Trends of colorectal cancer incidence and mortality rates from 2003 to 2014 in Italy.
To evaluate the trends of colorectal cancer (CRC) incidence and mortality rates from 2003 to 2014 in Italy by age groups and regions. We used the data of 48 cancer registries from 17 Italian regions to estimate standardized incidence and mortality rates overall and by sex, age groups (<50, 50-69, 70+ years), and geographic area (northwest, northeast, center, south, and islands). Time trends were expressed as annual percent change in rates (APC) with 95% confidence intervals (95% CI). Incidence rates decreased from 104.3 (2003) to 89.9 × 100,000 (2014) in men and from 64.3 to 58.4 × 100,000 in women. Among men, incidence decreased during 2007-2010 (APC -4.0, 95% CI -6.0 to -1.9) and 2010-2014 (APC -0.7, 95% CI -1.4 to 0.0), while in women it linearly decreased during the whole period (APC -1.1, 95% CI -1.4 to -0.8). Mortality rates showed a linear reduction both in men (APC -0.7, 95% CI -1.0 to -0.3) and women (APC -0.9, 95% CI -1.2 to -0.6) and decreased respectively from 41.1 to 39.2 × 100,000 and from 24.6 to 23.1 × 100,000. In the 50- to 69-year-old range (screening target age), incidence showed a prescreening increase, followed by a peak after screening started, and a decline thereafter. Incidence and mortality rates significantly decreased in all areas but in the south and islands, where incidence increased and mortality remained stable. A renewed commitment by all regional health systems to invest in primary (i.e., lifestyle) and secondary (i.e., screening programs) prevention is of utmost importance.


Insulin resistance and beta-cell dysfunction in normoglycaemic European women with a history of gestational diabetes.
Women with previous gestational diabetes (GDM) are at increased risk of subsequent type 2 diabetes. To characterize early metabolic abnormalities associated with this increased risk, we studied normoglycaemic women with a history of GDM. We performed an insulin-modified, frequently sampled intravenous glucose tolerance test (FSIVGTT) in 34 normoglycaemic European women with previous GDM and 44 European control women, deriving measures of insulin sensitivity, glucose effectiveness, glucose disappearance rate and acute insulin response to glucose. Post-GDM women were more obese than controls [body mass index (BMI), geometric mean (95% confidence interval); 25.3 kg/m2 (23.8-27.1 kg/m2) vs. 23.1 kg/m2 (21.9-24.3 kg/m2), P = 0.03]. Evidence of insulin resistance was provided by their lower insulin sensitivity as measured by FSIVGTT [0.6 x 10-4/min/pmol/l (0.3-1.2 x 10-4/min/pmol/l) vs. 1.5 x 10-4/min/pmol/l (1.2-1.8 x 10-4/min/pmol/l), P = 0.01] and by homeostatic model assessment [72% (49-107%) vs. 153% (113-206%), P = 0.004]; and by their higher fasting triglycerides [1.0 mmol/l (0.7-1.5 mmol/l) vs. 0.7 mmol/l (0.6-0.8 mmol/l), P = 0.001]. Though there was no difference between groups in fasting NEFA levels, acute NEFA suppression was diminished in the post-GDM group (P = 0.01). Concomitant beta-cell dysfunction in the post-GDM women was revealed by their lower disposition index [0.05/min (0.02-0.10/min) vs. 0.11/min (0.09-0.14/min), P = 0.02] compared to controls. The differences in insulin sensitivity, but not those of beta-cell function, were partly, though not completely, attributable to differences in regional and total adiposity. European normoglycaemic women with previous GDM display both glucoregulatory and antilipolytic insulin resistance, reduced beta-cell function and dyslipidaemia. These metabolic abnormalities are likely to contribute to their increased risk of future type 2 diabetes.


Dopamine D2 receptor gene -141C Insertion/Deletion polymorphism in Turkish schizophrenic patients.
Schizophrenia is a chronic and neuropsychiatric disease that affects about 0.5-1% of the world's population. An increase in dopamine and dopamine D2 receptor (DRD2) gene products has been well described in schizophrenic patients. Several groups have studied the relationship between dopaminergic hyperactivity and cellular communications have obtained discordant results. Studies searching for the relationship between the schizophrenia and DRD2 gene have gained more interest. Our objective was to determine the relationships among schizophrenic symptoms in schizophrenia subtypes and severity of symptoms in terms of DRD2 gene -141C Insertion/Deletion [Ins/Del; I/D] polymorphism by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) assay method. Genomic DNA was prepared from peripheral blood by using salt extraction method. After amplification of genomic DNA, PCR products were digested with BstNI restriction enzyme for the detection of DRD2 gene -141C Ins/Del polymorphism in 73 schizophrenic patients and 60 healthy control subjects. The allelic frequencies of the DRD2 gene -141C Ins/Del polymorphism in case and control groups were 79.5 and 77.5% for I allele; 20.5 and 22.5% for D allele respectively. There was no significant difference in frequencies of genotypes and alleles between the two groups. In schizophrenic and control subjects, there were no significant relationship in severity of the disease and schizophrenia types among the -141C Ins/Del genotypes and alleles.


Land-use history alters contemporary insect herbivore community composition and decouples plant-herbivore relationships.
Past land use can create altered soil conditions and plant communities that persist for decades, although the effects of these altered conditions on consumers are rarely investigated. Using a large-scale field study at 36 sites in longleaf pine (Pinus palustris) woodlands, we examined whether historic agricultural land use leads to differences in the abundance and community composition of insect herbivores (grasshoppers, families Acrididae and Tettigoniidae). We measured the cover of six plant functional groups and several environmental variables to determine whether historic agricultural land use affects the relationships between plant cover or environmental conditions and grasshopper assemblages. Land-use history had taxa-specific effects and interacted with herbaceous plant cover to alter grasshopper abundances, leading to significant changes in community composition. Abundance of most grasshopper taxa increased with herbaceous cover in woodlands with no history of agriculture, but there was no relationship in post-agricultural woodlands. We also found that grasshopper abundance was negatively correlated with leaf litter cover. Soil hardness was greater in post-agricultural sites (i.e. more compacted) and was associated with grasshopper community composition. Both herbaceous cover and leaf litter cover are influenced by fire frequency, suggesting a potential indirect role of fire on grasshopper assemblages. Our results demonstrate that historic land use may create persistent differences in the composition of grasshopper assemblages, while contemporary disturbances (e.g. prescribed fire) may be important for determining the abundance of grasshoppers, largely through the effect of fire on plants and leaf litter. Therefore, our results suggest that changes in the contemporary management regimes (e.g. increasing prescribed fire) may not be sufficient to shift the structure of grasshopper communities in post-agricultural sites towards communities in non-agricultural habitats. Rather, repairing degraded soil conditions and restoring plant communities are likely necessary for restoring grasshopper assemblages in post-agricultural woodlands.


Training to enhance the physiological determinants of long-distance running performance: can valid recommendations be given to runners and coaches based on current scientific knowledge?
This article investigates whether there is currently sufficient scientific knowledge for scientists to be able to give valid training recommendations to long-distance runners and their coaches on how to most effectively enhance the maximal oxygen uptake, lactate threshold and running economy. Relatively few training studies involving trained distance runners have been conducted, and these studies have often included methodological factors that make interpretation of the findings difficult. For example, the basis of most of the studies was to include one or more specific bouts of training in addition to the runners' 'normal training', which was typically not described or only briefly described. The training status of the runners (e.g. off-season) during the study period was also typically not described. This inability to compare the runners' training before and during the training intervention period is probably the main factor that hinders the interpretation of previous training studies. Arguably, the second greatest limitation is that only a few of the studies included more than one experimental group. Consequently, there is no comparison to allow the evaluation of the relative efficacy of the particular training intervention. Other factors include not controlling the runners' training load during the study period, and employing small sample sizes that result in low statistical power. Much of the current knowledge relating to chronic adaptive responses to physical training has come from studies using sedentary individuals; however, directly applying this knowledge to formulate training recommendations for runners is unlikely to be valid. Therefore, it would be difficult to argue against the view that there is insufficient direct scientific evidence to formulate training recommendations based on the limited research. Although direct scientific evidence is limited, we believe that scientists can still formulate worthwhile training recommendations by integrating the information derived from training studies with other scientific knowledge. This knowledge includes the acute physiological responses in the various exercise domains, the structures and processes that limit the physiological determinants of long-distance running performance, and the adaptations associated with their enhancement. In the future, molecular biology may make an increasing contribution in identifying effective training methods, by identifying the genes that contribute to the variation in maximal oxygen uptake, the lactate threshold and running economy, as well as the biochemical and mechanical signals that induce these genes. Scientists should be cautious when giving training recommendations to runners and coaches based on the limited available scientific knowledge. This limited knowledge highlights that characterising the most effective training methods for long-distance runners is still a fruitful area for future research.


Diplopia in autoimmune thyroid disease.
Diplopia without obvious exophthalmos, caused by infiltrative endocrine ophthalmopathy, developed in 12 patients with clinical and laboratory confirmation of autoimmune thyroid disease. In eight patients, the diplopia alone prompted medical attention, which led to the diagnosis of autoimmune thyroid disease. A hypotropia secondary to restrictive tightening of the inferior rectus muscle, producing vertical diplopia, was the most common manifestation of the disorder. The ocular muscle imbalance in autoimmune thyroid disease is caused by mechanical orbital restriction of the extraocular muscle, not by an innervational defect. Evidence of orbital restriction of the eye muscles can establish the diagnosis, regardless of the patient's thyroid function.


Modification of Salmonella Typhimurium motility by the probiotic yeast strain Saccharomyces boulardii.
Motility is an important component of Salmonella enterica serovar Typhimurium (ST) pathogenesis allowing the bacteria to move into appropriate niches, across the mucus layer and invade the intestinal epithelium. In vitro, flagellum-associated motility is closely related to the invasive properties of ST. The probiotic yeast Saccharomyces boulardii BIOCODEX (S.b-B) is widely prescribed for the prophylaxis and treatment of diarrheal diseases caused by bacteria or antibiotics. In case of Salmonella infection, S.b-B has been shown to decrease ST invasion of T84 colon cell line. The present study was designed to investigate the impact of S.b-B on ST motility. Experiments were performed on human colonic T84 cells infected by the Salmonella strain 1344 alone or in the presence of S.b-B. The motility of Salmonella was recorded by time-lapse video microscopy. Next, a manual tracking was performed to analyze bacteria dynamics (MTrackJ plugin, NIH image J software). This revealed that the speed of bacterial movement was modified in the presence of S.b-B. The median curvilinear velocity (CLV) of Salmonella incubated alone with T84 decreased from 43.3 µm/sec to 31.2 µm/sec in the presence of S.b-B. Measurement of track linearity (TL) showed similar trends: S.b-B decreased by 15% the number of bacteria with linear tract (LT) and increased by 22% the number of bacteria with rotator tract (RT). Correlation between ST motility and invasion was further established by studying a non-motile flagella-deficient ST strain. Indeed this strain that moved with a CLV of 0.5 µm/sec, presented a majority of RT and a significant decrease in invasion properties. Importantly, we show that S.b-B modified the motility of the pathogenic strain SL1344 and significantly decreased invasion of T84 cells by this strain. This study reveals that S.b-B modifies Salmonella's motility and trajectory which may account for the modification of Salmonella's invasion.


Short communication: Effect of feeding pooled and nonpooled high-quality colostrum on passive transfer of immunity, morbidity, and mortality in dairy calves.
Pooling colostrum is commonly practiced on Irish dairy farms. Pooling can result in dilution when colostrums with high and low IgG concentrations are mixed, thereby predisposing calves to failure of passive immunity. The objectives of this study were to compare IgG concentrations in colostrum from individual cows with colostrum pooled from several cows, and assess serum IgG concentrations, morbidity, and mortality among calves fed colostrum from their own dam, from a different cow, or pooled from several cows. We hypothesized that pooling colostrum reduces IgG concentration due to dilution compared with colostrum from individual cows, and that calves fed pooled colostrum achieve lower serum IgG concentrations than calves fed colostrum from individual cows. Calves were randomly assigned to 1 of 3 groups: (1) fed colostrum from their own dam (n = 20); (2) fed colostrum from a different dam (n = 20); or (3) fed pooled colostrum (n = 18). A sample of colostrum fed to each calf was collected. Serum samples were collected from calves at birth (0 h) and at 24 h after colostrum feeding. Colostrum and serum IgG concentrations were measured by radial immunodiffusion. Calves were weighed at birth and at weaning, and the health status of each calf was assessed twice daily. Health assessment was based on general demeanor, rectal temperature, fecal consistency, respiratory rate, and the presence of cough, nasal, or ocular discharge. Colostrum and serum IgG concentrations, and weaning weights were compared using ANOVA. Associations between group and morbidity or mortality rates were compared using χ2 or Fisher's exact tests. Median and 95% confidence intervals (95% CI) of IgG concentrations of colostrum were 99.4 (81.8-111.5), 95.2 (84.1-107.2), and 100.7 (90.5-104.4) g/L for own dam, different dam, and pooled groups, respectively. We did not find any differences in colostrum IgG concentrations among the colostrum sources. Median (95% CI) serum IgG concentrations at 24 h were 52.0 (45.6-65.9), 55.7 (51.2-65.9), and 53.1 (46.2-63.7) g/L for calves that received colostrum from own dam, different dam, and pooled, respectively. All calves achieved adequate passive immunity. Serum IgG concentrations at 24 h, weaning weights, and proportions of morbidity and mortality were not different among the 3 groups. Our results suggest that on dairy farms where median colostrum IgG concentrations are high and colostrum management is optimal, pooling has a minimal effect on passive immunity and subsequent calf health.


Adjustments of medication dosages in patients with renal impairment in Botswana; findings and implications to improve patient care.
Background and aims: Medication dosage adjustments for renally impaired patients have not been studied in Botswana. This study was conducted to determine prescribing practices among patients with renal impairment in medical wards to improve future patient care.Methods: We conducted a retrospective study involving medical charts of patients admitted at a tertiary level hospital in Gaborone Botswana. Study participants included all patients admitted between August and October 2016 who were hospitalized for ≥24 h. 'Drug prescribing in renal failure: dosing guidelines for adults and children'. was used to determine the extent of dosage adjustments. A logistic regression model was used to assess which patient factors were associated with inappropriate dosage adjustment.Results: Twenty-nine percent (233/804) of patients had renal impairment. Of these, 184 patients with renal impairment were included in the final analysis. There were 1143 prescription entries, of which 20.5% (n = 234) required dosage adjustment for renal function but only 45.7% (n = 107) were adjusted correctly. Of note, 112 patients were prescribed at least one drug that required dosage adjustment and only 30.4% (n = 34) patients had all of their medications appropriately adjusted. Patient factors associated with inappropriate dosage adjustment included a higher number of medicines being prescribed. Mortality among patients with renal impairment was independently associated with higher scores of the Charlson comorbidity index and hospital stay duration of 1-7 days.Conclusion: The renal function status of patients was not sufficiently taken into account when prescribing medicines especially in patients with severely impaired kidney function in Botswana. Continuous medical education needs to be encouraged to address this, which is being implemented. We will be following this up in future studies.


Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome.
It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma. Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called "asthma endotypes." An "endotype" is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit. This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.


Polarization-preserving angular shifter.
This study shows that by using a wedge plate the incident direction of light propagation can be rotated as desired while still preserving beam polarization. This study also deduces the basic condition of this preservation of polarization. Two typical wedge plates are analyzed for numerical demonstration. Simulation results verify that a collimated beam with a +45 degrees linear polarization can be guided to an expected direction while preserving the state of polarization with a square of the variation of the ellipse ratio of less than 0.0001%. This study also numerically shows that the wedge vertex angle is the most critical issue and that approximately 0.1 degrees accuracy is required to preserve the polarization state.


Adoption of electronic health records grows rapidly, but fewer than half of US hospitals had at least a basic system in 2012.
The US health care system is in the midst of an enormous change in the way health care providers and hospitals document, monitor, and share information about health and care delivery. Part of this transition involves a wholesale, but currently uneven, shift from paper-based records to electronic health record (EHR) systems. We used the most recent longitudinal survey of US hospitals to track how they are adopting and using EHR systems. Only 44 percent of hospitals report having and using what we define as at least a basic EHR system. And although 42.2 percent meet all of the federal stage 1 "meaningful-use" criteria, only 5.1 percent could meet the broader set of stage 2 criteria. Large urban hospitals continue to outpace rural and nonteaching hospitals in adopting EHR systems. The increase in adoption overall suggests that the positive and negative financial incentives currently in place across the US health care system are working as intended. However, achieving a nationwide health information technology infrastructure may require efforts targeted at smaller and rural hospitals.


PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL.
This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD-) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)-based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD-, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD-. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD-. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.


Effects of Microbiota on the Treatment of Obesity with the Natural Product Celastrol in Rats.
Obesity has become one of the most serious issues threatening the health of humankind, and we conducted this study to examine whether and how celastrol protects against obesity. We fed male Sprague-Dawley rats a high-fat diet and administered celastrol to obese rats for 3 weeks. By recording body weight (BW) and other measures, we identified the effective dose of celastrol for obesity treatment. Feces were collected to perform 16S rRNA sequencing, and hypothalami were extracted for transcriptome sequencing. We then treated leptin knockout rats with celastrol and explored the changes in energy metabolism. Male Institute of Cancer Research (ICR) mice were used to test the acute toxicity of celastrol. We observed that celastrol reduced BW and promoted energy expenditure at a dose of 500 µg/kg BW but that food intake was not changed after administration. The diversity of the gut microbiota was improved, with an increased ratio of Bacteroidetes to Firmicutes, and the gut microbiota played an important role in the anti-obesity effects of celastrol. Hypothalamic transcriptome analysis showed a significant enrichment of the leptin signaling pathway, and we found that celastrol significantly enhanced energy expenditure, which was mediated by the leptin signaling pathway. Acute lethal toxicity of celastrol was not observed at doses ranging from 0 to 62.5 mg/kg BW. Our study revealed that celastrol decreased the BW of obese rats by enhancing energy expenditure but not by suppressing food intake and that this effect was mediated by the improvement of the gut microbiota and the activation of the hypothalamic leptin signaling pathway.


DNA polymerase B from wheat embryos: a plant delta-like DNA polymerase.
Studies in eucaryotic cells (mainly animals and yeast) indicate that at least two DNA polymerases are involved in DNA replication at the level of the replication fork: DNA polymerase alpha, which is associated with DNA primase, is involved in the replication of the lagging strand; DNA polymerase delta, associated with an exonuclease activity, synthesizes the forward continuous DNA strand. Much less information exists concerning plant systems. Previous work from this laboratory provided preliminary evidence of an association between DNA polymerase B from wheat embryo and an exonucleolytic activity. In this paper, we present additional data on the biochemical properties of DNA polymerase B. An improved purification procedure described in this article has been developed. During all the purification steps the nuclease activity was associated with DNA polymerase activity. A biochemical study of this enzyme activity shows that it is an exonuclease which hydrolyses DNA in the 3' to 5' direction. Moreover, this exonuclease confers a proofreading function to DNA polymerase B. Comparison of DNA polymerase B properties (template specificity, sensitivity to DNA replication inhibitors like aphidicolin and butyl-phenyl dGTP, copurification of DNA polymerase and exonuclease activities) with those of animal DNA polymerase delta indicates that these enzymes share many common features. To our knowledge, this is the first report of DNA polymerase delta in higher plants.


A focal-spot diagnostic for on-shot characterization of high-energy petawatt lasers.
An on-shot focal-spot diagnostic for characterizing high-energy, petawatt-class laser systems is presented. Accurate measurements at full energy are demonstrated using high-resolution wavefront sensing in combination with techniques to calibrate on-shot measurements with low-power sample beams. Results are shown for full-energy activation shots of the OMEGA EP Laser System.


Role of the ionosphere for the atmospheric evolution of planets.
We have synthesized current understanding, mainly observations, with regard to ion escape mechanisms to space from the ionosphere and exosphere of Titan and Earth-type planets, with the intent to provide an improved input for models of atmospheric evolution on early Earth and Earth-type planets and exoplanets. We focus on the role of the ionosphere and its non-linear response to solar parameters, all of which have been underestimated in current models of ancient atmospheric escape (4 billion years ago). Factors that have been overlooked include the following: (1) Much larger variation of O(+) outflow than H(+) outflow from the terrestrial ionosphere, depending on solar and geomagnetic activities (an important consideration when attempting to determine the oxidized state of the atmosphere of early Earth); (2) magnetization of the ionopause, which keeps ionospheric ions from escaping and controls many other escape processes; (3) extra ionization by, for example, the critical ionization velocity mechanism, which expands the ionosphere to greater altitudes than current models predict; and (4) the large escape of cold ions from the dense, expanded ionosphere of Titan. Here we offer, as a guideline for quantitative simulations, a qualitative diagnosis of increases or decreases of non-thermal escape related to the ionosphere for magnetized and unmagnetized planets in response to changes in solar parameters (i.e., solar EUV/FUV flux, solar wind dynamic pressure, and interplanetary magnetic field).


Olfactory function in migraine both during and between attacks.
People with migraine often report being osmophobic, both during and between acute migraine attacks. It is not clear, however, whether such reports are associated with changes in olfaction such as hyperosmia, as measured by psychophysical testing. In this case-control study we quantitatively assessed olfactory identification ability, which correlates with threshold tests of olfactory acuity, in patients with migraine at baseline (no headache), during migraine episodes, and after a treated attack and compared the test scores to those of matched control subjects. Fifty episodic migraine subjects and 50 and sex- and age-matched controls without headache were tested. All completed the University of Pennsylvania Smell Identification Test (UPSIT), a standardized and well-validated olfactory test. At baseline, the UPSIT scores did not differ significantly between the migraine and control study groups (median paired score difference: -1, p = 0.18). During migraine attacks, a minority of migraine subjects (eight of 42) developed microsmia (i.e. lower test scores by at least four points), suggesting that, as compared to their matched controls, olfactory acuity was somewhat impaired during migraine attacks (p = 0.02). This difference was less pronounced and not statistically significant after a successfully treated attack (p = 0.15). People with episodic migraine were found to have similar olfactory function as age- and sex-matched controls, but a minority exhibit microsmia or hyposmia during acute attacks. The cause of this dysfunction is unknown, but could relate to autonomic symptoms, limbic system activation, or disorders of higher order sensory processing.


Comparison of digital intraoral scanner reproducibility and image trueness considering repetitive experience.
Because the digital workflow can begin directly in the oral cavity, intraoral scanners are being adopted in dental treatments. However, studies of the relationship between the experience of the practitioner and the accuracy of impression data are needed. The purpose of this clinical study was to investigate the effect of the experience curve on changes in trueness when a patient's complete dental arch is scanned. Twenty dental hygienists with more than 3 years of experience in dental clinical practice (group 1 had 3 to 5 years; group 2 had >6 years) were recruited to learn to operate 2 intraoral scanner systems. All learners scanned the assigned patient's oral cavity 10 times during the experience sessions. Precision was calculated as the mean deviation among all superimposition combinations from the 10 scanned data sets of each learner [n=10C2=45]. Trueness was evaluated by superimposing the 10 consecutive intraoral scan data onto the impression scan data from each patient's rubber impression body (n=10). The acquired images were processed and analyzed using a 3-dimensional analysis software. For statistical analysis, the independent 2-sample t test and repeated measures ANOVA were performed (α=.05). The mean precision of the Trios scanner was greater than that of the iTero (Trios, 52.30 μm; iTero, 60.46 μm; P<.01). The iTero group showed an improvement in trueness upon repeated experience (P<.05), whereas the Trios group did not (P>.05). In the iTero group but not in the Trios group, the length of clinical experience influenced the change of trueness as a result of repeated experience (P<.05). In terms of the scanned region, the results for trueness were better for the maxillary arch than the mandibular arch with repeated scanning in the iTero group (P<.05). The single-image based system required repeated learning sessions for effective clinical application. The newer system offered better trueness and precision and was less likely to be influenced by the length of clinical career or the region being scanned.


Toward Personalized Lymphoma Immunotherapy: Identification of Common Driver Mutations Recognized by Patient CD8+ T Cells.
A fundamental challenge in the era of next-generation sequencing (NGS) is to design effective treatments tailored to the mutational profiles of tumors. Many newly discovered cancer mutations are difficult to target pharmacologically; however, T-cell-based therapies may provide a valuable alternative owing to the exquisite sensitivity and specificity of antigen recognition. To explore this concept, we assessed the immunogenicity of a panel of genes that are common sites of driver mutations in follicular lymphoma, an immunologically sensitive yet currently incurable disease. Exon capture and NGS were used to interrogate tumor samples from 53 patients with follicular lymphoma for mutations in 10 frequently mutated genes. For 13 patients, predicted mutant peptides and proteins were evaluated for recognition by autologous peripheral blood T cells after in vitro priming. Mutations were identified in 1-5 genes in 81% (43/53) of tumor samples. Autologous, mutation-specific CD8(+) T cells were identified in 23% (3/13) of evaluated cases. T-cell responses were directed toward putative driver mutations in CREBBP and MEF2B. Responding T cells showed exquisite specificity for mutant versus wild-type proteins and recognized lymphoma cells expressing the appropriate mutations. Responding T cells appeared to be from the naïve repertoire, as they were found at low frequencies and only at single time points in each patient. Patients with follicular lymphoma harbor rare yet functionally competent CD8(+) T cells specific for recurrent mutations. Our results support the concept of using NGS to design individualized immunotherapies targeting common driver mutations in follicular lymphoma and other malignancies. Clin Cancer Res; 22(9); 2226-36. ©2015 AACR.


Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element.
Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we detected distinct folding patterns at the developmentally controlled β-globin locus. Specifically, new fetal stage-specific contacts were uncovered between a region separating the fetal (γ) and adult (δ and β) globin genes (encompassing the HBBP1 and BGLT3 noncoding genes) and two distal chromosomal sites (HS5 and 3'HS1) that flank the locus. In contrast, in adult cells, the HBBP1-BGLT3 region contacts the embryonic ε-globin gene, physically separating the fetal globin genes from the enhancer (locus control region [LCR]). Deletion of the HBBP1 region in adult cells alters contact landscapes in ways more closely resembling those of fetal cells, including increased LCR-γ-globin contacts. These changes are accompanied by strong increases in γ-globin transcription. Notably, the effects of HBBP1 removal on chromatin architecture and gene expression closely mimic those of deleting the fetal globin repressor BCL11A, implicating BCL11A in the function of the HBBP1 region. Our results uncover a new critical regulatory region as a potential target for therapeutic genome editing for hemoglobinopathies and highlight the power of chromosome conformation analysis in discovering new cis control elements.


De novo origins of multicellularity in response to predation.
The transition from unicellular to multicellular life was one of a few major events in the history of life that created new opportunities for more complex biological systems to evolve. Predation is hypothesized as one selective pressure that may have driven the evolution of multicellularity. Here we show that de novo origins of simple multicellularity can evolve in response to predation. We subjected outcrossed populations of the unicellular green alga Chlamydomonas reinhardtii to selection by the filter-feeding predator Paramecium tetraurelia. Two of five experimental populations evolved multicellular structures not observed in unselected control populations within ~750 asexual generations. Considerable variation exists in the evolved multicellular life cycles, with both cell number and propagule size varying among isolates. Survival assays show that evolved multicellular traits provide effective protection against predation. These results support the hypothesis that selection imposed by predators may have played a role in some origins of multicellularity.


Small amounts of alpha-myosin heavy chain isoform expression significantly increase power output of rat cardiac myocyte fragments.
Myocardial performance is likely affected by the relative expression of the two myosin heavy chain (MyHC) isoforms, namely alpha-MyHC and beta-MyHC. The relative expression of each isoform is regulated developmentally and in pathophysiological states. Many pathophysiological states are associated with small shifts in the relative expression of each MyHC isoform, yet the functional consequence of these shifts remains unclear. The purpose of this study was to determine the functional effect of a small shift in the relative expression of alpha-MyHC. To this end, power output was measured in rat cardiac myocyte fragments that expressed approximately 12% alpha-MyHC and in myocyte fragments that expressed approximately 0% alpha-MyHC, as determined in the same cells by SDS-PAGE analysis after mechanical experiments. Myocyte fragments expressing approximately 12% alpha-MyHC developed approximately 52% greater peak normalized power output than myocyte fragments expressing approximately 0% alpha-MyHC. These results indicate that small amounts of alpha-MyHC expression significantly augment myocyte power output.


NIR Laser Photobiomodulation Induces Neuroprotection in an In Vitro Model of Cerebral Hypoxia/Ischemia.
Brain photobiomodulation (PBM) is an innovative treatment for a variety of neurological conditions, including cerebral ischemia. However, the capability of PBM for ischemic stroke needs to be further explored and its mechanisms of action remain currently unclear. The aim of the present research was to identify a treatment protocol capable of inducing neuroprotection and to investigate the molecular mechanisms activated by a dual-wavelength near infrared (NIR) laser source in an organotypic hippocampal slice model of hypoxia/ischemia. Hippocampal slices were exposed to oxygen and glucose deprivation (OGD) for 30 min followed by NIR laser light (fluence 3.71, 7.42, or 14.84 J/cm2; wavelengths 808 nm and 905 nm) delivered immediately or 30 min or 60 min after OGD, in order to establish a therapeutic window. Neuronal injury was assessed by propidium iodide fluorescence 24 h later. Our results show that NIR laser irradiation attenuates OGD neurotoxicity once applied immediately or 30 min after OGD. Western blot analysis of proteins involved in neuroinflammation (iNOS, COX-2, NFkB subunit p65, and Bcl-2) and in glutamatergic-mediated synaptic activity (vGluT1, EAAT2, GluN1, and PSD95) showed that the protein modifications induced by OGD were reverted by NIR laser application. Moreover, CA1 confocal microscopy revealed that the profound morphological changes induced by OGD were reverted by NIR laser radiation. In conclusion, NIR laser radiation attenuates OGD neurotoxicity in organotypic hippocampal slices through attenuation of inflammatory mechanisms. These findings shed light on molecular definition of NIR neuroprotective mechanisms, thus underlining the potential benefit of this technique for the treatment of cerebral ischemia.


Dietary and Lifestyle Risk Factors Associated with Incident Kidney Stones in Men and Women.
Several dietary and lifestyle factors are associated with a higher risk of kidney stones. We estimated the population attributable fraction and the number needed to prevent for modifiable risk factors, including body mass index, fluid intake, DASH (Dietary Approaches to Stop Hypertension) style diet, dietary calcium intake and sugar sweetened beverage intake. We used data on the HPFS (Health Professionals Follow-Up Study) cohort and the NHS (Nurses' Health Study) I and II cohorts. Information was obtained from validated questionnaires. Poisson regression models adjusted for potential confounders were used to estimate the association of each risk factor with the development of incident kidney stones and calculate the population attributable fraction and the number needed to prevent. The study included 192,126 participants who contributed a total of 3,259,313 person-years of followup, during which an incident kidney stone developed in 6,449 participants. All modifiable risk factors were independently associated with incident stones in each cohort. The population attributable fraction ranged from 4.4% for a higher intake of sugar sweetened beverages to 26.0% for a lower fluid intake. The population attributable fraction for all 5 risk factors combined was 57.0% in HPFS, 55.2% in NHS I and 55.1% in NHS II. The number needed to prevent during 10 years ranged from 67 for lower fluid intake to 556 for lower dietary calcium intake. Five modifiable risk factors accounted for more than 50% of incident kidney stones in 3 large prospective cohorts. Assuming a causal relation, our estimates suggest that preventive measures aimed at reducing those factors could substantially decrease the burden of kidney stones in the general population.


Obesity increases length of stay and direct medical costs in total hip arthroplasty.
The number of obese patients undergoing THA is increasing. Previous studies have shown that obesity is associated with an increased likelihood of complications after THA, but there is little information regarding the impact of obesity on medical resource use and direct medical costs in THA. We sought to examine the relationship between obesity, length of stay, and direct medical costs in a large cohort of patients undergoing THAs. The study included 8973 patients who had undergone 6410 primary and 2563 revision THAs at a large US medical center between January 1, 2000, and September 31, 2008. Patients with bilateral procedures within 90 days after index admission and patients with acute trauma were excluded. Data regarding clinical, surgical characteristics, and complications were obtained from the original medical records and the institutional joint registry. Patients were classified into eight groups based on their BMI at the time of surgery. Direct medical costs were calculated by using standardized, inflation-adjusted costs for services and procedures billed during hospitalization and the 90-day window. Study end points were hospital length of stay, direct medical costs during hospitalization, and the 90-day window. End points were compared across the eight BMI categories in multivariable risk-adjusted linear regression models. Mean length of stay and the direct medical costs were lowest for patients with a BMI of 25 to 35 kg/m(2). Increasing BMI was associated with longer hospital stays and costs. Every five-unit increase in BMI beyond 30 kg/m(2) was associated with approximately USD $500 higher hospital costs and USD $900 higher 90-day costs in primary THA (p = 0.0001), which corresponded to 5% higher costs. The cost increase associated with BMI was greater in the revision THA cohort where every five-unit increase in BMI beyond 30 kg/m(2) was associated with approximately USD $800 higher hospital costs and USD $1500 higher 90-day costs. These estimates remained unchanged after adjusting for comorbidities or complications. Obesity is associated with longer hospital stays and higher costs in THA. The significant effect of obesity on costs persists even among patients without comorbidities but the increased costs associated with obesity may be balanced by the potential benefits of THA in the obese. Increasing prevalence of obesity likely contributes to the increasing financial burden of THA worldwide. Level IV, economic and decision analyses. See the Instructions for Authors for a complete description of levels of evidence.


The evolution of labile traits in sex- and age-structured populations.
Many quantitative traits are labile (e.g. somatic growth rate, reproductive timing and investment), varying over the life cycle as a result of behavioural adaptation, developmental processes and plastic responses to the environment. At the population level, selection can alter the distribution of such traits across age classes and among generations. Despite a growing body of theoretical research exploring the evolutionary dynamics of labile traits, a data-driven framework for incorporating such traits into demographic models has not yet been developed. Integral projection models (IPMs) are increasingly being used to understand the interplay between changes in labile characters, life histories and population dynamics. One limitation of the IPM approach is that it relies on phenotypic associations between parents and offspring traits to capture inheritance. However, it is well-established that many different processes may drive these associations, and currently, no clear consensus has emerged on how to model micro-evolutionary dynamics in an IPM framework. We show how to embed quantitative genetic models of inheritance of labile traits into age-structured, two-sex models that resemble standard IPMs. Commonly used statistical tools such as GLMs and their mixed model counterparts can then be used for model parameterization. We illustrate the methodology through development of a simple model of egg-laying date evolution, parameterized using data from a population of Great tits (Parus major). We demonstrate how our framework can be used to project the joint dynamics of species' traits and population density. We then develop a simple extension of the age-structured Price equation (ASPE) for two-sex populations, and apply this to examine the age-specific contributions of different processes to change in the mean phenotype and breeding value. The data-driven framework we outline here has the potential to facilitate greater insight into the nature of selection and its consequences in settings where focal traits vary over the lifetime through ontogeny, behavioural adaptation and phenotypic plasticity, as well as providing a potential bridge between theoretical and empirical studies of labile trait variation.


Neoadjuvant Therapy for Rectal Cancer Affects Lymph Node Yield and Status Without Clear Implications on Outcome: The Case for Eliminating a Metric and Using Preoperative Staging to Guide Therapy.
Nodal status has long been considered pivotal to oncologic care, staging, and management. This has resulted in the establishment of rudimentary metrics regarding adequate lymph node yield in colon and rectal cancers for accurate cancer staging. In the era of neoadjuvant treatment, the implications of lymph node yield and status on patient outcomes remains unclear. This study included 1,680 patients with locally advanced rectal cancer from the NCCN prospective oncology database stratified into 3 groups based on preoperative therapy received: no neoadjuvant therapy, neoadjuvant chemoradiation, and neoadjuvant chemotherapy. Clinicopathologic characteristics and survival were compared between the groups, with univariate and multivariate analyses undertaken. The clinicopathologic characteristics demonstrated statistically significant differences and heterogeneity among the 3 groups. The neoadjuvant chemoradiation group demonstrated the statistically lowest median lymph node yield (n=15) compared with 17 and 18 for no-neoadjuvant and neoadjuvant chemotherapy, respectively (P<.0001). Neoadjuvant treatment did impact survival, with chemoradiation demonstrating increased median overall survival of 42.7 compared with 37.3 and 26.6 months for neoadjuvant chemotherapy and no-neoadjuvant therapy, respectively (P<.0001). Patients with a yield of fewer than 12 lymph nodes had improved median overall survival of 43.3 months compared with 36.6 months in patients with 12 or more lymph nodes (P=.009). Multivariate analysis demonstrated that neither node yield nor status were predictors for overall survival. This analysis reiterates that nodal yield in rectal cancer is multifactorial, with neoadjuvant therapy being a significant factor. Node yield and status were not significant predictors of overall survival. A nodal metric may not be clinically relevant in the era of neoadjuvant therapy, and guidelines for perioperative therapy may need reconsideration.


Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis.
Necrotizing enterocolitis (NEC), the leading cause of gastrointestinal death from gastrointestinal disease in preterm infants, is characterized by exaggerated TLR4 signaling and decreased enterocyte proliferation through unknown mechanisms. Given the importance of beta-catenin in regulating proliferation of many cell types, we hypothesize that TLR4 impairs enterocyte proliferation in NEC via impaired beta-catenin signaling. Enterocyte proliferation was detected in IEC-6 cells or in ileum or colon from wild-type, TLR4-mutant, or TLR4(-/-) mice after induction of NEC or endotoxemia. beta-Catenin signaling was assessed by cell fractionation or immunoconfocal microscopy to detect its nuclear translocation. Activation and inhibition of beta-catenin were achieved via cDNA or small interfering RNA, respectively. TLR4 in the intestinal mucosa was inhibited with adenoviruses expressing dominant-negative TLR4. TLR4 activation significantly impaired enterocyte proliferation in the ileum but not colon in newborn but not adult mice and in IEC-6 enterocytes. beta-Catenin activation reversed these effects in vitro. To determine the mechanisms involved, TLR4 activation phosphorylated the upstream inhibitory kinase GSK3beta, causing beta-catenin degradation. NEC in both mouse and humans was associated with decreased beta-catenin and increased mucosal GSK3beta expression. Strikingly, the inhibition of enterocyte beta-catenin signaling in NEC could be reversed, and enterocyte proliferation restored, through adenoviral-mediated inhibition of TLR4 signaling in the small intestinal mucosa. We now report a novel pathway linking TLR4 with inhibition of beta-catenin signaling via GSK3beta activation, leading to reduced enterocyte proliferation in vitro and in vivo. These data provide additional insights into the pathogenesis of diseases of intestinal inflammation such as NEC.


Clinical and sero-molecular characterization of Escherichia coli with an emphasis on hybrid strain in healthy and diarrheic neonatal calves in Egypt.
The present study was carried out to characterize pathogenic E. coli in apparently healthy and diarrheic neonatal calves with special reference to the hybrid E. coli strains and evaluate their clinical and hematobiochemical consequences. One hundred and seventy calves (age 1-30 days) were divided into two groups: apparently healthy (n = 70) and diarrheic (n=100). Animals were subjected to thorough clinical, hematobiochemical and bacteriological examinations. Clinically, diarrheic calves showed various degree of diarrhea with the presence of cardinal signs of dehydration in moderate and severe cases. There was a significant increase (p<0.05) in the hemogram parameters with uremia and hyperkalemia in calves with severe diarrhea. The O-H serotyping of cultural and biochemically positive isolates identified 31 isolates belonging to 12 serotypes including O44:H18, O55:H7, O146:H21, O113:H4, O121:H7, O26:H11, O91:H21, O111:H2, O8, O127: H6, O86 and O128:H2. Molecular characterization of E. coli isolates on three toxin genes: heat-stable enterotoxin (sta), shiga toxin type 1 and 2 (stx1 and stx2) revealed two well-known pathotypes (EPEC O44:H18, O55:H7, O146:H21, O113:H4, O121:H7 and EHEC O26:H11 O91:H21 O111:H2) with high frequency of enterohemorrhagic E. coli (EHEC). Molecular analysis also showed a number of E. coli isolates that carry sta and stx1 or sta and stx2 gene and belonged to O8, and O127:H6, O86 and O128:H2. These isolates were identified as hybrid E. coli strains (ETEC-STEC) and found in both apparently healthy and diarrheic calves. In conclusion, the present study identified high frequency of pathogenic E. coli in both apparently healthy and diarrheic calves. Serological and molecular analysis of E. coli isolates showed that high frequency of EHEC and presence of a new phenotype, STEC-ETEC hybrid, revealing their importance in the etiopathogenesis of diarrhea in calves and reinforcing the role of these animals as a reservoir of potentially pathogenic E. coli for humans.


Death and survival during the 1994 genocide in Rwanda.
This paper reports a quantitative study of the genocide in the prefecture of Kibuye in western Rwanda in 1994. It uses a database produced from a house-to-house survey of victims by the organization of genocide survivors, Ibuka. For a total of 59,050 victims of the genocide, data were collected on age, sex, occupation, commune of residence before the genocide, and place and date of death. An analysis conducted for one commune (Mabanza), showed that the chance of surviving the genocide was higher in those sectors of the commune where the Tutsi population did not congregate at a football stadium in Kibuye. Those who went to a mountainous area and defended themselves were almost the only Tutsi still alive in the prefecture after the month of April 1994. Other determinants of survival included age, sex, and occupation. The number of deaths each day while the killing lasted is estimated for the whole of the prefecture.


Burned forests impact water supplies.
Wildland fire impacts on surface freshwater resources have not previously been measured, nor factored into regional water management strategies. But, large wildland fires are increasing and raise concerns about fire impacts on potable water. Here we synthesize long-term records of wildland fire, climate, and river flow for 168 locations across the United States. We show that annual river flow changed in 32 locations, where more than 19% of the basin area was burned. Wildland fires enhanced annual river flow in the western regions with a warm temperate or humid continental climate. Wildland fires increased annual river flow most in the semi-arid Lower Colorado region, in spite of frequent droughts in this region. In contrast, prescribed burns in the subtropical Southeast did not significantly alter river flow. These extremely variable outcomes offer new insights into the potential role of wildfire and prescribed fire in regional water resource management, under a changing climate.


Gene array analysis of neural crest cells identifies transcription factors necessary for direct conversion of embryonic fibroblasts into neural crest cells.
Neural crest cells (NC cells) are multipotent cells that emerge from the edge of the neural folds and migrate throughout the developing embryo. Although the gene regulatory network for generation of NC cells has been elucidated in detail, it has not been revealed which of the factors in the network are pivotal to directing NC identity. In this study we analyzed the gene expression profile of a pure NC subpopulation isolated from Sox10-IRES-Venus mice and investigated whether these genes played a key role in the direct conversion of Sox10-IRES-Venus mouse embryonic fibroblasts (MEFs) into NC cells. The comparative molecular profiles of NC cells and neural tube cells in 9.5-day embryos revealed genes including transcription factors selectively expressed in developing trunk NC cells. Among 25 NC cell-specific transcription factor genes tested, SOX10 and SOX9 were capable of converting MEFs into SOX10-positive (SOX10+) cells. The SOX10+ cells were then shown to differentiate into neurons, glial cells, smooth muscle cells, adipocytes and osteoblasts. These SOX10+ cells also showed limited self-renewal ability, suggesting that SOX10 and SOX9 directly converted MEFs into NC cells. Conversely, the remaining transcription factors, including well-known NC cell specifiers, were unable to convert MEFs into SOX10+ NC cells. These results suggest that SOX10 and SOX9 are the key factors necessary for the direct conversion of MEFs into NC cells.


Assessment of the influence of peripheral blood mononuclear cell stimulation with Streptococcus pneumoniae polysaccharides on expression of selected Toll-like receptors, activation markers and Fas antigen in patients with chronic lymphocytic leukemia.
Since 2012, both the 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPV23) have been recommended for pneumococcal infection prevention in patients with chronic lymphocytic leukemia (CLL). Available literature data indicate that leukemic cells may respond to the presence of pathogens through specific Toll-like receptors (TLR). The aim of the study was to assess the effect of in vitro PPV23 stimulation of peripheral blood mononuclear cells (PBMCs) on expression of TLR-2, TLR-4, CD25, CD69, and CD95 on the surface of CD3+ T cells and CD19+ B cells in CLL patients. A total of 30 previously untreated patients with CLL, stage 0 according to the Rai classification, were included in the study. PBMCs obtained from each patient were cultured with and without PPV23 antigens. After 24-, 48-, and 72 h cultures, the viable cells underwent labeling with fluorochrome-conjugated monoclonal antibodies, and were analyzed using a flow cytometer. Between 24 h and 72 h (p=0.002) stimulation with PPV23 and between 48 h and 72 h (p=0.034) stimulation with PPV23 the frequencies of CD3+TLR-2+ cells were diminished. Increase of the value of the percentage of CD19+CD69+ cells was observed after 24 h (p=0.003), 48 h (p=0.025) and 72 h (p=0.012) of stimulation with PPV23. Stimulation with PPV23 led to an increase of the percentage of CD19+CD95+ cells after 24 h (p=0.003), 48 h (p=0.015), and 72 h (p=0.006). We found that both T and B cells respond to antigens of PPV23 by inducing TLR-dependent pathways, lymphocyte activation and CD95 expression.


Effect of scanline orientation on ventricular flow propagation: assessment using high frame-rate color Doppler echocardiography.
Color M-mode echocardiography has recently been utilized to describe diastolic flow propagation velocity (Vp) in the left ventricle. While increasing temporal resolution from 15 to 200 Hz, this M-mode technique requires the user to select a single scanline, potentially limiting quantification of Vp due to the complex three-dimensional inflow pattern. We previously performed computational fluid dynamics simulations to demonstrate the insignificance of the scanline orientation, however geometric complexity was limited. The purpose of this study was to utilize high frame-rate 2D color Doppler images to investigate the importance of scanline selection in patients for the quantification of Vp. 2D color Doppler images were digitally acquired at 50 frames/s in 6 subjects from the apical 4-chamber window (System 5, GE/Vingmed, Milwaukee, WI). Vp was determined for a set of scanlines positioned through 5 locations across the mitral annulus (from the anterior to posterior mitral annulus). An analysis of variance was performed to examine the differences in Vp as a function of scanline position. Vp was not effected by scanline position in sampled locations from the center of the mitral valve towards the posterior annulus. Although not statistically significant, there was a trend to slower propagation velocities on the anterior side of the valve (60.8 +/- 16.7 vs. 54.4 +/- 13.6 cm/s). This study clinically validates our previous numerical experiment showing that Vp is insensitive to small perturbations of the scanline through the mitral valve. However, further investigation is necessary to examine the impact of ventricular geometry in pathologies including dilated cardiomyopathy.


Two regions of mode selection in resonators with biprismlike elements.
A resonator structure in which one reflector is replaced by a biprismlike reflecting surface is investigated theoretically. It is shown that such a modification leads to two regions of parameters, each with different regimes of mode selection. The first region has an improved laser power output because of the nearly flat-top mode shape. In the second region the biprism is inverted, with the result that the main oscillating mode can be the first odd mode. The line singularity contained in such a mode is one example of singular beams that are employed in various fields, such as micromanipulators and advanced high-resolution metrology.


Use of Zernike polynomials for efficient estimation of orthonormal aberration coefficients over variable noncircular pupils.
An efficient way of estimating orthonormal aberration coefficients on variable noncircular pupils is proposed. The method is based on the fact that all necessary pieces of information for constructing orthonormal polynomials (via the Gram-Schmidt process) can be numerically obtained during a routine least-squares fit of Zernike polynomials to wavefront data. This allows the method to use the usual Zernike polynomial fitting with an additional procedure that swiftly estimates the desired orthonormal aberration coefficients without having to use the functional forms of orthonormal polynomials. It is also shown that the method naturally accounts for the pixelation effect of pupil geometries, intrinsic to recording wavefront data on imaging sensors (e.g., CCDs), making the coefficient estimate optimal over a given pixelated pupil geometry. With these features, the method can be ideal for real-time wavefront analysis over dynamically changing pupils, such as in the Hobby-Eberly Telescope (HET), which is otherwise inefficient with analytic methods used in past studies.


Oral steroid prophylaxis is effective in preventing esophageal strictures after large endoscopic resection.
Strictures are frequent complications of large endoscopic mucosal resections (EMR) and endoscopic submucosal dissections of the esophagus. Local or systemic steroid therapy has shown promise in the prevention of secondary stenosis. The aim of this study was to evaluate the safety and efficacy of systemic steroid therapy following endoscopic resection of at least hemi-circumferential esophageal mucosa. This was a single-center retrospective study in a tertiary center. We evaluated patients who were treated with oral steroids between July 2013 and September 2015, after undergoing a large EMR for Barrett's esophagus associated with dysplasia or carcinoma. The steroid protocol used was an initial dose of 30 mg prednisolone, tapered over 8 weeks. Exclusion criteria were a previous attempt at radiofrequency ablation or resection. Thirty-one patients (27 men) were analyzed: 13 with low-grade dysplasia Barrett's esophagus, 16 with in situ adenocarcinoma, 1 with pT1SM1 adenocarcinoma, and 1 with pT1SM2 adenocarcinoma. Twenty-eight resections (28/31) were completed (R0) in 1-3 sessions (median 2), while 3 resections were R1. The median length of Barrett's esophagus was C3M5 (range C0M2-C10M11) according to the Prague classification. The median follow up was 10 months (range 4-17), during which 4 patients (13%) developed a secondary stenosis. All stenoses were successfully treated by endoscopic dilation (range 1-4). No complications related to dilation or to the steroid therapy were observed. Our rate of secondary stricture was lower than expected, given the rates of 17-88% in published studies. Systemic oral steroid therapy seems to be effective in reducing potential esophageal stenosis after EMR. Complementary randomized studies are required to confirm whether systemic steroids are an effective primary prophylaxis for esophageal stenosis.


Acute worsening of CADASIL in a patient with COVID-19 infection: illustrative case.
Reports of cerebrovascular ischemia and stroke occurring as predominant neurological sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), are increasingly evident within the literature. While various pathophysiological mechanisms have been postulated, including hypercoagulability, endothelial invasion, and systemic inflammation, discrete mechanisms for viral neurotropism remain unclear and controversial. The authors present a unique case study of a 64-year-old male with acute COVID-19 infection and acute worsening of previously stable cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare heritable arteriopathy due to mutation in the Notch3 gene, which is critical for vascular development and tone. Delayed cranial neuropathies, brainstem fluid-attenuated inversion recovery signal, and enhancement of olfactory and vagus nerves on magnetic resonance neurography in this patient further support viral neurotropism via cranial nerves in addition to cerebral vasculature. To the authors' knowledge, this is the first case in the literature that not only demonstrates the consequences of COVID-19 infection in a patient with altered cerebrovascular autoregulation such as CADASIL but also highlights the tropism of SARS-CoV-2 for (1) cranial nerves as a mode of entry to the central nervous system and (2) vessels as a cause of cerebrovascular ischemia.


Right ventricular endomyocardial fibrosis - A case report.
Endomyocardial fibrosis (EMF) is a progressive type of restrictive cardiomyopathy. It affects inflow portion of right and/or left ventricle and apex. It is a neglected tropical disease. Here we report a rare case of right ventricular endomyocardial fibrosis. A 70-year-old female presented to us with history suggestive of right-sided heart failure of two months duration. There was no eosinophilia. Chest X-ray showed cardiomegaly. Echocardiogram showed dilated right atrium and obliteration of the apex of the right ventricle. A diagnosis of Right ventricular Endomyocardial fibrosis was made. She was treated with diuretics and anticoagulants and she improved.


Mapping out the solid waste generation and collection models: The case of Kampala City.
This paper presents a mapping of the waste collection systems in Kampala city, using geographical information system (GIS) ArcGIS mapping software. It discusses the existing models of waste collection to the final disposal destinations. It was found that food and yard wastes constitute 92.7% of the waste generated in Kampala. Recyclables and other special wastes constitute only 7.3% of the total waste, mainly because of the increased level of reuse and recycling activities. The generation rate of solid wastes was on average, 582, 169, 105, and 90 tons/day from poor areas, upscale wealthier areas, business centers, and market areas respectively. This tonnage of waste was collected, transported, and disposed of at the city landfill. The study found that in total, residential areas of poor people generate more waste than other categories stated earlier, mainly because of their large populations. In total, there were 133 unofficial temporary storage sites acknowledged by Kampala Capital City Authority (KCCA) but not formally designated, 59 illegal dump sites, and 35 officially recognized temporary waste storage locations. This paper presents large-scale data that can help with understanding the collection models and their influence on solid waste management in Kampala city, which could be used for similar cities in developing countries.


Laser-gain scanning microscopy: a new characterization technique for dopant engineered gain media.
We demonstrate an optical technique, called laser-gain scanning microscopy (LGSM), to map dopant concentration profiles in engineered laser gain-media. The performance and application range of this technique are exampled on a Nd(3+) concentration profile embedded in a YAG transparent ceramic sample. Concentration profiles measured by both LGSM and SIMS techniques are compared and agree to within 5% over three-orders of magnitude in Nd(3+) doping level, from 0.001 at.% to 0.9 at.%. One of the unique advantages of LGSM over common physical methods such as SIMS, XPS and EMPA, is the ability to correlate optical defects with the final doping profile.


Inbreeding effects on gene-specific DNA methylation among tissues of Chinook salmon.
Inbreeding depression is the loss of fitness resulting from the mating of genetically related individuals. Traditionally, the study of inbreeding depression focused on genetic effects, although recent research has identified DNA methylation as also having a role in inbreeding effects. Since inbreeding depression and DNA methylation change with age and environmental stress, DNA methylation is a likely candidate for the regulation of genes associated with inbreeding depression. Here, we use a targeted, multigene approach to assess methylation at 22 growth-, metabolic-, immune- and stress-related genes. We developed PCR-based DNA methylation assays to test the effects of intense inbreeding on intragenic gene-specific methylation in inbred and outbred Chinook salmon. Inbred fish had altered methylation at three genes, CK-1, GTIIBS and hsp70, suggesting that methylation changes associated with inbreeding depression are targeted to specific genes and are not whole-genome effects. While we did not find a significant inbreeding by age interaction, we found that DNA methylation generally increases with age, although methylation decreased with age in five genes, CK-1, IFN-ɣ, HNRNPL, hsc71 and FSHb, potentially due to environmental context and sexual maturation. As expected, we found methylation patterns differed among tissue types, highlighting the need for careful selection of target tissue for methylation studies. This study provides insight into the role of epigenetic effects on ageing, environmental response and tissue function in Chinook salmon and shows that methylation is a targeted and regulated cellular process. We provide the first evidence of epigenetically based inbreeding depression in vertebrates.


Category-based induction from similarity of neural activation.
The idea that similarity might be an engine of inductive inference dates back at least as far as David Hume. However, Hume's thesis is difficult to test without begging the question, since judgments of similarity may be infected by inferential processes. We present a one-parameter model of category-based induction that generates predictions about arbitrary statements of conditional probability over a predicate and a set of items. The prediction is based on the unconditional probabilities and similarities that characterize that predicate and those items. To test Hume's thesis, we collected brain activation from various regions of the ventral visual stream during a categorization task that did not invite comparison of categories. We then calculated the similarity of those activation patterns using a simple measure of vectorwise similarity and supplied those similarities to the model. The model's outputs correlated well with subjects' judgments of conditional probability. Our results represent a promising first step toward confirming Hume's thesis; similarity, assessed without reference to induction, may well drive inductive inference.


Exploring the Most Important Negative Life Events in Older Adults Bereaved of Child, Spouse, or Both.
Losing a child or a spouse is described as the worst of experiences. However, it is not known whether older adults bereaved of a child, spouse, or both child and spouse experience these losses as among the most important negative events in their lifetime. The aim of this study was to investigate whether the 1,437 older adults bereaved of a child, spouse, or both included in the southern part of the Swedish National Study of Aging and Care mentioned these losses when asked about their three most important negative life events. Gender differences in their choices of important negative life events were also explored. About 70% of those bereaved of a child or a spouse mentioned these losses as among their three most important negative life experiences. In the child-and-spouse-bereaved group, 48% mentioned both the loss of their child and spouse, while 40% mentioned either the loss of a child or a spouse. Gender differences were only found in the child-and-spouse-bereaved group, with a few more women mentioning the loss of the child but not the spouse, and the men showing the opposite pattern.


Pattern-reversal visual evoked potential. Method of analysis and results in multiple sclerosis.
A detailed method of analysis of the pattern-reversal visual evoked potential is presented. This method takes into account a number of parameters in addition to the latency of the major surface-positive component (P2) and has been tested in a group of 50 normal subjects and in 98 patients with established or suspected multiple sclerosis (MS). It was found that this more detailed form of analysis improved the detection rate of abnormal responses in the MS subjects particularly in those classified in the suspected category. The potential value of this form of analysis, particularly in clinical neurophysiology laboratories where the recording of visual evoked potentials is the only technique employed in the investigation of patients with suspected MS, is discussed.


A revised version of the Healthy Eating Index for the Brazilian population.
The revised version of the Brazilian Healthy Eating Index is an indicator of dietary quality developed according to current nutritional recommendations. Dietary data were obtained from a population-based survey, the 2003 Inquérito de Saúde e Alimentação (ISA - Health and Diet Survey)-Capital. The Revised Index consists of 12 components: nine food groups included in the 2006 Brazilian Dietary Guidelines, in which daily portions are expressed in terms of energy density; two nutrients (sodium and saturated fats), and SoFAAS (calories from solid fat, alcohol and added sugar). The Revised Brazilian Healthy Eating Index allows for the measurement of dietary risk factors for chronic diseases, evaluating and monitoring the diet at both individual and population levels.


Screening to prevent fragility fractures among adults 40 years and older in primary care: protocol for a systematic review.
To inform recommendations by the Canadian Task Force on Preventive Health Care by systematically reviewing direct evidence on the effectiveness and acceptability of screening adults 40 years and older in primary care to reduce fragility fractures and related mortality and morbidity, and indirect evidence on the accuracy of fracture risk prediction tools. Evidence on the benefits and harms of pharmacological treatment will be reviewed, if needed to meaningfully influence the Task Force's decision-making. A modified update of an existing systematic review will evaluate screening effectiveness, the accuracy of screening tools, and treatment benefits. For treatment harms, we will integrate studies from existing systematic reviews. A de novo review on acceptability will be conducted. Peer-reviewed searches (Medline, Embase, Cochrane Library, PsycINFO [acceptability only]), grey literature, and hand searches of reviews and included studies will update the literature. Based on pre-specified criteria, we will screen studies for inclusion following a liberal-accelerated approach. Final inclusion will be based on consensus. Data extraction for study results will be performed independently by two reviewers while other data will be verified by a second reviewer; there may be some reliance on extracted data from the existing reviews. The risk of bias assessments reported in the existing reviews will be verified and for new studies will be performed independently. When appropriate, results will be pooled using either pairwise random effects meta-analysis (screening and treatment) or restricted maximum likelihood estimation with Hartun-Knapp-Sidnick-Jonkman correction (risk prediction model calibration). Subgroups of interest to explain heterogeneity are age, sex, and menopausal status. Two independent reviewers will rate the certainty of evidence using the GRADE approach, with consensus reached for each outcome rated as critical or important by the Task Force. Since the publication of other guidance in Canada, new trials have been published that are likely to improve understanding of screening in primary care settings to prevent fragility fractures. A systematic review is required to inform updated recommendations that align with the current evidence base.


Using registry data to characterize the incidence and causes of blindness in Oregon.
In the United States, there is no reliable data to describe the prevalence of eye diseases leading to visual impairment and little active surveillance to address this knowledge gap. Data that is readily available from many state blind registries may provide helpful information on trends and causes of blindness. We analyzed new registrations with the Oregon Commission for the Blind (OCB) and Oregon State Department of Administrative Services (DAS) from 1961 to 2016 for causes of and trends in blindness. Persons with blindness self-refer into the OCB registry and the Oregon State Department of Administrative Services (DAS) includes those receiving social security disability financial support and other state services. Data for 9,273 blind persons registered were analyzed. The most frequent causes of blindness were age related macular degeneration (AMD) 3,308 (38%), followed by diabetic retinopathy (DR) 729 (8%), congenital conditions 697 (8%), optic nerve atrophy 611 (7%), glaucoma 549 (6%), retinitis pigmentosa 546 (6%), retinopathy of prematurity192 (2%), cataract 180 (2%), and trauma 174 (2%). The mean age of onset of blindness was younger for Blacks (31 years) and Hispanics (33 years) than for Whites (44 years). Analysis of state-based registries can provide useful and locally relevant vision and eye health data where little information is otherwise available.


The impact of ART scale upon health workers: evidence from two South African districts.
This study explores the effects of antiretroviral treatment (ART) programmes on health-care human resources in South Africa. The study included two parts, a questionnaire-based survey of 269 health workers published earlier and a qualitative study of 21 purposively selected health practitioners involved in ART scale up. Contrary to what has been presented in literature, our survey showed that health workers in ART programmes experienced higher levels of morale, lower stress, lower sickness absenteeism and higher levels of job satisfaction. This paper uses qualitative data to provide insights into the working environment of ART workers and examines some possible explanations for our survey findings. The key factors that contribute to the different perception of working environment by ART workers identified in this study include bringing hope to patients, delaying deaths, acquiring training and the ability to better manage and monitor the disease.


Hippocampal place cells encode intended destination, and not a discriminative stimulus, in a conditional T-maze task.
The firing of hippocampal place cells encodes instantaneous location but can also reflect where the animal is heading (prospective firing), or where it has just come from (retrospective firing). The current experiment sought to explicitly control the prospective firing of place cells with a visual discriminada in a T-maze. Rats were trained to associate a specific visual stimulus (e.g., a flashing light) with the occurrence of reward in a specific location (e.g., the left arm of the T). A different visual stimulus (e.g., a constant light) signaled the availability of reward in the opposite arm of the T. After this discrimination had been acquired, rats were implanted with electrodes in the CA1 layer of the hippocampus. Place cells were then identified and recorded as the animals performed the discrimination task, and the presentation of the visual stimulus was manipulated. A subset of CA1 place cells fired at different rates on the central stem of the T depending on the animal's intended destination, but this conditional or prospective firing was independent of the visual discriminative stimulus. The firing rate of some place cells was, however, modulated by changes in the timing of presentation of the visual stimulus. Thus, place cells fired prospectively, but this firing did not appear to be controlled, directly, by a salient visual stimulus that controlled behavior.


A randomized controlled trial to compare cure and relapse rate of paucibacillary multidrug therapy with monthly rifampicin, ofloxacin, and minocycline among paucibacillary leprosy patients in Agra District, India.
To study cure rate and relapse rate of standard World Health Organization paucibacillary multidrug therapy (PB-MDT) with monthly rifampicin, ofloxacin, and minocycline for six months (ROM-6) among paucibacillary leprosy patients. A total of 268 patients, detected during active search in Agra district during 2001-2004, who had paucibacillary (PB) leprosy having 1-5 skin lesions and/or one nerve thickening/tenderness, were allocated, using random number tables, to two treatment groups; PB-MDT and ROM-6. On the first day of the month, dose of PB-MDT and of the ROM were given under supervision for 6 months. After completion of drug therapy, patients were followed every 6 months for first 5 years and later annually for next 3 years for monitoring disease status, cure rates, reactions and relapses. Cηi σθuαρε test was used to compare relapse rates. The cure rate at 2 years was 99% in ROM-6 and 97.0% in PB-MDT group, of those who completed treatment and the difference was statistically not significant. At 5 years, only 88 patients in PB-MDT group and 90 patients in ROM-6 group could be followed; all were observed to be cured. However, during the period of 5-8 years, 3 of 67 patients in PB-MDT group and 1 of 73 in ROM-6 group were observed to have relapsed. In all, 10 relapses were noted (3 in ROM-6 and 7 in PB-MDT group) giving a relapse rate of 1.10/100 person years in PB-MDT and 0.435/100 person years in ROM groups (P = 0.053 ; statistically not significant). Of the 10 relapses, 5 occurred within 5 years (3 in PB-MDT group and 2 in ROM-6), 4 during 5-8 years (3 in PB-MDT and 1 in ROM-6), and 1 occurred in MDT group after 8 years. A number of patients were lost to follow up after release from treatment and thus actual number of relapses in the study could not be assessed. Additionally, diagnosis was purely clinical and histology could not be done for reasons related to functional difficulties in the field. The study shows that PB-MDT and ROM-6 have almost similar acceptability, cure rate and relapse rate.


A new twist on sea silk: the peculiar protein ultrastructure of fan shell and pearl oyster byssus.
Numerous mussel species produce byssal threads - tough proteinaceous fibers, which anchor mussels in aquatic habitats. Byssal threads from Mytilus species, which are comprised of modified collagen proteins - have become a veritable archetype for bio-inspired polymers due to their self-healing properties. However, threads from different species are comparatively much less understood. In particular, the byssus of Pinna nobilis comprises thousands of fine fibers utilized by humans for millennia to fashion lightweight golden fabrics known as sea silk. P. nobilis is very different from Mytilus from an ecological, morphological and evolutionary point of view and it stands to reason that the structure-function relationships of its byssus are distinct. Here, we performed compositional analysis, X-ray diffraction (XRD) and transmission electron microscopy (TEM) to investigate byssal threads of P. nobilis, as well as a closely related bivalve species (Atrina pectinata) and a distantly related one (Pinctada fucata). This comparative investigation revealed that all three threads share a similar molecular superstructure comprised of globular proteins organized helically into nanofibrils, which is completely distinct from the Mytilus thread ultrastructure, and more akin to the supramolecular organization of bacterial pili and F-actin. This unexpected discovery hints at a possible divergence in byssus evolution in Pinnidae mussels, perhaps related to selective pressures in their respective ecological niches.


Halothane hepatitis in an animal model: time course of hepatic damage.
The present study extends previous reports of hepatic damage 24 h after halothane anaesthesia in the phenobarbitone pretreated hypoxic rat model by fully characterizing the lesion during the time course of its onset and recovery. Phenobarbitone treated animals exposed to halothane (1% for 2 h in 14% inspired oxygen) were killed 1, 2, 4, 6, 12 and 24 h and 2, 3, 5, 10, 15 and 30 days after commencement of the anaesthetic period. Blood was collected 1 day before the administration of halothane and at the time of killing for determination of serum alanine aminotransferase (ALT), a biochemical index of hepatic damage. Liver tissue was obtained immediately at post-mortem for histological examination. Serum ALT was increased at the end of the anaesthetic period, i.e. 2 h, with peak levels occurring at 12-24 h and remaining elevated for 3 days after exposure. Minor changes in liver histology were evident at 2 h in 50% of the animals and by 6 h all animals had mild hepatic injury. The extent of the necrosis was maximal at 24 h and this was sustained until 3 days. By 5 days after exposure minimal evidence of liver damage was observed and animals killed at 30 days had morphologically normal livers. Elevation of serum ALT or changes in liver histology were not observed in other treatment groups. The early onset of damage at 2-6 h is in keeping with direct hepatotoxicity associated with the biotransformation of halothane.


World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia - a short version for primary care.
Schizophrenia is a severe mental disorder and many patients are treated in primary care settings. Apart from the pharmacological management of disease-associated symptoms, the detection and treatment of side effects is of the utmost importance in clinical practice. The purpose of this publication is to offer relevant evidence-based recommendations for the biological treatment of schizophrenia in primary care. This publication is a short and practice-oriented summary of Parts I-III of the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia. The recommendations were developed by the authors and consented by a task force of international experts. Guideline recommendations are based on randomized-controlled trials and supplemented with non-randomized trials and meta-analyses where necessary. Antipsychotics of different chemical classes are the first-line pharmacological treatments for schizophrenia. Specific circumstances (e.g., suicidality, depression, substance dependence) may need additional treatment options. The pharmacological and non-pharmacological management of side effects is of crucial importance for the long-term treatment in all settings of the healthcare system. This summary of the three available evidence-based guidelines has the potential to support clinical decisions and can improve treatment of schizophrenia in primary care settings.


The sources and mechanisms of bioactive ingredients in coffee.
Coffee bioactive components include caffeine, chlorogenic acids (CGAs), trigonelline, tryptophan alkaloids, diterpenes and other secondary metabolites. During roasting, coffee metabolites undergo complex Maillard reactions, producing melanoidins and other degradation products, the most controversial among which is acrylamide, an ingredient widely found in baked food and listed as a second class carcinogen. Green and roasted coffee ingredients have good biological activities for the prevention of cardiovascular disease, and antibacterial, anti-diabetic, neuroprotection, and anti-cancer activities. To better understand the relationship between coffee ingredients and human health, and to effectively use the active ingredients, it is essential to understand the sources of coffee active ingredients and their mechanisms of action in the organism. This paper systematizes the available information and provides a critical overview of the sources of coffee active ingredients and the mechanisms of action in vivo or in vitro, and their combined effects on common human diseases.


The effects of an individualized exercise intervention on body composition in breast cancer patients undergoing treatment.
Changes in metabolism have been reported in the majority of patients undergoing cancer treatment, and these are usually characterized by progressive change in body composition. The effects of aerobic exercise programs to combat the cancer and cancer treatment-related side effects, which include the negative changes in body composition, have been extensively reported in the literature. However, few resistance exercise intervention studies have hypothesized that breast cancer patients might benefit from this type of exercise. The purpose of this study was to determine whether exercise protocols that emphasize resistance training would change body composition and strength in breast cancer patients undergoing treatment. Randomized controlled trial, at the Campus Recreation Center and Rocky Mountain Cancer Rehabilitation Institute of the University of Northern Colorado, and the North Colorado Medical Center. Twenty inactive breast cancer patients were randomly assigned to a 21-week exercise group (n = 10) or a control group (n = 10). The exercise group trained at low to moderate intensity for 60 minutes on two days/week. The primary outcome measurements included body composition (skinfold method) and muscle strength (one repetition maximum). Significant differences in lean body mass, body fat and strength (p = 0.004, p = 0.004, p = 0.025, respectively) were observed between the groups at the end of the study. The results suggest that exercise emphasizing resistance training promotes positive changes in body composition and strength in breast cancer patients undergoing treatment.


Food-web structure and ecosystem services: insights from the Serengeti.
The central organizing theme of this paper is to discuss the dynamics of the Serengeti grassland ecosystem from the perspective of recent developments in food-web theory. The seasonal rainfall patterns that characterize the East African climate create an annually oscillating, large-scale, spatial mosaic of feeding opportunities for the larger ungulates in the Serengeti; this in turn creates a significant annual variation in the food available for their predators. At a smaller spatial scale, periodic fires during the dry season create patches of highly nutritious grazing that are eaten in preference to the surrounding older patches of less palatable vegetation. The species interactions between herbivores and plants, and carnivores and herbivores, are hierarchically nested in the Serengeti food web, with the largest bodied consumers on each trophic level having the broadest diets that include species from a large variety of different habitats in the ecosystem. The different major habitats of the Serengeti are also used in a nested fashion; the highly nutritious forage of the short grass plains is available only to the larger migratory species for a few months each year. The longer grass areas, the woodlands and kopjes (large partially wooded rocky islands in the surrounding mosaic of grassland) contain species that are resident throughout the year; these species often have smaller body size and more specialized diets than the migratory species. Only the larger herbivores and carnivores obtain their nutrition from all the different major habitat types in the ecosystem. The net effect of this is to create a nested hierarchy of subchains of energy flow within the larger Serengeti food web; these flows are seasonally forced by rainfall and operate at different rates in different major branches of the web. The nested structure that couples sequential trophic levels together interacts with annual seasonal variation in the fast and slow chains of nutrient flow in a way that is likely to be central to the stability of the whole web. If the Serengeti is to be successfully conserved as a fully functioning ecosystem, then it is essential that the full diversity of natural habitats be maintained within the greater Serengeti ecosystem. The best way to do this is by controlling the external forces that threaten the boundaries of the ecosystem and by balancing the economic services the park provides between local, national and international needs. I conclude by discussing how the ecosystem services provided by the Serengeti are driven by species on different trophic levels. Tourism provides the largest financial revenue to the national economy, but it could be better organized to provide more sustained revenue to the park. Ultimately, ecotourism needs to be developed in ways that take lessons from the structure of the Serengeti food webs, and in ways that provide tangible benefits to people living around the park while also improving the experience of all visitors.


Synchrotron imaging of dentition provides insights into the biology of Hesperornis and Ichthyornis, the "last" toothed birds.
The dentitions of extinct organisms can provide pivotal information regarding their phylogenetic position, as well as paleobiology, diet, development, and growth. Extant birds are edentulous (toothless), but their closest relatives among stem birds, the Cretaceous Hesperornithiformes and Ichthyornithiformes, retained teeth. Despite their significant phylogenetic position immediately outside the avian crown group, the dentitions of these taxa have never been studied in detail. To obtain new insight into the biology of these 'last' toothed birds, we use cutting-edge visualisation techniques to describe their dentitions at unprecedented levels of detail, in particular propagation phase contrast x-ray synchrotron microtomography at high-resolution. Among other characteristics of tooth shape, growth, attachment, implantation, replacement, and dental tissue microstructures, revealed by these analyses, we find that tooth morphology and ornamentation differ greatly between the Hesperornithiformes and Ichthyornithiformes. We also highlight the first Old World, and youngest record of the major Mesozoic clade Ichthyornithiformes. Both taxa exhibit extremely thin and simple enamel. The extension rate of Hesperornis tooth dentine appears relatively high compared to non-avian dinosaurs. Root attachment is found for the first time to be fully thecodont via gomphosis in both taxa, but in Hesperornis secondary evolution led to teeth implantation in a groove, at least locally without a periodontal ligament. Dental replacement is shown to be lingual via a resorption pit in the root, in both taxa. Our results allow comparison with other archosaurs and also mammals, with implications regarding dental character evolution across amniotes. Some dental features of the 'last' toothed birds can be interpreted as functional adaptations related to diet and mode of predation, while others appear to be products of their peculiar phylogenetic heritage. The autapomorphic Hesperornis groove might have favoured firmer root attachment. These observations highlight complexity in the evolutionary history of tooth reduction in the avian lineage and also clarify alleged avian dental characteristics in the frame of a long-standing debate on bird origins. Finally, new hypotheses emerge that will possibly be tested by further analyses of avian teeth, for instance regarding dental replacement rates, or simplification and thinning of enamel throughout the course of early avian evolution.


Genetic depletion and pharmacological targeting of αv integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models.
Increased expression of αv integrins is frequently associated with tumor cell adhesion, migration, invasion and metastasis, and correlates with poor prognosis in breast cancer. However, the mechanism by which αv integrins can enhance breast cancer progression is still largely unclear. The effects of therapeutic targeting of αv integrins in breast cancer also have yet to be investigated. We knocked down αv integrin in MDA-MB-231 and MCF10A-M4 breast cancer cells, or treated these cells with the αv antagonist GLPG0187. The effects of αv integrin depletion on mesenchymal markers, transforming growth factor-β (TGF-β)/Smad signaling and TGF-β-induced target gene expression were analyzed in MDA-MB-231 cells by RNA analysis or Western blotting. The function of αv integrin on breast cancer cell migration was investigated by transwell assay in vitro, and its effect on breast cancer progression was assessed by both zebrafish and mouse xenografts in vivo. In the mouse model, GLPG0187 was administered separately, or in combination with the standard-of-care anti-resorptive agent zoledronate and the chemotherapeutic drug paclitaxel, to study the effects of combinational treatments on breast cancer metastasis. Genetic interference and pharmacological targeting of αv integrin with GLPG0187 in different breast cancer cell lines inhibited invasion and metastasis in the zebrafish or mouse xenograft model. Depletion of αv integrin in MDA-MB-231 cells inhibited the expression of mesenchymal markers and the TGF-β/Smad response. TGF-β induced αv integrin mRNA expression and αv integrin was required for TGF-β-induced breast cancer cell migration. Moreover, treatment of MDA-MB-231 cells with non-peptide RGD antagonist GLPG0187 decreased TGF-β signaling. In the mouse xenografts GLPG0187 inhibited the progression of bone metastasis. Maximum efficacy of inhibition of bone metastasis was achieved when GLPG0187 was combined with the standard-of-care metastatic breast cancer treatments. These findings show that αv integrin is required for efficient TGF-β/Smad signaling and TGF-β-induced breast cancer cell migration, and for maintaining a mesenchymal phenotype of the breast cancer cells. Our results also provide evidence that targeting αv integrin could be an effective therapeutic approach for treatment of breast cancer tumors and/or metastases that overexpress αv integrin.