructs containing the entire mRNA sequence. These results show that the increased transcription of the SSAT gene that occurs in the presence of polyamine analogues such as BESM is not sufficient for SSAT expression and that post-transcriptional regulation is critical for the control of SSAT content.


New insights from one case of female ejaculation.
Although there are historical records showing its existence for over 2,000 years, the so-called female ejaculation is still a controversial phenomenon. A shared paradigm has been created that includes any fluid expulsion during sexual activities with the name of "female ejaculation." To demonstrate that the "real" female ejaculation and the "squirting or gushing" are two different phenomena. Biochemical studies on female fluids expelled during orgasm. In this case report, we provided new biochemical evidences demonstrating that the clear and abundant fluid that is ejected in gushes (squirting) is different from the real female ejaculation. While the first has the features of diluted urines (density: 1,001.67 ± 2.89; urea: 417.0 ± 42.88 mg/dL; creatinine: 21.37 ± 4.16 mg/dL; uric acid: 10.37 ± 1.48 mg/dL), the second is biochemically comparable to some components of male semen (prostate-specific antigen: 3.99 ± 0.60 × 103 ng/mL). Female ejaculation and squirting/gushing are two different phenomena. The organs and the mechanisms that produce them are bona fide different. The real female ejaculation is the release of a very scanty, thick, and whitish fluid from the female prostate, while the squirting is the expulsion of a diluted fluid from the urinary bladder.


Odd Loop Regions of XenA and XenB Enzymes Modulate Their Interaction with Nitro-explosives Compounds and Provide Structural Support for Their Regioselectivity.
The nitro-explosive compounds 2,4,6-trinitrotoluene, 2,4,6-trinitrophenol, and 1,2,3-trinitroglycerol are persistent environmental contaminants. The presence of different functional groups in these molecules represents a great challenge to enzymatic catalysis. The chemical variety of these three substrates is such that they do not bind and interact with catalytic residues within an enzyme with the same affinity. In this context, two Xenobiotic Reductase enzymes produced by the bacteria Pseudomonas putida can catalyze the reduction of these compounds with different affinities and regioselectivity. The structural bases that support this substrate promiscuity and catalytic preferences are unknown. Therefore, through molecular dynamics simulations and free energy calculations, we explored the structural properties driving the specific interactions of these enzymes with their substrates and cofactor. Models of Xenobiotic Reductase A and B enzymes in complex with 2,4,6-trinitrotoluene, 2,4,6-trinitrophenol, or 1,2,3-trinitroglycerol were built, and the ligand enzyme interaction was simulated by molecular dynamics. The structural analysis of the molecular dynamics simulations shows that loops 3, 5, 7, 9, 11, and 13 of Xenobiotic Reductase B, and loops 4, 5, 7, 11, 13, and 15 Xenobiotic Reductase A, are in contact with the ligands during the first stages of the molecular recognition. These loops are the most flexible regions for both enzymes; however, Xenobiotic Reductase B presents a greater range of movement and a higher number of residues interacting with the ligands. Finally, the distance between the cofactor and the different reactive groups in the substrate reflects the regioselectivity of the enzymes, and the free energy calculations are consistent with the substrate specificity of both enzymes studied. The simulation shows a stable interaction between the aromatic ring of the substrates and Xenobiotic Reductase B. In contrast, a less stable interaction with the different nitro groups of the aromatic ligands was observed. In the case of 1,2,3-trinitroglycerol, Xenobiotic Reductase B interacts more closely with the nitro groups of carbon 1 or 3, while Xenobiotic Reductase A is more selective by nitro groups of carbon 2. The obtained results suggest that the flexibility of the loops in Xenobiotic Reductase B and the presence of polar and aromatic residues present in loops 5 and 7 are fundamental to determine the affinity of the enzyme with the different substrates, and they also contribute to the proper orientation of the ligands that directs the catalytic reaction.


Variability in tolerance to UV-B radiation among Beauveria spp. isolates.
Solar radiation, particularly the UV-B component, negatively affects survival of entomopathogenic fungi in the field. In an effort to identify Beauveria spp. isolates with promise for use in biological control settings with high insolation, we examined 53 Beauveria bassiana isolates, 7 isolates of 4 other Beauveria spp. and Engyodontium albus (=Beauveria alba). The origins of these fungi varied widely as to host/substrate and country, but approximately 30% of these isolates were B. bassiana from ticks in Brazil. A preliminary trial with three B. bassiana isolates (Bb 19, CG 310 and CG 481) at several UV-B dosages indicated that 2h of weighted UV-B irradiance at 978mWm(-2) (providing a total dose of 7.04kJm(-2)) allowed separation of isolates into low, medium or high UV-B tolerance. This dose, therefore, was selected as a single dose to compare UV-B tolerances of all 60 Beauveria spp. isolates. There was high variability in tolerance to UV-B radiation among the B. bassiana isolates, ranging from virtually zero tolerance (e.g., Bb 03) to almost 80% tolerance (e.g., CG 228). In addition, surviving B. bassiana conidia demonstrated delayed germination; and this is likely to reduce virulence. Conidia of the other species were markedly more sensitive to UV-B, with E. albus (UFPE 3138) being the least UV-B tolerant. Among B. bassiana isolates originating from 0 degrees to 22 degrees latitudes, those from lower latitudes demonstrated statistically significant greater UV-B tolerances than those isolates from higher latitudes. Isolates from above 22 degrees , however, were unaffected by latitude of origin. A similar analysis based on host type did not indicate a correlation between original host and UV-B tolerance. The identification in this study of several B. bassiana isolates with relatively high UV-B tolerance will guide the selection of isolates for future arthropod microbial control experiments.


The use of Internet technology for psychoeducation and support with dementia caregivers.
A large randomized trial evaluated the benefits of online education, support, and self-care promotion for caregivers of persons with dementia. Anecdotal reports from participants indicated enjoyment of the materials, convenient access from home, and support from professionals and other caregivers. A substantial number of screened caregivers experienced obstacles of access, cost, and time regarding use of technology. Telephone options are being explored, and future caregiving generations are expected to have increased exposure and willingness to use computer technology, such as the program described here.


Lymphedema in Canada: a qualitative study to help develop a clinical, research, and education strategy.
The aim of this study was to gather data from Canadian stakeholders to help construct a national strategy and agenda for lymphedema management. The Canadian Lymphedema Framework, a collaboration of medical academics, lymphedema therapists, patient advocates, and others, used participatory action research and Open Space Technology to identify issues and build consensus at a national meeting of lymphedema stakeholders. Proceedings were videotaped and underwent content analysis. Existing Canadian documentation on lymphedema services was analyzed. Using those data sources, the Canadian Lymphedema Framework drafted a development strategy. Of 320 invited stakeholders (patients, therapists, physicians, industry representatives, and health policymakers), 108 participated in a day-long videotaped meeting discussing strategies to improve the management of lymphedema and related disorders in Canada. Participants identified barriers, challenges, and issues related to the need to raise awareness about lymphedema with patients, physicians, and the public. Five priority areas for development were articulated: education, standards, research, reimbursement and access to treatment, and advocacy. The main barrier to development was identified as the lack of clear responsibility within the health care system for lymphedema care. Data from stakeholders was obtained to solidly define priority areas for lymphedema development at a national level. The Canadian Lymphedema Framework has created a working plan, an advisory board, and working groups to implement the strategy.


Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21.
The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid-primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had GATA1 mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo- and lymphopoiesis.


Developing risk models of Cryptosporidium transport in soils from vegetated, tilted soilbox experiments.
Transport of Cryptosporidium parvum through macroporous soils is poorly understood yet critical for assessing the risk of groundwater contamination. We developed a conceptual model of the physics of flow and transport in packed, tilted, and vegetated soilboxes during and immediately after a simulated rainfall event and applied it to 54 experiments implemented with different soils, slopes, and rainfall rates. Using a parsimonious inverse modeling procedure, we show that a significant amount of subsurface outflow from the soilboxes is due to macropore flow. The effective hydraulic properties of the macropore space were obtained by calibration of a simple two-domain flow and transport model that accounts for coupled flow in the matrix and in the macropores of the soils. Using linear mixed-effects analysis, macropore hydraulic properties and oocyst attenuation were shown to be associated with soil bulk density and rainfall rate. Macropore flow was shown to be responsible for bromide and C. parvum transport through the soil into the underlying pore space observed during the 4-h experiments. We confirmed this finding by conducting a pair of saturated soil column studies under homogeneously repacked conditions with no macropores in which no C. parvum transport was observed in the effluent. The linear mixed-effects and logistic regression models developed from the soilbox experiments provide a basis for estimating macropore hydraulic properties and the risk of C. parvum transport through shallow soils from bulk density, precipitation, and total shallow subsurface flow rate. The risk assessment is consistent with the reported occurrence of oocysts in springs or groundwater from fractured or karstic rocks protected only by shallow overlying soils.


Distinguishing metabolic heat from condensation heat during muscle recovery.
When a thermopile is used to measure the heat production of isolated muscle, the muscle is surrounded by gas saturated with water vapour, initially in equilibrium with the muscle. After contraction, the osmolarity of the muscle is raised so that it is no longer in equilibrium with the gas around it, and condensation will occur. When artificial muscles of known osmolarity were placed on a thermopile surrounded by gas in equilibrium with a solution of lower osmolarity, their temperature was found to be raised (by 102.7 mK osmol-1 l). This temperature increase was greatly reduced by covering the artificial muscle with a Teflon film. Experiments on living muscle from the dogfish Scyliorhinus canicula showed that muscle temperature was higher 2 min after a series of 20 twitches at 3 Hz if the muscle was not covered by Teflon than if it was covered. The Teflon covering did not diminish the muscle's contractile performance. We conclude that the condensation of water does contribute to the heat measured during the recovery period, but that when the muscle is covered by Teflon film condensation heat can largely be prevented so that only genuine metabolic recovery heat is produced.


Genome-wide methylation analyses in glioblastoma multiforme.
Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina) were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1), 5 methyl-deoxycytidine (5m-dC) and 5 hydroxylmethyl-deoxycytidine (5hm-dC) in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes) that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal.


Outcomes of Autologous Hematopoietic Cell Transplantation Compared With Chemotherapy Consolidation Alone for Non-High-Risk Acute Myeloid Leukemia in First Complete Remission in a Minority-Rich Inner-City Cohort With Limited Access to Allografts.
In the United States, autologous hematopoietic cell transplantation (autoHCT) has fallen out of favor over chemotherapy consolidation for non-high-risk acute myeloid leukemia (AML) when allogeneic hematopoietic cell transplantation (alloHCT) is unfeasible, which is common in racial minorities because of donor registry under-representation and socioeconomic challenges. We compared autoHCT consolidation outcomes with chemotherapy alone in a minority-rich cohort in the Bronx. We identified adults with favorable or intermediate cytogenetic risk AML in first complete remission after induction at Montefiore Medical Center from 1999 to 2015, and analyzed 81 patients who received consolidation with ≥2 cycles of chemotherapy, of whom 28 received autoHCT. The cohort predominantly consisted of ethnic/racial minorities (69%). Age, sex, race, presenting white cell count, and cytogenetic risk were similar between groups. The autoHCT group had longer relapse-free (RFS; 43 vs. 11 months; P = .003) and overall (OS) survival (not reached vs. 36 months; P = .043). Adjusted multivariable analysis showed significant benefit of autoHCT over chemotherapy alone for RFS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.37-0.75; P < .001) and OS (HR, 0.61; 95% CI, 0.40-0.95; P = .027). In this inner-city non-high-risk AML cohort, autoHCT provided OS and RFS benefit compared with chemotherapy alone. AutoHCT might constitute a valuable option for ethnic/racial minorities affected by significant barriers to alloHCT, whereas integration of measurable residual disease can help select patients more likely to benefit.


Multiple imputation in a large-scale complex survey: a practical guide.
The Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium is a multisite, multimode, multiwave study of the quality and patterns of care delivered to population-based cohorts of newly diagnosed patients with lung and colorectal cancer. As is typical in observational studies, missing data are a serious concern for CanCORS, following complicated patterns that impose severe challenges to the consortium investigators. Despite the popularity of multiple imputation of missing data, its acceptance and application still lag in large-scale studies with complicated data sets such as CanCORS. We use sequential regression multiple imputation, implemented in public-available software, to deal with non-response in the CanCORS surveys and construct a centralised completed database that can be easily used by investigators from multiple sites. Our work illustrates the feasibility of multiple imputation in a large-scale multiobjective survey, showing its capacity to handle complex missing data. We present the implementation process in detail as an example for practitioners and discuss some of the challenging issues which need further research.


Lack of habituation of the pattern of cardiovascular response evoked by sound in subjects with primary Raynaud's disease.
1. The vasospasm of primary Raynaud's disease can be triggered by acute emotional stress. We have studied the pattern of cardiovascular response evoked by acute emotional stress, a sound stimulus of 90 dB, 2 kHz for 30 s, in eight subjects with primary Raynaud's disease and in eight age- and sex-matched controls, the sound being repeated five times on each of days 1, 3 and 5. 2. In controls, the first sound evoked the pattern of the alerting response that is characteristic of acute emotional stress: a rise in arterial pressure and heart rate, a decrease in vascular conductance in the cutaneous circulation of the digit, assessed by laser Doppler recording of erythrocyte (red cell) flux in the digit divided by arterial pressure, and an increase in forearm muscle vascular conductance, assessed from forearm blood flow recorded by venous occlusion plethysmography divided by arterial pressure. 3. In the subjects with primary Raynaud's disease, baselines of arterial pressure, digital cutaneous vascular conductance and forearm vascular conductance were not significantly different from those of the controls and they too showed the alerting response to the first sound, the magnitudes of the changes being comparable to those of the controls. 4. In both the controls and subjects with primary Raynaud's disease, the evoked responses were consistent on repetition of the sound on day 1. In contrast, judging from the means of the changes evoked on each day, the controls showed habituation of the individual components of the alerting response over days 1, 3 and 5, whereas the subjects with primary Raynaud's disease showed no habituation of either the forearm muscle vasodilatation or the digital vasoconstriction. Conversely, the decrease in digital cutaneous vascular conductance evoked by a single deep breath was fully reproducible in both controls and subjects with primary Raynaud's disease when tested at the beginning and end of each experimental day. 5. These results allow the novel conclusion that subjects with primary Raynaud's disease have an abnormality of the central neural modulation of the brain stem areas that integrate the cardiovascular components of the alerting response to acute emotional stress, such that habituation of the vasodilator and vasoconstrictor components of the response on repetition of the stimulus is impaired. We propose that such persistence of vasoconstrictor responses to stressful stimuli predisposes to vasospasm, particularly if neurally mediated vasoconstriction is reinforced by locally released vasoconstrictor factors.


Visfatin/pre-B-cell colony-enhancing factor (PBEF), a proinflammatory and cell motility-changing factor in rheumatoid arthritis.
Adipokines such as adiponectin and visfatin/pre-B-cell colony-enhancing factor (PBEF) have been recently shown to contribute to synovial inflammation in rheumatoid arthritis (RA). In this study, we evaluated the pathophysiological implication of visfatin/PBEF in the molecular patterns of RA synovial tissue, focusing on RA synovial fibroblasts (RASFs), key players in RA synovium. Expression of visfatin/PBEF in synovial fluid and tissue of RA patients was detected by immunoassays and immunohistochemistry. RASFs were stimulated with different concentrations of visfatin/PBEF over varying time intervals, and changes in gene expression were evaluated at the RNA and protein levels using Affymetrix array, real-time PCR, and immunoassays. The signaling pathways involved were identified. The influence of visfatin/PBEF on fibroblast motility and migration was analyzed. In RA synovium, visfatin/PBEF was predominantly expressed in the lining layer, lymphoid aggregates, and interstitial vessels. In RASFs, visfatin/PBEF induced high amounts of chemokines such as IL-8 and MCP-1, proinflammatory cytokines such as IL-6, and matrix metalloproteinases such as MMP-3. Phosphorylation of p38 MAPK was observed after visfatin/PBEF stimulation, and inhibition of p38 MAPK showed strong reduction of visfatin-induced effects. Directed as well as general fibroblast motility was increased by visfatin/PBEF-induced factors. The results of this study indicate that visfatin/PBEF is involved in synovial fibroblast activation by triggering fibroblast motility and promoting cytokine synthesis at central sites in RA synovium.


The Forest Observation System, building a global reference dataset for remote sensing of forest biomass.
Forest biomass is an essential indicator for monitoring the Earth's ecosystems and climate. It is a critical input to greenhouse gas accounting, estimation of carbon losses and forest degradation, assessment of renewable energy potential, and for developing climate change mitigation policies such as REDD+, among others. Wall-to-wall mapping of aboveground biomass (AGB) is now possible with satellite remote sensing (RS). However, RS methods require extant, up-to-date, reliable, representative and comparable in situ data for calibration and validation. Here, we present the Forest Observation System (FOS) initiative, an international cooperation to establish and maintain a global in situ forest biomass database. AGB and canopy height estimates with their associated uncertainties are derived at a 0.25 ha scale from field measurements made in permanent research plots across the world's forests. All plot estimates are geolocated and have a size that allows for direct comparison with many RS measurements. The FOS offers the potential to improve the accuracy of RS-based biomass products while developing new synergies between the RS and ground-based ecosystem research communities.


Assessment of total sialic acid and lipid-bound sialic acid in management of brain tumors.
Glycoconjugate molecules expressed at the plasma membrane of mammalian cells have been reported to be associated with tumor progression. The measurement of total sialic acid (TSA) and lipid-bound sialic acid (LBSA) in the cerebrospinal fluid (CSF) is suggested to be useful for the diagnosis of brain tumors. But there are very few reports available on the serum glycoconjugate levels in patients with brain tumors. The objective of this study is to check the feasibility of using serum glycoconjugates such as TSA and LBSA as tumor markers in brain tumor patients. Colorimetric estimation of TSA using diphenylamine was done on 100 patients with intracranial tumors; follow-up study was carried out in 24 cases. The LBSA fraction was isolated from the serum of 68 brain tumor patients and evaluated using phosphotungstic acid and resorcinol; follow-up study was done on 23 patients. The various types of brain tumors included in this study were glioma, meningioma, and acoustic neurinoma as well as some other types such as medulloblastoma, secondary tumors, and craniopharyngioma. There was no significant difference between the TSA and LBSA concentrations seen in pretreatment or post-treatment cases and that seen in control subjects. TSA and LBSA do not have the ability to discriminate between benign and malignant brain tumors. TSA and LBSA appear to be tumor markers of very limited value in patients with brain tumors.


Mn doped porous cobalt nitride nanowires with high activity for water oxidation under both alkaline and neutral conditions.
We report the successful synthesis of Mn doped CoN nanowires on a carbon fiber cloth substrate (CFC) by a two-step strategy, which can be used as an efficient and stable OER electrocatalyst under both alkaline and neutral conditions. Benefiting from enhanced electronic interaction, high active area and electrical conductivity, the Mn doped CoN nanowires/CFC exhibits enhanced kinetics and improved cycling stability for the OER under both alkaline and neutral conditions. To achieve a current density of 10 mA cm-2, the Mn doped CoN nanowires/CFC requires an overpotential of 265 mV in alkaline solution and 285 mV in neutral solution.


Genomic Characterization Helps Dissecting an Outbreak of Listeriosis in Northern Italy.
Listeria monocytogenes (Lm) is a bacterium widely distributed in nature and able to contaminate food processing environments, including those of dairy products. Lm is a primary public health issue, due to the very low infectious dose and the ability to produce severe outcomes, in particular in elderly, newborns, pregnant women and immunocompromised patients. In the period between April and July 2015, an increased number of cases of listeriosis was observed in the area of Pavia, Northern Italy. An epidemiological investigation identified a cheesemaking small organic farm as the possible origin of the outbreak. In this work we present the results of the retrospective epidemiological study that we performed using molecular biology and genomic epidemiology methods. The strains sampled from patients and those from the target farm's cheese were analyzed using PFGE and whole genome sequencing (WGS) based methods. The performed WGS based analyses included: a) in-silico MLST typing; b) SNPs calling and genetic distance evaluation; c) determination of the resistance and virulence genes profiles; d) SNPs based phylogenetic reconstruction. Three of the patient strains and all the cheese strains resulted to belong to the same phylogenetic cluster, in Sequence Type 29. A further accurate SNPs analysis revealed that two of the three patient strains and all the cheese strains were highly similar (0.8 SNPs of average distance) and exhibited a higer distance from the third patient isolate (9.4 SNPs of average distance). Despite the global agreement among the results of the PFGE and WGS epidemiological studies, the latter approach agree with epidemiological data in indicating that one the patient strains could have originated from a different source. This result highlights that WGS methods can allow to better.


Dispensation of attention deficit hyperactivity disorder (ADHD) medications in patients receiving opioid agonist therapy; a national prospective cohort study in Norway from 2015 to 2017.
It is estimated that up to a third of patients on opioid agonist therapy (OAT) have attention deficit hyperactivity disorder (ADHD). Treatment by ADHD medication, including a centrally acting stimulant (CAS) or atomoxetine is one of the essential approaches. This study evaluates the use of dispensed ADHD medications in the Norwegian OAT population in the period from 2015 to 2017. Types and doses of ADHD medications, co-dispensations of other potentially addictive drugs like benzodiazepines, z-hypnotics, gabapentinoids, and non-OAT opioids, as well as direct-acting antivirals (DAA) against hepatitis C infection, are investigated. Information about all dispensed ADHD medication, OAT opioids, and the defined potentially addictive drugs were recorded from the Norwegian Prescription Database. Dispensation rates, the types, and the doses of dispensed ADHD medications were estimated by summarizing the number of dispensations, and the dispensed doses. Logistic regression analyses were employed to assess the associations between ADHD medication, and OAT opioid use, and dispensations of other potentially addictive drugs and DAAs against hepatitis C infection. A total of 9235 OAT patients were included. The proportion of patients who were dispensed ADHD medication increased from 3.5 to 4.6% throughout the study period. The three most dispensed CAS were short- and intermediate-acting methylphenidate (55%), lisdexamphetamine (24%), and dexamphetamine (17%) in 2017. Buprenorphine, rather than methadone, as OAT opioid (adjusted odds ratio: 1.6, CI: 1.2-2.1) was associated with being dispensed ADHD medication. Among patients who received CAS and OAT opioids each calendar year, the dispensed doses of methylphenidate increased from 63 mg/day in 2015 to 76 mg/day in 2017 (p = 0.01). Sixty percent of patients receiving ADHD medications were also dispensed other addictive drugs concomitantly in 2017. Similar results were found in 2015 and 2016. Co-prescription of ADHD medications was low among patients on OAT in Norway, considering a high prevalence of ADHD in this patient group. On the other hand, concurrent dispensations of multiple addictive drugs were common in this population. Understanding the underlying reasons for such prescribing is essential, and research on how to optimize ADHD medication of patients with ADHD receiving OAT is needed.


Bismuth oxyiodide coupled with bismuth nanodots for enhanced photocatalytic bisphenol A degradation: synergistic effects and mechanistic insight.
Bismuth based semiconductor photocatalysts are being generated as promising materials for photocatalysis. In this work, hydrothermal methods have been utilized to synthesize a bismuth oxyiodide semiconductor with deposited Bi nanodots (Bi-BiOI), which could create oxygen defects and accelerate photoinduced charge migration simultaneously. The resulting Bi-BiOI strongly demonstrates the high photocatalytic performance for bisphenol A and methylene blue degradation under visible light. 86% of BPA was degraded after an irradiation time of 4 hours. Electrospray ionization mass spectrometry was employed to detect the evolution of intermediates formed during the decomposition process of bisphenol A, and the following results suggested complete bisphenol A mineralization. Additionally, electron paramagnetic resonance results revealed the production of free radicals and the presence of oxygen vacancies. Furthermore, a distinctively increased photocurrent response and photoluminescence decay dynamics demonstrate that the interface between the Bi nanodots and BiOI semiconductor promotes the separation and migration of photoinduced electron-hole pairs. The lower valence band value (2.57 eV) of Bi-BiOI presented a higher oxidation potential, thus the production of hydroxyl radicals could be promoted considerably. Based on the experimental results, factors such as oxygen vacancies, effective charge migration, suppressed photoinduced electron-hole pair recombination and a high Bi-BiOI oxidation potential would result in advanced free radical production capacity, thereby enhancing the photocatalytic efficiency. The findings of our work will contribute to the fabrication of metal nanodot deposited semiconductor photocatalysts and pave the way for the utilization of advanced oxidation technology.


Nonrandom mating in an open-pollinated maize population.
Randomness of fertilization was studied in an open-pollinated population of maize (Zea mays L.) through allozyme assays of seedlings from open-pollinated seeds produced on both tasseled and detasseled plants. Mixed-mating-model estimates of the amount of outcrossing (t) were not significantly different from t = 1.00 for four enzyme loci ( Adh1, Idh2, Got1 and Acp1), indicating that fertilizations were at random in the population. However, for loci Prx1 and Est4 , estimates of t were significantly smaller than unity-0.80 and 0.70 for tasseled plants and 0.81 and 0.80 for detasseled plants. The excesses of homogametic fertilizations detected on the detasseled plants could not have been due to selffertilization, s = 1 - t, because the detasseled plants shed no pollen. Analyses of allelic frequencies in the pollen that produced seed on the detasseled plants established that different maternal plants sampled genetically different populations of pollen from the outcross pollen pool. It was suggested that the causes of the differential sampling were temporal variation in the pollen pool, and/or gametophytic selection, correlated with marker-locus genotype. Two-, three- and four-locus interactions among the marker loci were often statistically significant, indicating that the factors responsible for the nonrandom gametic unions observed in the maize population studied were complexly interactive.


[Climatic aspects in hantavirus transmission areas in São Paulo State, Brazil].
The objective of this study was to investigate the spatial distribution of reported hantavirus cases in São Paulo State, Brazil (n = 80), from 1993 to 2005 and identify local climatic patterns during this period. Kernel point estimation of density was used to show the highest concentrations in Ribeirão Preto, São Carlos, Franca, Tupi Paulista, and Greater São Paulo. Increase in the number of cases during this period suggests disease dissemination even when considering increased diagnostic capacity and higher sensitivity of the health services. There was a marked seasonal variation in hantavirus in the cerrado (savannah) areas; the common pattern is a higher incidence in drier months as compared to mean levels in the last 40 years. These coincide with periods of high rodent food source levels in grains, sugarcane, and other crops. Harvesting and storing grains increases human exposure to rodents. Climatic indicators together with ecological variables can be local transmission risk markers and should receive more attention in epidemiological monitoring and control of the disease.


In vitro epigenetic reprogramming of human cardiac mesenchymal stromal cells into functionally competent cardiovascular precursors.
Adult human cardiac mesenchymal-like stromal cells (CStC) represent a relatively accessible cell type useful for therapy. In this light, their conversion into cardiovascular precursors represents a potential successful strategy for cardiac repair. The aim of the present work was to reprogram CStC into functionally competent cardiovascular precursors using epigenetically active small molecules. CStC were exposed to low serum (5% FBS) in the presence of 5 µM all-trans Retinoic Acid (ATRA), 5 µM Phenyl Butyrate (PB), and 200 µM diethylenetriamine/nitric oxide (DETA/NO), to create a novel epigenetically active cocktail (EpiC). Upon treatment the expression of markers typical of cardiac resident stem cells such as c-Kit and MDR-1 were up-regulated, together with the expression of a number of cardiovascular-associated genes including KDR, GATA6, Nkx2.5, GATA4, HCN4, NaV1.5, and α-MHC. In addition, profiling analysis revealed that a significant number of microRNA involved in cardiomyocyte biology and cell differentiation/proliferation, including miR 133a, 210 and 34a, were up-regulated. Remarkably, almost 45% of EpiC-treated cells exhibited a TTX-sensitive sodium current and, to a lower extent in a few cells, also the pacemaker I(f) current. Mechanistically, the exposure to EpiC treatment introduced global histone modifications, characterized by increased levels of H3K4Me3 and H4K16Ac, as well as reduced H4K20Me3 and H3s10P, a pattern compatible with reduced proliferation and chromatin relaxation. Consistently, ChIP experiments performed with H3K4me3 or H3s10P histone modifications revealed the presence of a specific EpiC-dependent pattern in c-Kit, MDR-1, and Nkx2.5 promoter regions, possibly contributing to their modified expression. Taken together, these data indicate that CStC may be epigenetically reprogrammed to acquire molecular and biological properties associated with competent cardiovascular precursors.


A Ser315Thr substitution in KatG is predominant in genetically heterogeneous multidrug-resistant Mycobacterium tuberculosis isolates originating from the St. Petersburg area in Russia.
Parts of katG and rpoB from 27 Russian Mycobacterium tuberculosis isolates were sequenced to detect mutations causing resistance to isoniazid (INH) and rifampin (RMP), respectively. All 24 INH-resistant isolates had a mutated katG, and 22 of them (91.7%) carried a mutation coding for a Ser315Thr shift. An rpoB mutation was noted for each of the 21 RMP-resistant isolates, with Ser531Leu being the most prevalent change encoded. Only two isolates had identical IS6110 fingerprints.


The Eck fistula in animals and humans.
In all species so far studied, including man, portacaval shunt causes the same changes in liver morphology, including hepatocyte atrophy, fatty infiltration, deglycogenation, depletion and disorganization of the rough endoplasmic reticulum (RER) and its lining polyribosomes, and variable but less specific damage to other organelles. Many, perhaps all, biosynthetic processes are quickly depressed, largely secondary to the selective damage to the RER, which is the "factory" of the cell. These structural and metabolic changes in the liver after portal diversion are caused by the diversion around the liver of the hepatotrophic substances in portal venous blood, of which endogenous insulin is the most important. In experimental animals, the injury of Eck's fistula can be prevented by infusing insulin into the tied-off hilar portal vein. The subtle but far-reaching changes in hepatic function after portal diversion have made it possible to use this procedure in palliating three inborn errors of metabolism: glycogen storage disease, familial hypercholesterolemia, and alpha 1-antitrypsin deficiency. In these three diseases, the abnormalities caused by portal diversion have counteracted abnormalities in the patients that were caused by the inborn errors. In these diseases, amelioration of the inborn errors depends on the completeness of the portal diversion. In contrast, total portal diversion to treat complications of portal hypertension is undesirable and always will degrade hepatic function if a significant amount of hepatopetal portal venous blood is taken from the liver. When total portal diversion is achieved (and this is to be expected after all conventional shunts), the incidence of hepatic failure and hepatic encephalopathy is increased. If portal diversion must be done for the control of variceal hemorrhage, a selective procedure such as the Warren procedure is theoretically superior to the completely diverting shunt. In practice, better patient survival has not been achieved after selective shunts than after conventional shunts, but the incidence of hepatic encephalopathy has been less.


The human cytomegalovirus IE86 protein can block cell cycle progression after inducing transition into the S phase of permissive cells.
Human cytomegalovirus (HCMV) infection of permissive cells has been reported to induce a cell cycle halt. One or more viral proteins may be involved in halting progression at different stages of the cell cycle. We investigated how HCMV infection, and specifically IE86 protein expression, affects the cell cycles of permissive and nonpermissive cells. We used a recombinant virus that expresses the green fluorescent protein (GFP) to determine the effects of HCMV on the cell cycle of permissive cells. Fluorescence by GFP allowed us to select for only productively infected cells. Replication-defective adenovirus vectors expressing the IE72 or IE86 protein were also used to efficiently transduce 95% or more of the cells. The adenovirus-expressed IE86 protein was determined to be functional by demonstrating negative autoregulation of the major immediate-early promoter and activation of an early viral promoter in the context of the viral genome. To eliminate adenovirus protein effects, plasmids expressing GFP for fluorescent selection of only transfected cells and wild-type IE86 protein or a mutant IE86 protein were tested in permissive and nonpermissive cells. HCMV infection induced the entry of U373 cells into the S phase. All permissive cells infected with HCMV were blocked in cell cycle progression and could not divide. After either transduction or transfection and IE86 protein expression, the number of all permissive or nonpermissive cell types in the S phase increased significantly, but the cells could no longer divide. The IE72 protein did not have a significant effect on the S phase. Since IE86 protein inhibits cell cycle progression, the IE2 gene in a human fibroblast IE86 protein-expressing cell line was sequenced. The IE86 protein in these retrovirus-transduced cells has mutations in a critical region of the viral protein. The locations of the mutations and the function of the IE86 protein in controlling cell cycle progression are discussed.


GlobAl Distribution of GEnetic Traits (GADGET) web server: polygenic trait scores worldwide.
Human populations from around the world show striking phenotypic variation across a wide variety of traits. Genome-wide association studies (GWAS) are used to uncover genetic variants that influence the expression of heritable human traits; accordingly, population-specific distributions of GWAS-implicated variants may shed light on the genetic basis of human phenotypic diversity. With this in mind, we developed the GlobAl Distribution of GEnetic Traits web server (GADGET http://gadget.biosci.gatech.edu). The GADGET web server provides users with a dynamic visual platform for exploring the relationship between worldwide genetic diversity and the genetic architecture underlying numerous human phenotypes. GADGET integrates trait-implicated single nucleotide polymorphisms (SNPs) from GWAS, with population genetic data from the 1000 Genomes Project, to calculate genome-wide polygenic trait scores (PTS) for 818 phenotypes in 2504 individual genomes. Population-specific distributions of PTS are shown for 26 human populations across 5 continental population groups, with traits ordered based on the extent of variation observed among populations. Users of GADGET can also upload custom trait SNP sets to visualize global PTS distributions for their own traits of interest.


Vascular normalization by loss of Siah2 results in increased chemotherapeutic efficacy.
Tumor hypoxia is associated with resistance to antiangiogenic therapy and poor prognosis. The Siah E3 ubiquitin ligases regulate the hypoxic response pathway by modulating the turnover of the master proangiogenic transcription factor hypoxia-inducible factor-1α (Hif-1α). In this study, we show that genetic deficiency in the Siah family member Siah2 results in vascular normalization and delayed tumor growth in an established transgenic model of aggressive breast cancer. Tumors arising in a Siah2(-/-) genetic background showed increased perfusion and pericyte-associated vasculature, similar to that occurring with antiangiogenic therapy. In support of the role of Siah2 in regulating levels of Hif-1α, expression of angiogenic factors was decreased in Siah2(-/-) tumors. Blood vessel normalization in Siah2(-/-) tumors resulted in an increased response to chemotherapy and prolonged survival. Together, our findings offer a preclinical proof of concept that targeting Siah2 is sufficient to attenuate Hif-1α-mediated angiogenesis and hypoxia signaling, thereby improving responses to chemotherapy.


Out-of-Body Experiences and Other Complex Dissociation Experiences in a Patient with Unilateral Peripheral Vestibular Damage and Deficient Multisensory Integration.
Out-of-body experiences (OBEs) are illusory perceptions of one's body from an elevated disembodied perspective. Recent theories postulate a double disintegration process in the personal (visual, proprioceptive and tactile disintegration) and extrapersonal (visual and vestibular disintegration) space as the basis of OBEs. Here we describe a case which corroborates and extends this hypothesis. The patient suffered from peripheral vestibular damage and presented with OBEs and lucid dreams. Analysis of the patient's behaviour revealed a failure of visuo-vestibular integration and abnormal sensitivity to visuo-tactile conflicts that have previously been shown to experimentally induce out-of-body illusions (in healthy subjects). In light of these experimental findings and the patient's symptomatology we extend an earlier model of the role of vestibular signals in OBEs. Our results advocate the involvement of subcortical bodily mechanisms in the occurrence of OBEs.


Birds invest wingbeats to keep a steady head and reap the ultimate benefits of flying together.
Flapping flight is the most energetically demanding form of sustained forwards locomotion that vertebrates perform. Flock dynamics therefore have significant implications for energy expenditure. Despite this, no studies have quantified the biomechanical consequences of flying in a cluster flock or pair relative to flying solo. Here, we compared the flight characteristics of homing pigeons (Columba livia) flying solo and in pairs released from a site 7 km from home, using high-precision 5 Hz global positioning system (GPS) and 200 Hz tri-axial accelerometer bio-loggers. As expected, paired individuals benefitted from improved homing route accuracy, which reduced flight distance by 7% and time by 9%. However, realising these navigational gains involved substantial changes in flight kinematics and energetics. Both individuals in a pair increased their wingbeat frequency by 18% by decreasing the duration of their upstroke. This sharp increase in wingbeat frequency caused just a 3% increase in airspeed but reduced the oscillatory displacement of the body by 22%, which we hypothesise relates to an increased requirement for visual stability and manoeuvrability when flying in a flock or pair. The combination of the increase in airspeed and a higher wingbeat frequency would result in a minimum 2.2% increase in the total aerodynamic power requirements if the wingbeats were fully optimised. Overall, the enhanced navigational performance will offset any additional energetic costs as long as the metabolic power requirements are not increased above 9%. Our results demonstrate that the increases in wingbeat frequency when flying together have previously been underestimated by an order of magnitude and force reinterpretation of their mechanistic origin. We show that, for pigeons flying in pairs, two heads are better than one but keeping a steady head necessitates energetically costly kinematics.


Learning a hierarchical representation of the yeast transcriptomic machinery using an autoencoder model.
A living cell has a complex, hierarchically organized signaling system that encodes and assimilates diverse environmental and intracellular signals, and it further transmits signals that control cellular responses, including a tightly controlled transcriptional program. An important and yet challenging task in systems biology is to reconstruct cellular signaling system in a data-driven manner. In this study, we investigate the utility of deep hierarchical neural networks in learning and representing the hierarchical organization of yeast transcriptomic machinery. We have designed a sparse autoencoder model consisting of a layer of observed variables and four layers of hidden variables. We applied the model to over a thousand of yeast microarrays to learn the encoding system of yeast transcriptomic machinery. After model selection, we evaluated whether the trained models captured biologically sensible information. We show that the latent variables in the first hidden layer correctly captured the signals of yeast transcription factors (TFs), obtaining a close to one-to-one mapping between latent variables and TFs. We further show that genes regulated by latent variables at higher hidden layers are often involved in a common biological process, and the hierarchical relationships between latent variables conform to existing knowledge. Finally, we show that information captured by the latent variables provide more abstract and concise representations of each microarray, enabling the identification of better separated clusters in comparison to gene-based representation. Contemporary deep hierarchical latent variable models, such as the autoencoder, can be used to partially recover the organization of transcriptomic machinery.


Glutamate. Its applications in food and contribution to health.
This article reviews application of glutamate in food and its benefits and role as one of the common food ingredients used. Monosodium glutamate is one of the most abundant naturally occurring amino acids which frequently added as a flavor enhancer. It produced a unique taste that cannot be provided by other basic taste (saltiness, sourness, sweetness and bitterness), referred to as a fifth taste (umami). Glutamate serves some functions in the body as well, serving as an energy source for certain tissues and as a substrate for glutathione synthesis. Glutamate has the potential to enhance food intake in older individuals and dietary free glutamate evoked a visceral sensation from the stomach, intestine and portal vein. Small quantities of glutamate used in combination with a reduced amount of table salt during food preparation allow for far less salt to be used during and after cooking. Because glutamate is one of the most intensely studied food ingredients in the food supply and has been found safe, the Joint Expert Committee on Food Additives of the United Nations Food and Agriculture Organization and World Health Organization placed it in the safest category for food additives. Despite a widespread belief that glutamate can elicit asthma, migraine headache and Chinese Restaurant Syndrome (CRS), there are no consistent clinical data to support this claim. In addition, findings from the literature indicate that there is no consistent evidence to suggest that individuals may be uniquely sensitive to glutamate.


Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum.
To characterize the ABCC6 R1141X nonsense mutation, which is implicated in more than 25% of a cohort of patients from The Netherlands with pseudoxanthoma elasticum (PXE). A combination of single-strand conformational polymorphism (SSCP), PCR, sequencing, and Southern blot analysis was used to identify mutations in the ABCC6 gene in 62 patients. Haplotypes of 16 patients with the R1141X mutation were determined with eight polymorphic markers spanning the ABCC6 locus. The effect of the R1141X mutation on the expression of ABCC6 was studied in leukocytes and cultured dermal fibroblasts from affected skin in patients heterozygous or homozygous for the R1141X mutation. ABCC6 expression was analyzed by RT-PCR and immunocytochemistry with ABCC6-specific monoclonal antibodies. The ABCC6 R1141X mutation was found on 19 alleles in 16 patients with PXE and occurred in heterozygous, homozygous, or compound heterozygous form. All R1141X alleles were associated with a common haplotype, covering at least three intragenic ABCC6 markers. None of the patients or healthy control subjects had a similar ABCC6 haplotype. Furthermore, the results showed that the expression of the normal allele in R1141X heterozygotes was predominant, whereas no detectable, or very low, ABCC6 mRNA levels were found in R1141X homozygotes. Immunocytochemical staining of cultured dermal fibroblasts with ABCC6-specific monoclonal antibodies showed no evidence of the presence of a truncated protein in patients with PXE who were homozygous for R1141X. A specific founder effect for the R1141X mutation exists in Dutch patients with PXE. The R1141X mutation induces instability of the aberrant mRNA. Functional haploinsufficiency or loss of function of ABCC6 caused by mechanisms, such as nonsense-mediated decay (NMD), may be involved in the PXE phenotype.


"Doctor, please tell me it's nothing serious": an exploration of patients' worrying and reassuring cognitions using stimulated recall interviews.
Many patients who consult their GP are worried about their health, but there is little empirical data on strategies for effective reassurance. To gain a better understanding of mechanisms for effective patient reassurance, we explored cognitions underlying patients' worries, cognitions underlying reassurance and factors supporting patients' reassuring cognitions. In a qualitative study, we conducted stimulated recall interviews with 21 patients of 12 different GPs shortly after their consultation. We selected consultations in which the GPs aimed to reassure worried patients and used their videotaped consultation as a stimulus for the interview. The interviews were analysed with thematic coding and by writing interpretive summaries. Patients expressed four different core cognitions underlying their concerns: 'I have a serious illness', 'my health problem will have adverse physical effects', 'my treatment will have adverse effects' and 'my health problem will negatively impact my life'. Patients mentioned a range of person-specific and context-specific cognitions as reasons for these core cognitions. Patients described five core reassuring cognitions: 'I trust my doctor's expertise', 'I have a trusting and supporting relationship with my doctor', 'I do not have a serious disease', 'my health problem is harmless' and 'my health problem will disappear.' Factors expressed as reasons for these reassuring cognitions were GPs' actions during the consultation as well as patients' pre-existing cognitions about their GP, the doctor-patient relationship and previous events. Patients' worrying cognitions were counterbalanced by specific reassuring cognitions, i.e. worrying and reassuring cognitions seemed to be interrelated. Patients described a wide range of worrying cognitions, some of which were not expressed during the consultation. Gaining a thorough understanding of the specific cognitions and tailoring reassuring strategies to them should be an effective way of achieving reassurance. The identified reassuring cognitions can guide doctors in applying these strategies in their daily practice.


Temporal stability of the mouse gut microbiota in relation to innate and adaptive immunity.
Gut microbial community properties of mammals are thought to be partly shaped by a combination of host immunity and environmental factors, but their relative importance is not firmly established. To address this gap, we first characterized the faecal bacteria of mice with a functioning immune system (wild-type, WT), mice with defective immune responses (CD45), mice lacking an adaptive immune system (RAG), and mice with both immune dysfunctions (45RAG). Using fingerprinting of 16S rRNA genes, we observed significant differences in gut microbiota composition across all mouse strains (P < 0.001) and identified several mouse strain-specific genera via pyrosequencing, including Turicibacter sp. (in WT mice) and Allobaculum sp. (in CD45-deficient animals). To define the role of the host immune system in constraining gut microbiota stability after perturbation, we cohoused CD45-deficient and WT mice and monitored gut bacterial community dynamics during 8 weeks. Cohousing caused the WT bacterial communities to become indistinguishable from those of CD45 mice (P > 0.05). Time-series analysis indicated that the communities of cohoused mice changed directionally as opposed to the relatively stable communities of non-cohoused controls. When we considered only taxonomic membership, it was the communities of CD45 non-cohoused mice that experienced the highest rate of change. Rather than be governed by fluctuations in the relative abundance of taxa, we suggest that CD45-regulated immune responses either are stimulated by the presence of bacteria per se or promote temporal stability by selecting for the occurrence of specific taxa.


Coupling characteristics of dielectric-loaded surface plasmon polariton waveguides: a simple method of analysis.
A simple method to obtain the coupling characteristics of a directional coupler consisting of two dielectric-loaded surface plasmon polariton waveguides is reported. The method is found to give accurate results in comparison with the widely used effective index method. Theoretical results are also found to match excellently with recently reported measurements on coupling lengths in such waveguides [Opt. Lett.34, 310 (2009)OPLEDP0146-959210.1364/OL.34.000310].


Cyclin A2 transcriptional regulation: modulation of cell cycle control at the G1/S transition by peripheral cues.
Several types of cyclins have been identified and among these, cyclin A2 is synthesized in somatic cells at the onset of DNA synthesis as well as during the G2/M transition associated with cyclin-dependent protein kinases 1 and 2. Modulation of cyclin A transcription is due to the interplay between a cell cycle-dependent periodic relief of a transcriptional repression and signals transduced through adenosine 3',5'-cyclic monophosphate, transforming growth factor-beta, and the integrin-mediated pathways. Using primary mouse embryonic fibroblasts from embryos where the genes coding for the protein responsible for susceptibility to retinoblastoma (pRB) and the related p107 and p130 proteins had been individually inactivated, we showed that cyclin A is a functional target of pRB-mediated cell cycle arrest. The factors involved are discussed.


The C-type lectin receptors dectin-1, MR, and SIGNR3 contribute both positively and negatively to the macrophage response to Leishmania infantum.
Macrophages act as the primary effector cells during Leishmania infection through production of reactive oxygen species (ROS) and interleukin-1β (IL-1β). However, how macrophage-killing mechanisms are activated during Leishmania-macrophage interactions is poorly understood. Here, we report that the macrophage response against Leishmania infantum in vivo is characterized by an M2b-like phenotype and C-type lectin receptors (CLRs) signature composed of Dectin-1, mannose receptor (MR), and the DC-SIGN homolog SIGNR3 expression. Dectin-1 and MR were crucial for the microbicidal response as indicated by the fact that they activated Syk-p47phox and arachidonic acid (AA)-NADPH oxidase signaling pathways, respectively, needed for ROS production and also triggered Syk-coupled signaling for caspase-1-induced IL-1β secretion. In contrast, SIGNR3 has divergent functions during Leishmania infantum pathogenesis; this CLR favored parasite resilience through inhibition of the LTB4-IL-1β axis. These pathways also operated during infection of primary human macrophages. Therefore, our study promotes CLRs as potential targets for treatment, diagnosis, and prevention of visceral leishmaniasis.


Gingival Fibromatosis with Significant De Novo Formation of Fibrotic Tissue and a High Rate of Recurrence.
BACKGROUND Hereditary gingival fibromatosis is characterized by slowly progressive enlargement of the gingiva that can present as an isolated condition or present as part of various syndromes. CASE REPORT An 11-year-old female reported with a gingival lesion that caused masticatory problems and poor oral hygiene. Periodontal examination revealed a dense tissue covering 30% of her teeth crowns within both jaws. Panoramic x-ray showed a normal bone height and teeth positioning. The patient did not use any medications, but a similar condition was also present in other family members. The patient was diagnosed with hereditary gingival fibromatosis. Surgery was carried out to remove excess of gingival tissue. Post-surgical healing was uneventful, but four weeks after the first surgery, the condition recurred amounting to 45% of the initial tissue volume presenting in the mandible, and 25% in the maxilla. Two months later, no significant growth was noted in the mandible, while in the maxilla, growth increased to 40% of the preoperative state. Analysis by polarized microscope showed a significant increase of thin fibrotic fibrils that contributed 80% of the total pool of collagen fibrils in the patient's gingiva, but only 25% in healthy gingiva. The patient was receiving outpatient care for follow-up every three months and surgical intervention had not been planned as long as her periodontal health was not be compromised. CONCLUSIONS It is currently not clear whether the extent of the fibrosis had a mechanistic association with the ratio of gingival tissue re-growth in our case study. Further studies are needed to explain this association and improve the management of this condition.


Identification of the mouse cytomegalovirus genomic region affecting major histocompatibility complex class I molecule transport.
Mouse cytomegalovirus (MCMV) functions expressed at the beginning of the early phase of the viral replication cycle interfere with the major histocompatibility complex (MHC) class I-restricted pathway of antigen presentation (M. J. Reddehase, M. R. Fibi, G. M. Keil, and U. H. Koszinowski, J. Virol. 60:1125-1129, 1986; M. Del Val, K. Münch, M. J. Reddehase, and U. H. Koszinowski, Cell 58:305-315, 1989). Nascent MHC class I heavy chains associate with beta 2-microglobulin and peptide, but the assembled trimolecular complex is retained in the endoplasmatic reticulum/cis-Golgi compartment (M. Del Val, H. Hengel, H. Häcker, U. Hartlaub, T. Ruppert, P. Lucin, and U. H. Koszinowski, J. Exp. Med. 176:729-738, 1992). To locate the responsible genomic region, the cytoplasmic retention of MHC class I molecules after injection of MCMV DNA was tested. The function was mapped to the HindIII E fragment. A recombinant MCMV deletion mutant delta MS94.5 lacking 15.8 kb in HindIII-E was constructed. Restoration of MHC class I molecule maturation and recognition of antigenic peptides by cytolytic T lymphocytes during the first hours of the early phase in mutant virus-infected cells proved the correct location to a 6.8-kb region in the HindIII E fragment. At later stages of the early phase, membrane-resident MHC class I molecules and cytolytic T lymphocyte recognition disappeared in delta MS94.5 mutant virus-infected cells. These results demonstrate that more than one early-gene function of MCMV affects the MHC class I pathway of antigen presentation. The redundant MHC class I-reactive functions target the transport of MHC class I molecules at different steps.