SU-E-J-103: Characteristics of Bladder Wall Deformation as a Function of Bladder Filling.
ICRU report 83 recommends delineation of the wall for hollow organs such as the bladder. For image guided radiotherapy, there is no guidance as to how to delineate deformed walls as the filling of hollow organs change. This work investigates characteristics of bladder wall deformation as a function of bladder filling in a controlled process. CT images of a fresh pig bladder are obtained in-air with different bladder air fillings. A plastic hose inserted into and glued to the bladder neck forms an air-tight seal for filling with a syringe. At each air-filling level, a helical CT (90kV, 90mAs) of the bladder is obtained. The pixel size on all CT images is <0.5 mm. Images are imported into a commercial planning system for delineation and statistical evaluation. Bladder walls at each filling status are auto-contoured, then edited for quality assurance slice by slice. The auto-contouring threshold is selected to obtain consistent volumes of the resulting region-of-interest at each filling status. When the bladder wall interior volume increases by 360 cm3 from injecting air, the wall thickness decreases from 2.9 mm to 1.2 mm. The decrease in wall thickness is accompanied by a decrease in the wall CT number. For a pig bladder, the wall thickness decreases with increased air filling. The CT number (hence apparent density) of the volume decreases as the bladder expands. Further investigation is ongoing to determine if the apparent density decrease is real, due to CT reconstruction, or due to the bladder being in an air, rather than liquid environment. Characterization of hollow organ wall thickness variations may be important for image guided radiation therapy and organ wall dose evaluation. Support: P01CA116602.


Indirect evidence from DNA sequence diversity for genetic degeneration of the Y-chromosome in dioecious species of the plant Silene: the SlY4/SlX4 and DD44-X/DD44-Y gene pairs.
The action of natural selection is expected to reduce the effective population size of a nonrecombining chromosome, and this is thought to be the chief factor leading to genetic degeneration of Y-chromosomes, which cease recombining during their evolution from ordinary chromosomes. Low effective population size of Y chromosomes can be tested by studying DNA sequence diversity of Y-linked genes. In the dioecious plant, Silene latifolia, which has sex chromosomes, one comparison (SlX1 vs. SlY1) indeed finds lower Y diversity compared with the homologous X-linked gene, and one Y-linked gene with no X-linked homologue has lower species-wide diversity than a homologous autosomal copy (SlAp3Y vs. SlAp3A). To test whether this is a general pattern for Y-linked genes, we studied two further recently described X and Y homologous gene pairs in samples from several populations of S. latifolia and S. dioica. Diversity is reduced for both Y-linked genes, compared with their X-linked homologues. Our new data are analysed to show that the low Y effective size cannot be explained by different levels of gene flow for the X vs. the Y chromosomes, either between populations or between these closely related species. Thus, all four Y-linked genes that have now been studied in these plants (the two studied here, and two previously studied genes, have low diversity). This supports other evidence for an ongoing degeneration process in these species.


"Fleeting pulmonary infiltrates in allergic bronchopulmonary aspergillosis" Misdiagnosed as tuberculosis.
Allergic bronchopulmonary aspergillosis (ABPA) is underdiagnosed and underevaluated routinely because of clinical and radiological overlap with tuberculosis (TB), especially in tropical setting with high TB burden countries like India. ABPA is the best-recognized manifestation of Aspergillus-associated hypersensitivity to Aspergillus antigens in patients with long-standing atopic asthma. ABPA with varied clinical presentation has been reported to occur in 20% of asthmatic patients admitted to hospitals and in 5% of all rhinitis cases. In this case report, we documented middle age male with known asthma case for many years with constitutional symptoms such as cough, fever, and shortness of breath diagnosed as TB and received anti-TB treatment for 4 weeks. Finally, we confirmed as a case of ABPA and documented complete clinical and radiological response to medical treatment with antifungals and systemic corticosteroids.


Task analysis in neurosciences programme design--neurological problems in general practice.
Defining educational objectives is the key to achieving the goal of professional competence in students. The technique of task analysis was selected to determine components of competence in clinical neurology appropriate to the needs of primary care. A survey of neurological problems in general practice revealed that these constitute a significant proportion of consultations, and that teaching programmes have failed to provide the appropriate knowledge and skills to manage the commonest problems effectively. Consideration is given to innovations in curriculum and programme design whereby the graduating student might be more suitably prepared to give primary care.


Apparent remote synchronization of amplitudes: A demodulation and interference effect.
A form of "remote synchronization" was recently described, wherein amplitude fluctuations across a ring of non-identical, non-linear electronic oscillators become entrained into spatially-structured patterns. According to linear models and mutual information, synchronization and causality dip at a certain distance, then recover before eventually fading. Here, the underlying mechanism is finally elucidated through novel experiments and simulations. The system non-linearity is found to have a dual role: it supports chaotic dynamics, and it enables the energy exchange between the lower and higher sidebands of a predominant frequency. This frequency acts as carrier signal in an arrangement resembling standard amplitude modulation, wherein the lower sideband and the demodulated baseband signals spectrally overlap. Due to a spatially-dependent phase relationship, at a certain distance near-complete destructive interference occurs between them, causing the observed dip. Methods suitable for detecting non-trivial entrainment, such as transfer entropy and the auxiliary system approach, nevertheless, reveal that synchronization and causality actually decrease with distance monotonically. Remoteness is, therefore, arguably only apparent, as also reflected in the propagation of external perturbations. These results demonstrate a complex mechanism of dynamical interdependence, and exemplify how it can lead to incorrectly inferring synchronization and causality.


Differences in the Surgical Treatment of Lower Back Pain Among Spine Surgeons in the United States.
Electronic survey. To identify the surgical treatment patterns for low back pain (LBP), among U.S. spine surgeons. Specifically determine (1) differences in surgical treatment responses based on various demographic variables; (2) probability of disagreement based on surgeon subgroups. Multiple surgical and nonsurgical treatments exist for LBP. Without strong evidence or clear guidelines for the indications and optimal treatments, there is substantial variability in surgical treatments used. A total of 445 U.S. spine surgeons completed a survey of clinical and radiographic case scenarios on patients with mechanical LBP, no leg pain, and concordant discograms. Surgical treatment options included no surgery, anterior lumbar interbody fusion (ALIF), posterolateral fusion with pedicle screws, transforaminal/posterior lumbar interbody fusion (TLIF/PLIF), etc. Statistical significance was set at 0.01 to account for multiple comparisons. There was substantial clinical equipoise (∼75% disagreement) among surgeons on the approach to treat patients with LBP. Disagreement was highest in the southwest and lowest in the Midwest (82% vs. 69%, respectively); there was significantly lower disagreement among those in academic practices versus those in private/hybrid practices (56% vs.79%, respectively). Those in academic practices had approximately four times greater odds of choosing no surgery as compared to those in hybrid and private practices, who were more likely to choose ALIF or PLIF/TLIF. Those with fellowship training had approximately two times greater odds of selecting no surgery and four times greater odds of selecting ALIF as compared to those without fellowship training who were more likely to select TLIF/PLIF. Significant differences exist among U.S. spine surgeons in the treatment of LBP. These differences stem from geographical location of the practice, specialty, practice type, and fellowship training. Recognizing the substantial variability underlies the importance of additional studies aimed at identifying the proper indications and most cost-effective treatments for LBP. 3.


Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex.
Tuberous sclerosis is one of the few established medical causes of autism spectrum disorder and is a unique neurogenetic model for testing theories about the brain basis of the syndrome. We conducted a retrospective case study of the neuro-epileptic risk factors predisposing to autism spectrum disorder in individuals with tuberous sclerosis to test current neurobiological theories of autism spectrum disorder. We found that an autism spectrum disorder diagnosis was associated with the presence of cortical tubers in the temporal but not other lobes of the brain. Indeed, the presence of tubers in the temporal lobes appeared to be a necessary but not sufficient risk factor for the development of an autism spectrum disorder. However, contrary to the predictions of some theories, the location of tubers in specific regions of the temporal lobe, such as the superior temporal gyrus or the right temporal lobe, did not determine which individuals with temporal lobe tubers developed an autism spectrum disorder. Instead, outcome was associated with various indices of epileptic activity including evidence of temporal lobe epileptiform discharges on EEG, the age to onset of seizures in the first 3 years of life and a history of infantile spasms. The results indicated that individuals with tuberous sclerosis are at very high risk of developing an autism spectrum disorder when temporal lobe tubers are present and associated with temporal lobe epileptiform discharges and early-onset, persistent spasm-like seizures. These risk markers constitute useful clinical indicators of prognosis, but further research is required to identify the neurobiological mechanisms responsible for their association with outcome. Most especially, it will be important to test whether, as the findings suggest, there is a critical early stage of brain maturation during which temporal lobe epilepsy perturbs the development of brain systems that underpin 'social intelligence' and possibly other cognitive skills, thereby inducing an autism spectrum disorder.


Cognitive impairment and celiac disease.
To characterize the clinical, radiological, and electrophysiological laboratory profiles and histological features of patients who developed cognitive impairment temporally associated with celiac disease. Case series. Referral center. Patients with the onset of progressive cognitive decline within 2 years of symptomatic onset or with a severe exacerbation of biopsy-proved adult celiac disease were identified from the Mayo Clinic medical records from January 1, 1970, to December 31, 2005. Patients were excluded if an alternate cause of their cognitive impairment was identified. Thirteen patients (5 women) were identified. The median age at cognitive impairment onset was 64 years (range, 45-79 years), which coincided with symptom onset or exacerbation of diarrhea, steatorrhea, and abdominal cramping in 5 patients. Amnesia, acalculia, confusion, and personality changes were the most common presenting features. The average initial Short Test of Mental Status score was 28 of a total of 38 (range, 18-34), which was in the moderately impaired range. The results of neuropsychological testing suggested a trend of a frontosubcortical pattern of impairment. Ten patients had ataxia, and 4 of them also had peripheral neuropathy. Magnetic resonance imaging of the head showed nonspecific T2 hyperintensities, and electroencephalography showed nonspecific diffuse slowing. Deficiencies in folate, vitamin B(12), vitamin E, or a combination were identified in 4 patients, yet supplementation did not improve their neurological symptoms. Three patients improved or stabilized cognitively with gluten withdrawal. A detailed histological analysis revealed nonspecific gliosis. A possible association exists between progressive cognitive impairment and celiac disease, given the temporal relationship and the relatively high frequency of ataxia and peripheral neuropathy, more commonly associated with celiac disease. Given the impact for potential treatment of similar cases, recognition of this possible association and additional studies are warranted.


Course of HIV-I infection in a cohort of homosexual and bisexual men: an 11 year follow up study.
OBJECTIVE--To characterise the natural history of sexually transmitted HIV-I infection in homosexual and bisexual men. DESIGN--Cohort study. SETTING--San Francisco municipal sexually transmitted disease clinic. PATIENTS--Cohort included 6705 homosexual and bisexual men originally recruited from 1978 to 1980 for studies of sexually transmitted hepatitis B. This analysis is of 489 cohort members who were either HIV-I seropositive on entry into the cohort (n = 312) or seroconverted during the study period and had less than or equal to 24 months between the dates of their last seronegative and first seropositive specimens (n = 177). A subset of 442 of these men was examined in 1988 or 1989 or had been reported to have developed AIDS. MAIN OUTCOME MEASURES--Development of clinical signs and symptoms of HIV-I infection, including AIDS, AIDS related complex, asymptomatic generalised lymphadenopathy, and no signs or symptoms of infection. MEASUREMENTS AND MAIN RESULTS--Of the 422 men examined in 1988 or 1989 or reported as having AIDS, 341 had been infected from 1977 to 1980; 49% (167) of these men had died of AIDS, 10% (34) were alive with AIDS, 19% (65) had AIDS related complex, 3% (10) had asymptomatic generalised lymphadenopathy, and 19% (34) had no clinical signs or symptoms of HIV-I infection. Cumulative risk of AIDS by duration of HIV-I infection was analysed for all 489 men by the Kaplan-Meier method. Of these 489 men, 226 (46%) had been diagnosed as having AIDS. We estimated that 13% of cohort members will have developed AIDS within five years of seroconversion, 51% within 10 years, and 54% within 11.1 years. CONCLUSION--Our analysis confirming the importance of duration of infection to clinical state and the high risk of AIDS after infection underscores the importance of continuing efforts both to prevent transmission of HIV-I and to develop further treatments to slow or stall the progression of HIV-I infection to AIDS.


Characterization of cotJ, a sigma E-controlled operon affecting the polypeptide composition of the coat of Bacillus subtilis spores.
The outermost protective structure found in endospores of Bacillus subtilis is a thick protein shell known as the coat, which makes a key contribution to the resistance properties of the mature spore and also plays a role in its interaction with compounds able to trigger germination. The coat is organized as a lamellar inner layer and an electron-dense outer layer and has a complex polypeptide composition. Here we report the cloning and characterization of an operon, cotJ, located at about 62 degrees on the B. subtilis genetic map, whose inactivation results in the production of spores with an altered pattern of coat polypeptides. The cotJ operon was identified by screening a random library of lacZ transcriptional fusions for a conditional (inducer-dependent) Lac+ phenotype in cells of a strain in which the structural gene (spoIIGB) for the early-acting, mother-cell-specific transcriptional factor sigma E was placed under the control of the IPTG (isopropyl-beta-D-thiogalactopyranoside)-inducible Pspac promoter. Sequence analysis of cloned DNA from the cotJ region complemented by genetic experiments revealed a tricistronic operon preceded by a strong sigma E-like promoter. Expression of an SP beta-borne cotJ-lacZ fusion commences at around h 2 of sporulation, as does expression of other sigma E-dependent genes, and shows an absolute requirement for sigma E. Studies with double-reporter strains bearing a cotJ-gusA fusion and lacZ fusions to other cot genes confirmed that expression of cotJ is initiated during sporulation prior to activation of genes known to encode coat structural proteins (with the sole exception of cotE). An in vitro-constructed insertion-deletion mutation in cotJ resulted in the formation of spores with no detectable morphological or resistance deficiency. However, examination of the profile of electrophoretically separated spore coat proteins from the null mutant revealed a pattern that was essentially identical to that of a wild-type strain in the range of 12 to 65 kDa, except for polypeptides of 17 and 24 kDa, the putative products of the second (cotJB) and third (cotJC) cistrons of the operon, that were missing or reduced in amount in the coat of the mutant. Polypeptides of the same apparent sizes are detected in spores of a cotE null mutant, on which basis we infer that the products of the cotJ operon are required for the normal formation of the inner layers of the coat or are themselves structural components of the coat. Because the onset of cotJ transcription is temporally coincident with the appearance of active sigma E, we speculate that the cotJ-encoded products may be involved in an early state of coat assembly.


Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study.
Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16-59) in group A, 10% (2-33) in group B, and 30% (13-54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. Cyclacel Limited.


Impact of early hyperoxia on 28-day in-hospital mortality in patients with myocardial injury.
Despite relevant evidence that supplemental oxygen therapy can be harmful to patients with myocardial injury, the association between hyperoxia and the clinical outcome of such patients has not been evaluated. We assessed whether early hyperoxia negatively affects outcomes in hospitalized patients with myocardial injury. This was a retrospective study conducted at a tertiary referral teaching hospital. Between January 2010 and December 2016, 2,376 consecutive emergency department patients with myocardial injury, defined as a peak troponin-I level ≥ 0.2 ng/mL, within the first 24 hours of presentation were included. The metrics used to define hyperoxia were the maximum average partial pressure of oxygen (PaO2MAX), average partial pressure of oxygen (PaO2AVG), and area under the curve during the first 24 hours (AUC24). The association between early hyperoxia within 24 hours after presentation and clinical outcomes was evaluated using multiple imputation and logistic regression analysis. The primary outcome was 28-day in-hospital mortality. The secondary outcomes were new-onset cardiovascular, coagulation, hepatic, renal, and respiratory dysfunctions (sequential organ failure sub-score ≥ 2). Compared with normoxic patients, the adjusted odds ratios (ORs) for PaO2MAX, PaO2AVG, and AUC24 were 1.55 (95% confidence interval (CI) 1.05-2.27; p = 0.026), 2.13 (95% CI 1.45-3.12; p = 0.001), and 1.73 (95% CI 1.15-2.61; p = 0.008), respectively, in patients with mild hyperoxia and 6.01 (95% CI 3.98-9.07; p < 0.001), 8.92 (95% CI 3.33-23.88; p < 0.001), and 7.32 (95% CI 2.72-19.70; p = 0.001), respectively, in patients with severe hyperoxia. The incidence of coagulation and hepatic dysfunction (sequential organ failure sub-score ≥ 2) was significantly higher in the mild and severe hyperoxia group. Hyperoxia during the first 24 hours of presentation is associated with an increased 28-day in-hospital mortality rate and risks of coagulation and hepatic dysfunction in patients with myocardial injury.


Activating Ru nanoparticles on oxide supports for ring-opening metathesis polymerization.
Nano-sized particles mounted on heterogeneous oxide supports such as silica have altered reactivity when compared to their homogeneous analogs. In particular, catalyzed olefin metathesis using supported Ru nanoparticles has shown great promise and various methods have been employed to develop functional heterogeneous Ru catalysts. This article reports a method for synthesizing Ru nanoparticles supported on silica and titania. The nanoparticles were characterized using XPS showing Ru(0) dominates when not exposed to air. TEM showed Ru nanoparticle sizes of 3.1 ± 0.8 nm for Ru supported on SiO2 and 5.6 ± 1.3 nm for Ru supported on TiO2. The materials demonstrated modest activity in ring-opening metathesis reactions via diazo activation and nanoparticle-embedded polymers of norbornene and norbornadiene were synthesized using dry box and Schlenk line techniques. The Ru/support/polymer composite materials were characterized using proton NMR, XPS, and SEM/EDS.


Inferring the physical properties of yeast chromatin through Bayesian analysis of whole nucleus simulations.
The structure and mechanical properties of chromatin impact DNA functions and nuclear architecture but remain poorly understood. In budding yeast, a simple polymer model with minimal sequence-specific constraints and a small number of structural parameters can explain diverse experimental data on nuclear architecture. However, how assumed chromatin properties affect model predictions was not previously systematically investigated. We used hundreds of dynamic chromosome simulations and Bayesian inference to determine chromatin properties consistent with an extensive dataset that includes hundreds of measurements from imaging in fixed and live cells and two Hi-C studies. We place new constraints on average chromatin fiber properties, narrowing down the chromatin compaction to ~53-65 bp/nm and persistence length to ~52-85 nm. These constraints argue against a 20-30 nm fiber as the exclusive chromatin structure in the genome. Our best model provides a much better match to experimental measurements of nuclear architecture and also recapitulates chromatin dynamics measured on multiple loci over long timescales. This work substantially improves our understanding of yeast chromatin mechanics and chromosome architecture and provides a new analytic framework to infer chromosome properties in other organisms.


Transporters MRP1 and MRP2 Regulate Opposing Inflammatory Signals To Control Transepithelial Neutrophil Migration during Streptococcus pneumoniae Lung Infection.
Streptococcus pneumoniae remains a source of morbidity and mortality in both developed and underdeveloped nations of the world. Disease can manifest as pneumonia, bacteremia, and meningitis, depending on the localization of infection. Interestingly, there is a correlation in experimental murine infections between the development of bacteremia and influx of neutrophils into the pulmonary lumen. Reduction of this neutrophil influx has been shown to improve survivability during infection. In this study, we use in vitro biotinylation and neutrophil transmigration and in vivo murine infection to identify a system in which two epithelium-localized ATP-binding cassette transporters, MRP1 and MRP2, have inverse activities dictating neutrophil transmigration into the lumen of infected mouse lungs. MRP1 effluxes an anti-inflammatory molecule that maintains homeostasis in uninfected contexts, thus reducing neutrophil infiltration. During inflammatory events, however, MRP1 decreases and MRP2 both increases and effluxes the proinflammatory eicosanoid hepoxilin A3. If we then decrease MRP2 activity during experimental murine infection with S. pneumoniae, we reduce both neutrophil infiltration and bacteremia, showing that MRP2 coordinates this activity in the lung. We conclude that MRP1 assists in depression of polymorphonuclear cell (PMN) migration by effluxing a molecule that inhibits the proinflammatory effects of MRP2 activity.IMPORTANCEStreptococcus pneumoniae is a Gram-positive bacterium that normally inhabits the human nasopharynx asymptomatically. However, it is also a major cause of pneumonia, bacteremia, and meningitis. The transition from pneumonia to bacteremia is critical, as patients that develop septicemia have ~20% mortality rates. Previous studies have shown that while neutrophils, a major bacterium-induced leukocyte, aid in S. pneumoniae elimination, they also contribute to pathology and may mediate the lung-to-blood passage of the bacteria. Herein, we show that epithelium-derived MRP1 and MRP2 efflux immunomodulatory agents that assist in controlling passage of neutrophils during infection and that limiting neutrophil infiltration produced less bacteremia and better survival during murine infection. The importance of our work is twofold: ours is the first to identify an MRP1/MRP2 axis of neutrophil control in the lung. The second is to provide possible therapeutic targets to reduce excess inflammation, thus reducing the chances of developing bacteremia during pneumococcal pneumonia.


Mycophenolate mofetil inducing remission of lupus enteritis.
We report the case of a young woman with a background history of discoid lupus who presented with abdominal pain, vomiting and intermittent diarrhoea. Physical examination revealed tenderness in the right upper quadrant with a palpable right inguinal lymph node without any other clinical signs of active lupus. Laboratory investigations showed normal inflammatory markers, positive ANA and Anti-Ro antibodies, persistent hypocomplementemia and lymphopenia, CT showed marked bowel oedema involving the small and large bowel (halo sign) with massive ascites and moderate right-sided pleural effusion. Mantoux test, AFB and TB cultures were negative. A diagnosis of lupus enteritis was made and treatment with high-dose steroids was commenced with little improvement. Treatment with cyclophosphamide was discussed but declined by the patient. Mycophenolate mofetil was commenced and resulted in significant clinical and radiological resolution. To the best of the authors' knowledge this is the first report of the successful use of mycophenolate mofetil in inducing and maintaining remission in lupus enteritis.


Insights into the evolution of a cryptic radiation of bats: dispersal and ecological radiation of Malagasy Miniopterus (Chiroptera: Miniopteridae).
The past decade has seen a proliferation of new species of Miniopterus bats (family Miniopteridae) recognized from Madagascar and the neighboring Comoros archipelago. The interspecific relationships of these taxa, their colonization history, and the evolution of this presumed adaptive radiation have not been sufficiently explored. Using the mitochondrial cytochrome-b gene, we present a phylogeny of the Malagasy members of this widespread Old World genus, based on 218 sequences, of which 82 are new and 136 derived from previous studies. Phylogenetic analyses recovered 18 clades, which divide into five primary lineages: (1) M. griveaudi; (2) M. mahafaliensis, M. sororculus and X3; (3) M. majori, M. gleni and M. griffithsi; (4) M. brachytragos; M. aelleniA, and M. aelleniB; and (5) M. manavi and M. petersoni recovered as sister species, which were in turn linked to a group comprising M. egeri and five genetically distinct populations referred to herein as P3, P4, P5, P6 and P7. Beast analysis indicated that the initial divergence within the Malagasy Miniopterus radiation took place 4.5 Myr; most species diverged between 4 and 2.5 Myr, and a secondary period was between 1.25 and 1 Myr. DNA K2P-distances between recognized taxa ranged from 12.9% to 2.5% and intraspecific variation was less than 1.8%. Of the 18 identified clades, Latin binomials are only associated with 11, which indicates much greater differentiation than currently recognized for Malagasy Miniopterus. These data are placed in a context of the dispersal history of this genus on the island and patterns of ecological diversity.


N'-Phenyl-N'-[3-(2,4,5-triphenyl-2,5-di-hydro-1H-pyrazol-3-yl)quinoxalin-2-yl]benzohydrazide.
The mol-ecule of the title compound, C42H32N6O, is built up from one pyrazole ring linked to three phenyl rings and to an approximately planar [maximum deviation = 0.0455 (15) Å] quinoxaline system connected to a phenyl-benzohydrazide group. The pyrazole ring assumes an envelope conformation, the C atom attached to the quinoxalin-3-yl ring system being the flap atom. The dihedral angle between the two phenyl rings of the phenyl-benzohydrazide group is of 58.27 (9)°. The mean plane through the pyrazole ring is nearly perpendicular to the quinoxaline ring system and to the phenyl ring attached to the opposite side, forming dihedral angles of 82.58 (7) and 87.29 (9)°, respectively. An intra-molecular C-H⋯O hydrogen bond is present. In the crystal, mol-ecules are linked by pairs of N-H⋯N hydrogen bonds, forming inversion dimers, which are further connected by C-H⋯N hydrogen bonds into chains parallel to the b axis.


Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells.
Hematopoietic stem cells (HSCs) are exposed to various insults such as genotoxic stress, inflammation, and infection, which have a direct effect. These insults deplete, cause a functional decline in, and promote HSC aging and transformation. However, the impact of hematopoietic insults on niche cells remains largely unknown. We have reported previously that p53 is activated in blood vessels by various stresses, including hypoxia, inflammation, and aging, and contributes to tissue dysfunction and metabolic abnormalities. We hypothesized that hematopoietic insults also affect the bone marrow (BM) vascular niche. Here, we demonstrate that p53 becomes activated in BM endothelial cells upon hematopoietic stresses such as irradiation and chemotherapeutic treatments. The conditional activation of p53 in VE-cadherin+ vascular niche cells by deleting Mdm2 induces the expression of p53 target genes specifically in vascular endothelial cells, resulting in the dilation and collapse of vascular endothelial cells and reductions in perivascular mesenchymal stromal cell numbers. Consequently, hematopoietic stem cells (HSCs) fail to maintain dormancy, mobilize to the periphery, and are depleted significantly. Our results indicate that various hematopoietic insults affect HSCs, not only directly, but also indirectly by altering vascular integrity, which is critical for perivascular niche formation and maintenance of HSCs.


The evaluation of processed cancellous bovine bone as a bone graft substitute.
To determine the ability of a novel bovine cancellous bone xenoimplant to act as an osteoconductive graft in an ovine femoral defect model. An autograft harvested from the xenoimplant site was placed in a contralateral limb defect for comparison. The xenoimplant used had been rendered immunologically inert by a novel defatting and deproteinating process. Following surgical implantation of cores into condylar cancellous bone defects, fluorochrome labels were administered to 12 sheep at 2 1/2, 4 1/2 and 8 weeks. Incorporation of the xenoimplants and autografts into the host bone was compared radiographically and histomorphometrically at 10 weeks. Radiographically, the degree of osteointegration was comparable. Histomorphometric data, consisting of labelled surface (LS) estimates, confirmed osteoconductive properties of both the xenoimplants and autografts. Remodelling activity was greatest in the xenoimplants at 2 1/2, weeks. At 4 1/2 weeks, there was more activity in the autograft, but by 8 weeks they were performing similarly. Xenoimplant-LS estimates were comparable or greater than those of the autograft at all times. Processed bovine cancellous bone xenoimplants were osteoconductive in this model and show promise for development as a biomaterial in human and veterinary orthopaedic surgery.


Transcriptional repression of E-cadherin by human papillomavirus type 16 E6.
There is increasing evidence supporting DNA virus regulation of the cell adhesion and tumour suppressor protein, E-cadherin. We previously reported that loss of E-cadherin in human papillomavirus (HPV) type 16-infected epidermis is contributed to by the major viral proto-oncogene E6 and is associated with reduced Langerhans cells density, potentially regulating the immune response. The focus of this study is determining how the HPV16 E6 protein mediates E-cadherin repression. We found that the E-cadherin promoter is repressed in cells expressing E6, resulting in fewer E-cadherin transcripts. On exploring the mechanism for this, repression by increased histone deacetylase activity or by increased binding of trans-repressors to the E-cadherin promoter Epal element was discounted. In contrast, DNA methyltransferase (DNMT) activity was increased in E6 expressing cells. Upon inhibiting DNMT activity using 5-Aza-2'-deoxycytidine, E-cadherin transcription was restored in the presence of HPV16 E6. The E-cadherin promoter was not directly methylated, however a mutational analysis showed general promoter repression and reduced binding of the transactivators Sp1 and AML1 and the repressor Slug. Expression of E7 with E6 resulted in a further reduction in surface E-cadherin levels. This is the first report of HPV16 E6-mediated transcriptional repression of this adhesion molecule and tumour suppressor protein.


Surgical treatment for acute spinal cord injury study pilot study #2: evaluation of protocol for decompressive surgery within 8 hours of injury.
Acute spinal cord injury (SCI) is a major public health problem for which there is still only limited treatment available. The National Acute Spinal Cord Injury Study-2 (NASCIS-2) and -3 clinical trials demonstrated that the use of acute pharmacotherapy with methylprednisolone can attenuate the secondary injury cascade if administered within 8 hours of acute SCI. However, no trial has been performed to examine whether acute surgical decompressive procedures within this critical 8-hour time window can improve patients' neurological outcome. The purpose of the current prospective Surgical Treatment for Acute Spinal Cord Injury Study (STASCIS) pilot study was to determine the feasibility of obtaining a radiological diagnosis of spinal canal compromise of 25% or more and to perform spinal cord (C3-T1) decompressive procedures by 8 hours postinjury. One of the following three decompressive methods was used: 1) traction alone; 2) traction and surgery; or 3) surgery alone. Twenty-six patients from eight North American centers were entered into the study between 1996 and 1997. Significant difficulties were encountered in many centers in performing immediate magnetic resonance imaging examination in patients with acute SCI. Fewer than 10% of acute cervical SCI patients could be enrolled into this protocol mainly because the combination of the required time for rescue, resuscitation, transport, imaging study, and surgical preparation exceeded the 8-hour injury-to-decompressive surgery window. Eleven patients underwent decompressive procedures initially by being placed in traction at a mean time of 10.9 hours postinjury. Those patients not undergoing this procedure underwent decompressive surgery at a mean time of 40.1 hours. However, the surgical decompressive procedure was completed within 12 hours in seven patients. As a result of these findings, several major changes have been made to the STASCIS protocol for early decompressive therapy.


Breakfast Cereal Consumption and Obesity Risk amongst the Mid-Age Cohort of the Australian Longitudinal Study on Women's Health.
Obesity affects 27.5% of Australian women. Breakfast cereal consumption has been proposed to be protective against obesity. This study investigated the association of breakfast cereal consumption with the risk of developing obesity (Body Mass Index (BMI) ≥ 30 kg/m²) over 12 years among mid-age participants in the Australian Longitudinal Study on Women's Health (ALSWH). Dietary data were obtained at S3 and obesity incidence at S4-S7. Women were excluded if: dietary data were incomplete, energy intake was <4500 or >20,000 kJ/day, or they reported being overweight or obese at S3. Logistic regressions with discrete time survival analysis investigated the association between breakfast cereal intake and incident obesity and were adjusted for: area of residency, income, smoking, physical activity, hypertension, dietary intakes and a discrete measure of time. There were 308 incident cases of obesity. Any breakfast cereal intake was not associated with incident obesity (Odds Ratio (OR): 0.92; p = 0.68). Oat-based cereal (OR: 0.71; p = 0.01), muesli (OR: 0.57; p = 0.00) and All-Bran (OR: 0.62; p = 0.01) intakes were associated with a significant reduction in obesity risk. Among this cohort, muesli on its own, or as part of oat-based cereals, and All-Bran, were associated with a reduction in obesity. This effect may be due to particular characteristics of these cereal eaters, but the relationship warrants further investigation.


Na+/H+ exchange activity in the plasma membrane of Arabidopsis.
In plants, Na+/H+ exchangers in the plasma membrane are critical for growth in high levels of salt, removing toxic Na+ from the cytoplasm by transport out of the cell. The molecular identity of a plasma membrane Na+/H+ exchanger in Arabidopsis (SOS1) has recently been determined. In this study, immunological analysis provided evidence that SOS1 localizes to the plasma membrane of leaves and roots. To characterize the transport activity of this protein, purified plasma membrane vesicles were isolated from leaves of Arabidopsis. Na+/H+ exchange activity, monitored as the ability of Na to dissipate an established pH gradient, was absent in plants grown without salt. However, exchange activity was induced when plants were grown in 250 mm NaCl and increased with prolonged salt exposure up to 8 d. H+-coupled exchange was specific for Na, because chloride salts of other monovalent cations did not dissipate the pH gradient. Na+/H+ exchange activity was dependent on Na (substrate) concentration, and kinetic analysis indicated that the affinity (apparent Km) of the transporter for Na+ is 22.8 mm. Data from two experimental approaches supports electroneutral exchange (one Na+ exchanged for one proton): (a) no change in membrane potential was measured during the exchange reaction, and (b) Na+/H+ exchange was unaffected by the presence or absence of a membrane potential. Results from this research provide a framework for future studies into the regulation of the plant plasma membrane Na+/H+ exchanger and its relative contribution to the maintenance of cellular Na+ homeostasis during plant growth in salt.


Protection levels of vaccinated pigeons (Columba livia) against a highly pathogenic Newcastle disease virus strain.
The purposes of this study were to model a vaccination regimen for Newcastle disease virus (NDV) in pigeons, and to evaluate the susceptibility and behavior of vaccinated birds against a highly pathogenic NDV Brazilian strain. Antibody response was assessed by means of hemagglutination inhibition test (HI), and viral genome excretion by means of RT-PCR. Vaccinal strains (La Sota and Ulster) induced high antibody titers without any adverse effects, both in inoculated and in sentinel birds. A viral strain pathogenic for chickens did not produce clinical signs of the disease in experimentally infected pigeons. Only 4 out of 10 vaccinated pigeons shed NDV genome, and just for two days. Results confirmed the high infectivity of the vaccinal strains used, as all nonvaccinated pigeons showed antibody titers as high as those of vaccinated birds.


A therapeutic Porphyromonas gingivalis gingipain vaccine induces neutralising IgG1 antibodies that protect against experimental periodontitis.
Porphyromonas gingivalis infected mice with an established P. gingivalis-specific inflammatory immune response were protected from developing alveolar bone resorption by therapeutic vaccination with a chimera (KAS2-A1) immunogen targeting the major virulence factors of the bacterium, the gingipain proteinases. Protection was characterised by an antigen-specific IgG1 isotype antibody and Th2 cell response. Adoptive transfer of KAS2-A1-specific IgG1 or IgG2 expressing B cells confirmed that IgG1-mediated protection. Furthermore, parenteral or intraoral administration of KAS2-A1-specific polyclonal antibodies protected against the development of P. gingivalis-induced bone resorption. The KAS2-A1-specific antibodies neutralised the gingipains by inhibiting: proteolytic activity, binding to host cells/proteins and co-aggregation with other periodontal bacteria. Combining key gingipain sequences into a chimera vaccine produced an effective therapeutic intervention that protected against P. gingivalis-induced periodontitis.


High-Fidelity Prototyping for Mobile Electronic Data Collection Forms Through Design and User Evaluation.
Mobile data collection systems are often difficult to use for nontechnical or novice users. This can be attributed to the fact that developers of such tools do not adequately involve end users in the design and development of product features and functions, which often creates interaction challenges. The main objective of this study was to assess the guidelines for form design using high-fidelity prototypes developed based on end-user preferences. We also sought to investigate the association between the results from the System Usability Scale (SUS) and those from the Study Tailored Evaluation Questionnaire (STEQ) after the evaluation. In addition, we sought to recommend some practical guidelines for the implementation of the group testing approach particularly in low-resource settings during mobile form design. We developed a Web-based high-fidelity prototype using Axure RP 8. A total of 30 research assistants (RAs) evaluated this prototype in March 2018 by completing the given tasks during 1 common session. An STEQ comprising 13 affirmative statements and the commonly used and validated SUS were administered to evaluate the usability and user experience after interaction with the prototype. The STEQ evaluation was summarized using frequencies in an Excel sheet while the SUS scores were calculated based on whether the statement was positive (user selection minus 1) or negative (5 minus user selection). These were summed up and the score contributions multiplied by 2.5 to give the overall form usability from each participant. Of the RAs, 80% (24/30) appreciated the form progress indication, found the form navigation easy, and were satisfied with the error messages. The results gave a SUS average score of 70.4 (SD 11.7), which is above the recommended average SUS score of 68, meaning that the usability of the prototype was above average. The scores from the STEQ, on the other hand, indicated a 70% (21/30) level of agreement with the affirmative evaluation statements. The results from the 2 instruments indicated a fair level of user satisfaction and a strong positive association as shown by the Pearson correlation value of .623 (P<.01). A high-fidelity prototype was used to give the users experience with a product they would likely use in their work. Group testing was done because of scarcity of resources such as costs and time involved especially in low-income countries. If embraced, this approach could help assess user needs of the diverse user groups. With proper preparation and the right infrastructure at an affordable cost, usability testing could lead to the development of highly usable forms. The study thus makes recommendations on the practical guidelines for the implementation of the group testing approach particularly in low-resource settings during mobile form design.


Increasing organ donation via anticipated regret (INORDAR): protocol for a randomised controlled trial.
Throughout the world there is an insufficient supply of donor organs to meet the demand for organ transplantations. This paper presents a protocol for a randomised controlled trial, testing whether a simple, theory-based anticipated regret manipulation leads to a significant increase in posthumous organ donor registrations. We will use a between-groups, prospective randomised controlled design. A random sample of 14,520 members of the adult Scottish general public will be contacted via post. These participants will be randomly allocated into 1 of the 4 conditions. The no questionnaire control (NQC) group will simply receive a letter and donor registration form. The questionnaire control (QC) arm will receive a questionnaire measuring their emotions and non-cognitive affective attitudes towards organ donation. The theory of planned behavior (TPB) group will complete the emotions and affective attitudes questionnaire plus additional items assessing their cognitive attitudes towards organ donation, perceived control over registration and how they think significant others view this action. Finally, the anticipated regret (AR) group will complete the same indices as the TPB group, plus two additional anticipated regret items. These items will assess the extent to which the participant anticipates regret for not registering as an organ donor in the near future. The outcome variable will be NHS Blood and Transplant verified registrations as an organ donor within 6 months of receiving our postal intervention. This study will assess whether simply asking people to reflect on the extent to which they may anticipate regret for not registering as an organ donor increases organ donor registration 6 months later. If successful, this simple and easy to administer theory-based intervention has the potential to save lives and money for the NHS by reducing the number of people receiving treatments such as dialysis. This intervention may also be incorporated into future organ donor campaigns. ISRCTN: ISRCTN92204897.


Modulation of HCV replication after combination antiretroviral therapy in HCV/HIV co-infected patients.
The hepatitis C virus (HCV) is an important contributor to morbidity and mortality in patients co-infected with HIV. Co-infection results in increased HCV replication and more rapid rates of liver disease progression. The effect of HIV combination antiretroviral therapy (cART) on HCV replication has not been studied in depth. To address this issue, we enrolled a small cohort of HCV/HIV co-infected patients into a cART initiation trial and used dynamic modeling combined with evaluation of immune responses and microarray profiles to determine how effective treatment of HIV affects HCV. Treatment with cART resulted in increased HCV replication and increased alanine aminotransferase (ALT) in a subset of patients. Subjects with evidence of hepatic injury (increased ALT) were more likely to have HCV-specific immune responses directed against HCV epitopes. Over time, HCV viral loads declined. Reproducible and biologically important gene expression changes occurred in co-infected patients who underwent successful cART. The effective suppression of HIV by cART initiated a cascade of early and late events in treated patients. Early events involving down-regulation of interferon-stimulated genes may have led to transiently increased viral replication and hepatic injury. At later time points, HCV viral load declined to levels comparable to those seen in the setting of HCV monoinfection. These findings support early antiretroviral therapy in those with HCV/HIV co-infection.


Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study.
Genetic variants have been associated with the risk of developing glioma, but functional mechanisms on disease phenotypic traits remain to be investigated. One phenotypic trait of glioblastoma is the mutation and amplification of the epidermal growth factor receptor (EGFR) gene. We investigated associations between pre-diagnostic serum protein concentrations of EGFR and ErbB2, both members of the EGFR family, and future risk of glioma. Further, we studied if EGFR glioma risk variants were associated with EGFR and ErbB2 serum levels. We assessed the associations between genetic glioma risk variants and serum concentrations of EGFR and ErbB2, as measured in pre-diagnostic cohort serum samples of 593 glioma patients and 590 matched cancer-free controls. High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13-2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09-2.44, respectively). High serum ErbB2 concentration was also associated with glioma risk overall (P = 0.049; OR = 1.39, 95 % CI = 1.00-1.93). Glioma risk variants were not associated with high serum protein abundance. In contrast, the EGFR risk variant rs4947986 (T) was correlated with decreased EGFR serum levels (study cohort P = 0.024 and controls P = 0.009). To our knowledge, this is the first study showing an association of EGFR and ErbB2 serum levels with glioma more than a decade before diagnosis, indicating that EGFR and ErbB2 serum proteins are important in early gliomagenesis. However, we did not find evidence that glioma risk variants were associated with high pre-diagnostic serum concentrations of EGFR and ErbB2.


Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats.
Butyl benzyl phthalate (BBP) was administered in the diet at 0, 750, 3750, and 11,250 ppm ad libitum to 30 rats per sex per dose for two offspring generations, one litter/breeding pair/generation, through weaning of F2 litters. Adult F0 systemic toxicity and adult F1 systemic and reproductive toxicity were present at 11,250 ppm (750 mg/kg per day). At 11,250 ppm, there were reduced F1 and F2 male anogenital distance (AGD) and body weights/litter during lactation, delayed acquisition of puberty in F1 males and females, retention of nipples and areolae in F1 and F2 males, and male reproductive system malformations. At 3750 ppm (250 mg/kg per day), only reduced F1 and F2 offspring male AGD was present. There were no effects on parents or offspring at 750 ppm (50 mg/kg per day). The F1 parental systemic and reproductive toxicity no observable adverse effect level (NOAEL) was 3750 ppm. The offspring toxicity NOAEL was 3750 ppm. The offspring toxicity no observable effect level (NOEL) was 750 ppm, based on the presence of reduced AGD in F1 and F2 males at birth at 3750 ppm, but no effects on reproductive development, structures, or functions.


Transcriptome Analysis of the SL221 Cells at the Early Stage during Spodoptera litura Nucleopolyhedrovirus Infection.
Spodoptera litura (S. litura) is one of the most destructive agricultural pests worldwide. There is urgent need for a nuclear polyhedrosis virus that is specific to S. litura. To date, there have been no reports regarding the responses of S. litura cells to early Spodoptera litura nucleopolyhedrovirus (SpltNPV) infection due to the lack of a reference genome and transcriptome for S. litura. In this study, a cell transcriptome from the host S. litura was assembled and used for Illumina strand-specific RNA sequencing (RNA-seq) to generate 99180 unigenes, representing the 18 hour infection cycle. More than 2000 S. litura genes were significant differentially regulated throughout the infection. The levels of viral mRNAs began to increase dramatically at 6 hpi, and this increase continued throughout the remainder of the infection. We focused on the expression of genes related to stress responses, apoptosis, metabolic enzymes and host cell innate immune system. A small subset of genes related to host stress response, especially for 62 ones being able to annotated as enzyme, ligand and receptor genes, were observed to be specifically differentially expressed at 6 hpi. At 18 hpi, 104 unigenes were continuously significantly changing from 0 hpi to 18 hpi, considered to be viral multiplication related genes, including 3 annotated SL221 unigenes and 81 viral genes, such as tetraspanin and iap gene. This information and further studies on the regulation of host gene expression by baculovirus infection at early stage will provide the tools needed to enhance the utility of this virus as an effective insecticide.


Physical Educators' Qualifications and Instructional Practices Toward Students With Disabilities.
The purposes of this study were (a) to investigate the prevalence of physical educators who report delivering high-quality instructional practices to students with disabilities and (b) to examine the relationships between teachers' qualifications and the delivery of high-quality instructional practices. A secondary analysis using data from the School Health Policy and Practice Study 2014 data set was employed. The analytic sample included 256 physical educators who taught students with disabilities. Prevalence estimates of physical educators who reported using high-quality instructional practices were calculated. Two separate binary logistic regressions using weighted data were conducted to evaluate the relative contribution of (a) teacher qualifications and (b) educational degrees in accounting for differences in the use of high-quality instructional practices. Less than half of the sample reported using high-quality instructional practices. Considering the increasing prevalence of students with disabilities in general education classrooms, teacher education programs should prioritize providing teacher candidates with coursework that aligns with the expectations of physical educators who teach students with disabilities.


The Association of Early and Recent Psychosocial Life Stress With Leukocyte Telomere Length.
Chronic exposure to psychosocial stressors is related to worse somatic health. This association applies both to stressors early in life, such as childhood adversities, and more recent life stress, such as stressful life events. This study examined whether accelerated telomere shortening, as an indicator of cellular aging, might be an explanatory mechanism. We examined whether childhood adversities and recent stressful life events were associated with shorter telomeres in 2936 participants (mean [standard deviation] age = 41.8 [13.1] years, 66% women, 57% current depression) of the Netherlands Study of Depression and Anxiety. Telomeres are specialized nucleic acid-protein complexes at the ends of linear DNA that shorten with age; telomere length (TL) was measured with quantitative polymerase chain reaction. Childhood life events (β = .004, p = .805) and childhood trauma (β = -.023, p = .205) were not related to shorter TL. However, we found negative associations between recent stressful life events and TL. Persons had shorter telomeres if they reported more stressful life events in the past year (β = -.039, p = .028) and 1 to 5 years ago (β = -.042, p = .018, adjusted for sociodemographics). The relationship between stressful life events and TL became borderline significant when further adjusted for smoking status. No associations with TL were found when stressful life events occurred more than 6 years ago (p > .10). Results show that recent stressful life events are associated with shorter TL. This association is not observed for psychosocial stressors that occur earlier in life. Whether these results are indicative of physiological resiliency remains to be explored by future longitudinal research.


Self-reported sexually transmitted infection testing behaviour amongst incarcerated young male offenders: findings from a qualitative study.
Sexually transmitted infections (STIs) are a major public health problem in the UK. Here we describe young men's self-reported STI testing behaviour, and explore why testing is and is not sought in two locales: the community and the Young Offender Institute (YOI). In-depth interviews were conducted with 40 men, aged 16-20 years, whilst incarcerated in a Scottish YOI. The participants were purposively sampled using answers from a questionnaire administered to 67 inmates. The majority (n = 24) of those interviewed reported having undergone STI testing: eight in the community, 12 within the YOI, and four in both the community and the YOI. The extent to which they were worried about STIs and perceived themselves 'at risk' was important in understanding openness to testing. The convenience of testing within the YOI boosted the numbers seeking testing once incarcerated. Not getting tested in the YOI was due to not realising that it was available or not getting around to it rather than objecting to, or being embarrassed about, testing. Increasing awareness of the availability of STI testing within YOIs would be likely to result in higher uptake. An opt-out YOI STI screening programme would probably result in very high testing rates. Accessibility and convenience are key elements of testing procedures for this group, in both the YOI and community settings.


Epigenetic regulation in myelodysplastic syndromes: implications for therapy.
Myelodysplastic syndromes (MDS), characterized by ineffective hematopoiesis and dysplasia in one or more lineages, produce life-threatening cytopenias and progress to acute myeloid leukemia (AML). Growing evidence suggests that targeting epigenetic mechanisms improves MDS/AML pathophysiology. This review provides an understanding of studies investigating novel agents published up to January 2011 aimed at normalizing and monitoring the epigenetic profile of the MDS cancer cell. The authors discuss how non-intensive epigenetic therapy can 're-programme' gene expression patterns of abnormal hematopoiesis in MDS. Recently FDA-approved DNA-methyltransferase inhibitors, 5-azacytidine and 5-aza-2'-deoxycytidine or decitabine, represent frontline nonablative treatments, while combinations with histone deacetylase inhibitors show promising synergism in preclinical and Phase I/II trials in tumor suppressor gene re-expression and overall survival. Additional epigenetic mechanisms including non-encoding transcripts with inhibitory posttranscriptional regulatory functions, such as microRNAs, though not fully understood, present novel molecular and clinical implications in these disorders. Alongside current single-agent epigenetic regimens, combination therapies represent potentially effective options for intermediate-2 and high-risk MDS. Methylation profiles and gene mutation predictors provide promising areas of development for monitoring MDS disease progression and outcome, while targeting microRNA dysregulation represents an important therapeutic goal.


Vision in the natural world.
Historically, the study of visual perception has followed a reductionist strategy, with the goal of understanding complex visually guided behavior by separate analysis of its elemental components. Recent developments in monitoring behavior, such as measurement of eye movements in unconstrained observers, have allowed investigation of the use of vision in the natural world. This has led to a variety of insights that would be difficult to achieve in more constrained experimental contexts. In general, it shifts the focus of vision away from the properties of the stimulus toward a consideration of the behavioral goals of the observer. It appears that behavioral goals are a critical factor in controlling the acquisition of visual information from the world. This insight has been accompanied by a growing understanding of the importance of reward in modulating the underlying neural mechanisms and by theoretical developments using reinforcement learning models of complex behavior. These developments provide us with the tools to understanding how tasks are represented in the brain, and how they control acquisition of information through use of gaze. WIREs Cogni Sci 2011 2 158-166 DOI: 10.1002/wcs.113 For further resources related to this article, please visit the WIREs website.


[Evaluation of 2015-2016 MOTAKK HBV DNA and HCV RNA external quality assessment national program results].
MOTAKK, as a national external quality control program has been launched to evaluate the molecular detection of viral infections including HBV DNA and HCV RNA in molecular microbiology diagnostic laboratories in Turkey. This program is prepared in compliance with ISO 17043:2010 (Conformity assessment general requirements for proficiency testing) standards, and aims to take the place of external quality control programs from abroad, contributing to standardization and accuracy of molecular diagnostic tests in our country. The aim of this study was to evaluate 2015 and 2016 results of the MOTAKK External Quality Control Program for HBV DNA and HCV RNA viral load . The calls were announced on the web page of MOTAKK (www.motakk.org). The quality control samples were sent to participating laboratories in 2015 and 2016. Main stocks were prepared from patients with chronic hepatitis B and C who had viral load detection with reference methods according to WHO reference materials for viral load studies to improve quality control sera. From these main stocks, samples with different viral loads were prepared from dilutions of plasma with HBV, HCV, HAV, HIV, Parvovirus B19 and CMV negative serologic markers. Quality control samples were sent to the participating laboratories along with the negative samples in the cold chain. The laboratories accomplished the related tests within 2-3 weeks and entered their results on the MOTAKK web page. These results were analysed according to ISO 13528 (Statistical methods for use in proficiency testing by interlaboratory comparison) and scoring reports were created by a software developed by MOTAKK and sent to participating labs. Each laboratory evaluated their own results in comparison with the other laboratory results, reassessed the tests via observing the distance from the mean result and the reference values. The number of laboratories participating in the HBV DNA and HCV RNA external quality control program was 70-73 in 2015-2016. Participants were able to comply with the program tools, registering, entering results and receiving the results reports without problem. In HBV panel, 72.6-89.1% and 84.7-90.3% of the participant laboratories were in 1 standard deviation (SD) in 2015-2016, respectively. In HCV panel, 70.8-89.1% and 84.7-90.3% of the participant laboratories were in 1 SD in 2015-2016, respectively. A national external quality control program for HBV DNA and HCV RNA in Turkey has been prepared for the first time with this project and implemented successfully. All the data provided in the MOTAKK external quality control program final report, compensate all the data provided by the quality control program final reports from abroad; additionally, the report allows comparison of used technologies and commercial products.


Whole-Brain Multimodal Neuroimaging Model Using Serotonin Receptor Maps Explains Non-linear Functional Effects of LSD.
Understanding the underlying mechanisms of the human brain in health and disease will require models with necessary and sufficient details to explain how function emerges from the underlying anatomy and is shaped by neuromodulation. Here, we provide such a detailed causal explanation using a whole-brain model integrating multimodal imaging in healthy human participants undergoing manipulation of the serotonin system. Specifically, we combined anatomical data from diffusion magnetic resonance imaging (dMRI) and functional magnetic resonance imaging (fMRI) with neurotransmitter data obtained with positron emission tomography (PET) of the detailed serotonin 2A receptor (5-HT2AR) density map. This allowed us to model the resting state (with and without concurrent music listening) and mechanistically explain the functional effects of 5-HT2AR stimulation with lysergic acid diethylamide (LSD) on healthy participants. The whole-brain model used a dynamical mean-field quantitative description of populations of excitatory and inhibitory neurons as well as the associated synaptic dynamics, where the neuronal gain function of the model is modulated by the 5-HT2AR density. The model identified the causative mechanisms for the non-linear interactions between the neuronal and neurotransmitter system, which are uniquely linked to (1) the underlying anatomical connectivity, (2) the modulation by the specific brainwide distribution of neurotransmitter receptor density, and (3) the non-linear interactions between the two. Taking neuromodulatory activity into account when modeling global brain dynamics will lead to novel insights into human brain function in health and disease and opens exciting possibilities for drug discovery and design in neuropsychiatric disorders.


Evaluating Active U: an Internet-mediated physical activity program.
Engaging in regular physical activity can be challenging, particularly during the winter months. To promote physical activity at the University of Michigan during the winter months, an eight-week Internet-mediated program (Active U) was developed providing participants with an online physical activity log, goal setting, motivational emails, and optional team participation and competition. This study is a program evaluation of Active U. Approximately 47,000 faculty, staff, and graduate students were invited to participate in the online Active U intervention in the winter of 2007. Participants were assigned a physical activity goal and were asked to record each physical activity episode into the activity log for eight weeks. Statistics for program reach, effectiveness, adoption, and implementation were calculated using the Re-Aim framework. Multilevel regression analyses were used to assess the decline in rates of data entry and goal attainment during the program, to assess the likelihood of joining a team by demographic characteristics, to test the association between various predictors and the number of weeks an individual met his or her goal, and to analyze server load. Overall, 7,483 individuals registered with the Active U website ( approximately 16% of eligible), and 79% participated in the program by logging valid data at least once. Staff members, older participants, and those with a BMI < 25 were more likely to meet their weekly physical activity goals, and average rate of meeting goals was higher among participants who joined a competitive team compared to those who participated individually (IRR = 1.28, P < .001). Internet-mediated physical activity interventions that focus on physical activity logging and goal setting while incorporating team competition may help a significant percentage of the target population maintain their physical activity during the winter months.


Facile manufacture of porous organic framework membranes for precombustion CO2 capture.
The development of new membranes with high H2 separation performance under industrially relevant conditions (high temperatures and pressures) is of primary importance. For instance, these membranes may facilitate the implementation of energy-efficient precombustion CO2 capture or reduce energy intensity in other industrial processes such as ammonia synthesis. We report a facile synthetic protocol based on interfacial polymerization for the fabrication of supported benzimidazole-linked polymer membranes that display an unprecedented H2/CO2 selectivity (up to 40) at 423 K together with high-pressure resistance and long-term stability (>800 hours in the presence of water vapor).


The people around you are inside your head: Social context shapes spontaneous thought.
Humans are highly social. We spend most of our time interacting with the social world, and we spend most of our thoughts thinking about the social world. Are we social beings by default, or is our sociality a response to the social world? On the one hand, fundamental social needs may drive social behavior. According to this account, social thoughts fulfill social needs when the environment is insufficiently social. On the other hand, spontaneous thoughts may process incoming information. According to this account, social thoughts reflect the social information in the environment. To arbitrate between these possibilities, we assessed the content of spontaneous thought during mind wandering in three social contexts: solitude (Study 1), social presence (Study 2), and social interaction (Study 3). Additionally, in Study 1, we used functional neuroimaging to measure neural activity while participants considered social and nonsocial targets. Results consistently showed that spontaneous thought reflects the sociality of the world around us: Solitude decreased spontaneous social thought and decreased neural activity in the mentalizing network when thinking about a close friend. Social presence did not change spontaneous social thought. Social interaction increased spontaneous social thought. Finally, individual differences analyses (Study 4) showed that people in more social environments have more social thoughts. Together, the results show a pattern of increasing social thought in increasingly social environments. The predominance of social content in spontaneous thought can thus be explained by the predominance of social content in the world around us, rather than our innate, fundamental social needs. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


CDH13 and LPHN3 Gene Polymorphisms in Attention-Deficit/Hyperactivity Disorder: Their Relation to Clinical Characteristics.
Genetic factors play a major role in the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD). In this study, we aimed to investigate the relationship between the CDH13 (rs6565113, rs11150556) and LPHN3 (rs6551665, rs6858066, rs1947274, rs2345039) gene polymorphisms and ADHD. We also sought to examine possible relationships between these polymorphisms and the clinical course and treatment response in ADHD. A total of 120 patients (79% boys), aged 6 to 18 years, newly diagnosed (medication-naïve) with ADHD according to the DSM-5 and a group of 126 controls (74% girls) were enrolled in the study. We examined the association between the aforementioned polymorphisms and ADHD. Univariate and multivariate logistic regression analysis were used to evaluate factors influencing the treatment response of ADHD. A significant difference was found between ADHD and control groups in terms of genotype distribution of the LPHN3 rs6551665 and rs1947274 polymorphisms. The results also showed that having the GG genotype of rs6551665 and CC genotype of rs1947274 of the LPHN3 gene was associated with risk for ADHD, and this relationship was more prominent in male participants. In the multivariate logistic regression model established with variables shown to have a significant relationship with treatment response, the presence of the GG genotype of the LPHN3 rs6551665 polymorphism and high severity of ADHD assessed by CGI-S were associated with poor response to treatment. This study is the first study to investigate the relationship between ADHD and these polymorphisms among Turkish adolescents. Our results imply that the LPHN3 rs6551665 and rs1947274 polymorphisms have a significant effect on ADHD in a Turkish population, and support previous observations that the presence of the GG genotype of the LPHN3 rs6551665 polymorphism may be associated with poor response to treatment in ADHD.


All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results.
Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2 per day) for 90 days. Of the 22, four patients were previously untreated, two were resistant after conventional chemotherapy, and 16 were in first (n = 11), second (n = 4), or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0, 15, 30, 45, 60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(15;17) initially present in 20 patients was not found. The in vitro studies showed a differentiation in the presence of all-trans RA in 16 of the 18 tested cases. The single nonresponder to all trans RA in vitro did not respond in vivo. Adverse effects of RA therapy--skin and mucosa dryness, hypertriglyceridemia, and increase of hepatic transaminases--were frequently noted. We also observed bone pain in 11 patients and hyperleukocytosis in four patients. Whether maintenance treatment consisted of low-dose chemotherapy or all-trans RA, early relapses were observed. Five patients are still in complete remission (CR) at 4 to 13 months. Our study confirms the major efficacy of all-trans RA in M3, even in relapsing patients. Remissions are obtained by a differentiation process.


Novel strategies for enhanced removal of persistent Bacillus anthracis surrogates and Clostridium difficile spores from skin.
Removing spores of Clostridium difficile and Bacillus anthracis from skin is challenging because they are resistant to commonly used antimicrobials and soap and water washing provides only modest efficacy. We hypothesized that hygiene interventions incorporating a sporicidal electrochemically generated hypochlorous acid solution (Vashe(®)) would reduce the burden of spores on skin. Hands of volunteers were inoculated with non-toxigenic C. difficile spores or B. anthracis spore surrogates to assess the effectiveness of Vashe solution for reducing spores on skin. Reduction in spores was compared for Vashe hygiene interventions versus soap and water (control). To determine the effectiveness of Vashe solution for removal of C. difficile spores from the skin of patients with C. difficile infection (CDI), reductions in levels of spores on skin were compared for soap and water versus Vashe bed baths. Spore removal from hands was enhanced with Vashe soak (>2.5 log10 reduction) versus soap and water wash or soak (~2.0 log10 reduction; P<0.05) and Vashe wipes versus alcohol wipes (P<0.01). A combined approach of soap and water wash followed by soaking in Vashe removed >3.5 log10 spores from hands (P<0.01 compared to washing or soaking alone). Bed baths using soap and water (N =26 patients) did not reduce the percentage of positive skin cultures for CDI patients (64% before versus 57% after bathing; P =0.5), whereas bathing with Vashe solution (N =21 patients) significantly reduced skin contamination (54% before versus 8% after bathing; P =0.0001). Vashe was well-tolerated with no evidence of adverse effects on skin. Vashe was safe and effective for reducing the burden of B. anthracis surrogates and C. difficile spores on hands. Bed baths with Vashe were effective for reducing C. difficile on skin. These findings suggest a novel strategy to reduce the burden of spores on skin.


Apertureless near-field vibrational imaging of block-copolymer nanostructures with ultrahigh spatial resolution.
Nanodomains formed by microphase separation in thin films of the diblock copolymers poly(styrene-b-2-vinylpyridine) (PS-b-P2VP) and poly(styrene-b-ethyleneoxide) (PS-b-PEO) were imaged by means of infrared scattering-type near-field microscopy. When probing at 3.39 mum (2950 cm(-1)), contrast is obtained due to spectral differences between the C--H stretching vibrational resonances of the respective polymer constituents. An all-optical spatial resolution better than 10 nm was achieved, which corresponds to a sensitivity of just several thousand C--H groups facilitated by the local-field enhancement at the sharp metallic probe tips. The results demonstrate that infrared spectroscopy with access to intramolecular dimensions is within reach.


Exploring the Continuum of Vaccine Hesitancy Between African American and White Adults: Results of a Qualitative Study.
Vaccine delay and refusal present very real threats to public health. Since even a slight reduction in vaccination rates could produce major consequences as herd immunity is eroded, it is imperative to understand the factors that contribute to decision-making about vaccines. Recent scholarship on the concept of "vaccine hesitancy" emphasizes that vaccine behaviors and beliefs tend to fall along a continuum from refusal to acceptance. Most research on hesitancy has focused on parental decision-making about childhood vaccines, but could be extended to explore decision-making related to adult immunization against seasonal influenza. In particular, vaccine hesitancy could be a useful approach to understand the persistence of racial/ethnic disparities between African American and White adults. This study relied on a thematic content analysis of qualitative data, including 12 semi-structured interviews, 9 focus groups (N=90), and 16 in-depth interviews, for a total sample of 118 (N=118) African American and White adults. All data were transcribed and analyzed with Atlas.ti. A coding scheme combining both inductive and deductive codes was utilized to identify themes related to vaccine hesitancy. The study found a continuum of vaccine behavior from never-takers, sometimes-takers, and always-takers, with significant differences between African Americans and Whites. We compared our findings to the Three Cs: Complacency, Convenience, and Confidence framework. Complacency contributed to low vaccine acceptance with both races. Among sometimes-takers and always-takers, convenience was often cited as a reason for their behavior, while never-takers of both races were more likely to describe other reasons for non-vaccination, with convenience only a secondary explanation. However, for African Americans, cost was a barrier. There were racial differences in trust and confidence that impacted the decision-making process. The framework, though not a natural fit for the data, does provide some insight into the differential sources of hesitancy between these two populations. Complacency and confidence clearly impact vaccine behavior, often more profoundly than convenience, which can contribute either negatively or positively to vaccine acceptance. The Three Cs framework is a useful, but limited tool to understanding racial disparities. Understanding the distinctions in those cultural factors that drive lower vaccine confidence and greater hesitancy among African Americans could lead to more effective communication strategies as well as changes in the delivery of vaccines to increase convenience and passive acceptance.


Towards understanding the evolution of the human commensal yeast Candida albicans.
Allelic frequencies and relationships for one dimorphic locus and three unlinked polymorphic loci have been determined for 114 unrelated isolates of Candida albicans, including 14 laboratory reference strains and 50 strains from each of two geographic regions. Although there was no indication of geographical partitioning, there were significant correlations for specific allelic pairs among loci and little evidence that any alleles were in Hardy-Weinberg equilibrium. This gives additional support for the concept that the primary mode of genetic inheritance in this species is clonal, with other intracellular genetic events playing a lesser role in the creation of genomic diversity. Through inference of this and other known attributes of closely related Candida species, such as sequence analysis of IS1 and the ITS2 (internal transcribed spacer 2) region of the rDNA cistron, the deduced phylogeny suggests an evolutionarily recent origin for many frequently isolated strains. This finding will be of interest in the context of understanding pathogenicity and drug resistance in this human commensal yeast.


Chemical induced fragmentation of MOFs for highly efficient Ni-based hydrogen evolution catalysts.
A highly efficient catalyst for the hydrogen evolution reaction (HER) composed of Ni nanoparticles encapsulated in thin layers of N-doped carbon (Ni@NC) can be obtained by NH3 induced fragmentation of a Ni based MOF at mild temperature (450 °C). A mechanistic study shows that the high chemical reactivity of NH3 causes ammonolysis of the ligands and allows ligand removal well below their carbonization temperature. In conventional thermal decomposition in Ar, metal-ligand bond dissociation and ligand carbonization occurs in the same temperature region, resulting in a catalyst with high carbon content and much poorer HER performance. We further improve the HER performance by combining the NH3 induced fragmentation and destabilization of the Ni-MOF structure by low levels of Co substitution, which results in smaller, more uniform catalyst particles. Using the noble metal free HER catalyst, an overall solar-to-hydrogen efficiency of 7.9% is achieved in an electrolyzer driven by a commercial polycrystalline solar cell with an efficiency of 12.9%.


Regulation of transcription of the human T cell antigen receptor delta chain gene. A T lineage-specific enhancer element is located in the J delta 3-C delta intron.
We have defined transcriptional enhancing sequences inside the TCR-delta gene locus, using transient transfections with constructs containing DNA fragments cloned upstream to a reporter gene fused to a heterologous promoter. A 14-kb DNA region extending from the J delta 3 segment to 6 kb 3' to C delta was analyzed. We show the presence of positive regulatory sequences inside the J delta 3-C delta intron and have localized these sequences to two DNA fragments of approximately 300 and 258 bp. Analysis of cell specificity of the activation of such sequences demonstrates a T cell pattern for one of the two fragments. The nucleotide sequence of the T cell-specific element shows motifs sharing homology with previously described core enhancers.


Blood-based biomarkers for Parkinson's disease.
There is a pressing need for biomarkers to diagnose Parkinson's disease (PD), assess disease severity, and prognosticate course. Various types of biologic specimens are potential candidates for identifying biomarkers--defined here as surrogate indicators of physiological or pathophysiological states--but blood has the advantage of being minimally invasive to obtain. There are, however, several challenges to identifying biomarkers in blood. Several candidate biomarkers identified in other diseases or in other types of biological fluids are being pursued as blood-based biomarkers in PD. In addition, unbiased discovery is underway using techniques including metabolomics, proteomics, and gene expression profiling. In this review, we summarize these techniques and discuss the challenges and successes of blood-based biomarker discovery in PD. Blood-based biomarkers that are discussed include α-synuclein, DJ-1, uric acid, epidermal growth factor, apolipoprotein-A1, and peripheral inflammatory markers.


Glass formation and thermodynamics of supercooled monatomic liquids.
Atomic mechanism of glass formation of a supercooled simple monatomic liquid with Lennard-Jones-Gauss (LJG) interatomic potential is studied by molecular dynamics (MD) simulation. Supercooled and glassy states are obtained by cooling from the melt. Glassy state obtained at low temperatures is annealed for very long time, on the order of microsecond, and we find that glassy state remains unchanged and that the long-lived glassy state of a simple monatomic system in three dimensions is realized. We analyze the spatiotemporal properties of solid-like and liquid-like atoms that are defined by the Lindemann-like freezing criterion. The number of solid-like atoms, distributed throughout the liquid, increases with decreasing temperature toward glass transition and they form clusters. In the deeply supercooled region, almost all solid-like atoms form a single percolation cluster and its characteristic size increases sharply on further cooling. Glass formation in supercooled liquid occurs when a single percolation cluster of solid-like atoms involves a majority of atoms to form a relatively rigid solid phase. We also obtain several physical quantities of the system, including temperature dependence of mass density, Lindemann ratio, incoherent intermediate scattering function, α-relaxation time, evolution of radial distribution function, and local bond-pair orders detected by Honeycutt-Andersen analysis. We identify three characteristic temperatures related to the vitrification: a temperature at which crossover from liquid-like to solid-like dynamics occurs on cooling, the glass transition temperature, and the Vogel-Fulcher-Tammann temperature. Behavior of liquid-like atoms in glassy state has been analyzed and discussed.


[Factors influencing vitality among nurses].
This study was conducted to understand the degree of vitality, meaning in life and self-efficacy and to elucidate the factors influencing this vitality in the nurses of Korea. A cross-sectional survey of nurses from 4 hospitals was conducted by convenience sampling. Data collection was conducted through the use of questionnaires which were constructed to include a Vitality Self Test, Purpose in Life Test and Self-efficacy Scale. The degree of vitality in nurses was in the middle range. The nurses of this study had few goals towards meaning in life, and an existential vacuum state. A positive relationship was found between vitality and the research variables. The significant predictors influencing vitality in nurses were meaning in life, self-efficacy, and clinical career, and these variables accounted for 28.7% of the variance in vitality. This results support that vitality is an important link with meaning in life and self-efficacy. There should be a comprehensive study in the future for in-depth understanding of the vitality of nurses.


The perinatal development of epoxide-metabolizing enzyme activities in liver and extrahepatic organs of guinea pig and rabbit.
We have measured the activities of epoxide hydrase in microsomes and glutathione S-epoxidetransferase and glutathione S-aryltransferase in cytosol fractions of liver, lungs, kidneys, and small intestine from fetal and neonatal guinea pigs and rabbits. The rates at which adult values of these enzyme activities are reached in extrahepatic tissues differ from the rates of maturation of the hepatic enzyme activities for both species. In addition, the two pathways of epoxide metabolism studied here developed with age at different rates in any one organ. However, both cytosol glutathione S-transferases showed very similar developmental profiles in any one organ. It was especially interesting that the activities of both glutathione S-transferases were within the adult range in pulmonary cytosol fraction of guinea pig and rabbit before birth. Intestinal microsomes did not have adult values for epoxide hydrase activity until several weeks after birth. A feature common to both epoxide-metabolizing activities in hepatic and extrahepatic organs was a drop in mean specific activity, sometimes not statistically significant, around the time of birth. This decrease appeared to be due to dilution of the active enzyme with other protein, inasmuch as the total organ activity, in general, showed no such decline. We found that the pattern of development of hepatic microsomal epoxide hydrase activity was similar to developmental patterns published by others for hepatic microsomal mixed-function oxidases, and also that development of hepatic cytosol glutathione S-transferase was similar to hepatic development of glutathione S-transferase towards other substrates described in the literature.


Fipronil-induced genotoxicity and DNA damage in vivo: Protective effect of vitamin E.
Fipronil, an insecticide of the phenylpyrazole class has been classified as a carcinogen by United States Environmental Protection Agency, yet very limited information is available about its genotoxic effects. Adult male and female animals were gavaged with various doses of fipronil (2.5, 12.5, and 25 mg/kg body weight (bw)) to evaluate micronucleus test (mice), chromosome aberration (CA), and comet assay (rats), respectively. Cyclophosphamide (40 mg/kg bw; intraperitoneal) was used as positive control. Another group of animals were pretreated with vitamin E orally (400 mg/kg bw) for 5 days prior to administration of fipronil (12.5 mg/kg). Fipronil exposure in both male and female mice caused significant increase in the frequency of micronuclei (MN) in polychromatic erythrocytes. Similarly, structural CAs in bone marrow cells and DNA damage in the lymphocytes was found to be significantly higher in the male and female rats exposed to fipronil as compared to their respective controls. The average degree of protection (male and female animals combined together) shown by pretreatment of vitamin E against fipronil-induced genotoxicity was 63.28%: CAs; 47.91%: MN formation; and 74.70%: DNA damage. Findings of this study demonstrate genotoxic nature of fipronil regardless of gender effect and documents protective role of vitamin E.


Subcortical loop activation during selection of currently relevant memories.
Clinical studies on spontaneous confabulation and imaging studies with healthy subjects indicate that the anterior limbic system, in particular, the orbitofrontal cortex (OFC), is necessary to adjust thought and behavior to current reality. It appears to achieve this by continuously suppressing activated memories that do not pertain to ongoing reality, even before their content is consciously recognized. In the present study, we explored through what anatomical connections the OFC exerts this influence. Healthy subjects were scanned with H(2)(15)O PET as they performed four blocks of continuous recognition tasks, each block composed of a different type of stimuli (meaningful designs, geometric designs, words, nonwords). Within each block, three runs composed of exactly the same picture series, arranged in different order each time, were made. Subjects were asked to indicate item recurrences only within the currently ongoing run and to disregard familiarity from previous runs. In the combined first runs, in which all items were initially new and responses could be based on familiarity judgement (with repeated items) alone, we found medial temporal and right orbitofrontal activation. In the combined third runs, when all items were already known and selection of currently relevant memories was required, we found left orbitofrontal activation contingent with distinct activation of the ventral striatum, head and body of the caudate nucleus, substantia nigra, and medial thalamus. The study indicates that the OFC influences the cortical representation of memories through subcortical connections including the basal ganglia and the thalamus. The data are compatible with a role of the dopaminergic reward system in the monitoring of ongoing reality in thinking.


Role of gut microbiota in the pathogenesis of colorectal cancer; a review article.
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Lifestyle is identified as one of the most important risk factors for CRC, especially in sporadic colorectal cancer. The natural composition of the gut microbiota changes rapidly during the first decade of life. Maintaining homeostasis in the gut is essential as structural and metabolic functions of the commensal microbiota inhibit gut colonization of pathogens. Dysbiosis, imbalance in function or structure of gut microbiota, has been associated with a variety of diseases, such as colorectal cancer. The aim of this review was to investigate the possible links between the dysbiosis in gut microbiota and colorectal cancer, and the potential role of anaerobic gut microbiota in the pathogenesis of colorectal cancer. Based on this review, various studies have shown that some of the gut microbiota such as anaerobic bacteria significantly increased in CRC patients, but we suggest more investigations are required to assess the importance of these bacteria and their metabolites in the pathogenesis of CRC are required.


Is premenstrual dysphoric disorder a distinct clinical entity?
Does the evidence now available support the concept of premenstrual dysphoric disorder (PMDD) as a distinct clinical disorder such that the relative safety and efficacy of potential treatment can be evaluated? In a roundtable discussion of this question, a wealth of information was reviewed by a panel of experts. The key characteristics of PMDD, with clear onset and offset of symptoms closely linked to the menstrual cycle and the prominence of symptoms of anger, irritability, and internal tension, were contrasted with those of known mood and anxiety disorders. PMDD displays a distinct clinical picture that, in the absence of treatment, is remarkably stable from cycle to cycle and over time. Effective treatment of PMDD can be accomplished with serotinergic agents. At least 60% of patients respond to selective serotonin reuptake inhibitors (SSRIs). In comparison with other disorders, PMDD symptoms respond to low doses of SSRIs and to intermittent dosing. Normal functioning of the hypothalamic-pituitary-adrenal (HPA) axis, biologic characteristics generally related to the serotonin system, and a genetic component unrelated to major depression are further features of PMDD that separate it from other affective (mood) disorders. Based on this evidence, the consensus of the group was that PMDD is a distinct clinical entity. Potential treatments for this disorder can now be evaluated on this basis to meet the clear need for effective therapy.


The Drosophila maternal gene sésame is required for sperm chromatin remodeling at fertilization.
The spermatozoon features an extremely condensed and inactive nucleus. The unique sperm chromatin organization is acquired during the late stages of spermatid differentiation by the replacement of somatic histones with sperm-specific chromosomal proteins. At fertilization, the inactive sperm nucleus must be rapidly transformed into a DNA replication competent male pronucleus before the formation of the zygote. The sequential events of this crucial process are well conserved among animals and are controlled by molecules present in the egg. We have previously identified a Drosophila maternal effect mutation called sésame, which specifically arrests male pronucleus formation at a late stage of chromatin decondensation. In this study, we show that sésame affects maternal histone incorporation in the male pronucleus, a situation that is expected to prevent nucleosomal organization of the paternal chromatin. As an apparent consequence, the male pronucleus is arrested before the first S-phase and does not condense mitotic chromosomes. However, centromeric heterochromatin is present on paternal centromeres, which occasionally interact with microtubules. The abnormal chromatin organization of the male pronucleus does not prevent the formation of a male pronuclear envelope, which breaks down and reassembles in synchrony with maternally derived nuclei present in the same cytoplasm.