Association of bisphenol A, bisphenol F, and bisphenol S with ADHD symptoms in children.
Bisphenol A (BPA) has been linked to attention-deficit/hyperactivity disorder (ADHD) symptoms, but the neurotoxic effects of bisphenol substitutes such as bisphenol F (BPF) and S (BPS) have not been well investigated. We investigated the associations between BPA, BPF, and BPS with ADHD symptoms at multiple time points in children. The levels of BPA (at ages 4, 6, and 8), BPF (at ages 6 and 8), and BPS (at ages 6 and 8) were measured in 619 children. Because of the low detection frequency of BPF and BPS levels, participants were divided into categories (<or ≥ limit of detection (LOD) for BPF; < LOD, ≥ LOD and < median, or ≥ median for BPS). ADHD symptoms were assessed using the ADHD Rating Scale IV (ARS). The relationship between bisphenols and ARS scores was analyzed using Poisson regression models, and generalized additive models and piecewise regression models were further explored for BPA. BPA was detected in most participants (>97%), whereas BPF and BPS were less frequently detected (age 6: 17.5% for BPF and 42.0% for BPS; age 8: 51.6% for BPF and 73.3% for BPS). Doubling in BPA levels was associated with increased ARS scores by 4.7% (95% confidence intervals [CI]: 0.5, 9.2) at age 6. The association was greater with BPA levels higher than 3.0 μg/g creatinine (24.2% [95% CI: 15.5, 33.6] increase). The BPF ≥ LOD group had 10.8% (95% CI: 1.2, 21.4) higher ARS scores than the BPF < LOD group. The BPS ≥ median group had 11.4% (95% CI: 2.0, 21.7) higher ARS scores than the BPS < LOD group. All bisphenols, in particular those at or above the LOD or median levels, were associated with ADHD symptoms at age 6. Further prospective studies are warranted to determine causal inference.


Exploration of the impact of messages about genes and race on lay attitudes.
The effect of messages about genetics on lay audiences was assessed through an experimental study that exposed participants (n = 96) to a Public Service Announcement about race, genes, and heart disease. Participants who received a message that specified either 'Whites' or 'Blacks' as the subject of the message demonstrated elevated levels of racism, genetic basis for racism, and one dimension of genetic discrimination as compared to those receiving a version of the message with no race specification or in a no-message control condition. The presentation of such messages to the public is not recommended until additional research clarifies this finding and perhaps describes mitigating vocabularies or approaches.


Characterization of temperature and light effects on the defense response phenotypes associated with the maize Rp1-D21 autoactive resistance gene.
Rp1 is a complex locus of maize, which carries a set of genes controlling race-specific resistance to the common rust fungus, Puccinia sorghi. The resistance response includes the "Hypersensitive response" (HR), a rapid response triggered by a pathogen recognition event that includes localized cell death at the point of pathogen penetration and the induction of pathogenesis associated genes. The Rp1-D21gene is an autoactive allelic variant at the Rp1 locus, causing spontaneous activation of the HR response, in the absence of pathogenesis. Previously we have shown that the severity of the phenotype conferred by Rp1-D21 is highly dependent on genetic background. In this study we show that the phenotype conferred by Rp1-D21 is highly dependent on temperature, with lower temperatures favoring the expression of the HR lesion phenotype. This temperature effect was observed in all the 14 genetic backgrounds tested. Significant interactions between the temperature effects and genetic background were observed. When plants were grown at temperatures above 30°C, the spontaneous HR phenotype conferred by Rp1-D21 was entirely suppressed. Furthermore, this phenotype could be restored or suppressed by alternately reducing and increasing the temperature appropriately. Light was also required for the expression of this phenotype. By examining the expression of genes associated with the defense response we showed that, at temperatures above 30°C, the Rp1-D21 phenotype was suppressed at both the phenotypic and molecular level. We have shown that the lesion phenotype conferred by maize autoactive resistance gene Rp1-D21 is temperature sensitive in a reversible manner, that the temperature-sensitivity phenotype interacts with genetic background and that the phenotype is light sensitive. This is the first detailed demonstration of this phenomenon in monocots and also the first demonstration of the interaction of this effect with genetic background. The use of temperature shifts to induce a massive and synchronous HR in plants carrying the Rp1-D21 genes will be valuable in identifying components of the defense response pathway.


Flowering phenology, fruiting success and progressive deterioration of pollination in an early-flowering geophyte.
Spatio-temporal patterns of snowmelt and flowering times affect fruiting success in Erythronium grandiflorum Pursh (Liliaceae) in subalpine western Colorado, USA. From 1990 to 1995, I measured the consistency across years of snowmelt patterns and flowering times along a permanent transect. In most years since 1993, I have monitored fruit set in temporal cohorts (early- to late-flowering groups of plants) at one site. To assess 'pollination limitation', I have also conducted supplemental hand-pollination experiments at various times through the blooming season. The onset of blooming is determined by snowmelt, with the earliest years starting a month before the latest years owing to variation in winter snowpack accumulation. Fruit set is diminished or prevented entirely by killing frosts in some years, most frequently but not exclusively for the earlier cohorts. When frosts do not limit fruit set, pollination limitation is frequent, especially in the earlier cohorts. Pollination limitation is strongest for middle cohorts: it tends to be negated by frost in early cohorts and ameliorated by continuing emergence of bumble-bee queens in later cohorts. This lily appears to be poorly synchronized with its pollinators. Across the years of the study, pollination limitation appears to be increasing, perhaps because the synchronization is getting worse.


Identification of spermatozoa using a novel 3-plex MSRE-PCR assay for forensic examination of sexual assaults.
Identification of semen and then spermatozoa is essential to verify that sexual activity has occurred in alleged cases of sexual assault. Microscopic examination commonly used for spermatozoa identification is however time-consuming and can often lead to false-negative results for samples with deformed and, or, limited number of spermatozoa. To address this limitation, we report on a novel 3-plex MSRE-PCR (methylation-sensitive restriction enzyme-PCR) assay to specifically identify spermatozoa. This assay is comprised of 3 markers: a digestive control marker (DC), sperm-specific marker (SP), and Y chromosome marker (SRY). A total of 214 samples from 10 body fluids or tissues were analyzed. Specificity testing showed that all the normal semen samples were unambiguously identified as being sperm-positive, and no other body fluid (or tissues) showed a sperm-specific signal in the electropherogram. Testing for sensitivity showed that 0.1 ng of DNA from a semen extract was sufficient to identify the presence of spermatozoa by this assay. Mixture analyses illustrated the sensitivity of the assay when the vaginal/semen DNA ratio (80/0.1) was under 800 or the menstrual blood/semen DNA ratio (5/0.1) was under 50, the trace amounts (approximately 0.1 ng) of DNA from semen can still be identified by this 3-plex MSRE-PCR assay. This assay was also applied to the identification of 31 non-probative forensic samples from 18 sexual assault cases. The case studies showed that the 3-plex MSRE-PCR assay was an improvement in the sensitivity of spermatozoa detection.


Failure to Find a Conditioned Placebo Analgesic Response.
Background: Associative learning has, in several studies, been modulated by the sex of the participant. Consistent with this, a recent review found that conditioned nocebo effects are stronger in females than in males. Purpose: It has been suggested that conditioned placebo responses are stronger in females, and this hypothesis was investigated in the present study. Cortisol and measures of negative emotions were taken to investigate if these processes could mediate any conditioned placebo effects. Methods: Cold pain was applied to the volar forearm. The Conditioned group received inert capsules prior to two presentations of less painful stimulations, to associate intake of the capsules with reduced pain. The pain control group received the same painful stimulation as the Conditioned group, but no capsules. The Capsule control group received the capsules in the same way as the Conditioned group, but no decrease in the painful stimulation. Participant sex was crossed across groups. It was hypothesized that in the Conditioned group, an expectation of reduced pain should be induced after administration of the capsules, and this should generate placebo analgesia, and mostly so in females. Results: The Conditioned group reported lower pain during conditioning, and rated the capsules as more effective painkillers than the capsule control group. However, placebo analgesia was not reliably observed in the Conditioned group. Conclusion: The placebo capsules were rated as effective painkillers, but this did not translate into a placebo analgesic effect. This could be due to violation of response expectancies, too few conditioning trials, and differences in pain ratings in the pre-test that could be due to previous experience with painkillers.


Mode of growth of bacterial pathogens in chronic polymicrobial human osteomyelitis.
Direct examination of material from two cases of persistent (2 and 60 years) osteomyelitis by morphological and culture techniques showed that the pathogens comprised several bacterial species whose cells grew predominantly in discrete exopolysaccharide-enclosed microcolonies made up of a single bacterial morphotype. Bacterial microcolonies were seen between tissue elements in infected connective tissue, and the microcolonies adherent to bone surfaces coalesced to form extensive biofilms that occluded the surfaces of dead bone in sequestrae. Decalcification techniques were required to examine the interior of infected bone, but recognizable remnants were associated with very large amounts of fibrous, ruthenium red-stained material. All bacterial growth in these persistent infections occurred within an intercellular matrix, and some elements of this matrix, which was fibrous in transmission electron microscopy and amorphous in scanning electron microscopy, were associated with the surfaces of bacterial cells in a manner that suggested their production by these organisms. All of the implications of this microcolony mode of bacterial growth in osteomyelitis, and in other chronic bacterial diseases, have yet to be determined.


Self-Efficacy for Sexual Risk Reduction and Partner HIV Status as Correlates of Sexual Risk Behavior Among HIV-Positive Adolescent Girls and Women.
Little is known about the correlates of sexual risk behavior among HIV-positive adolescent girls and women in the United States. This study investigates two potential factors related to unprotected vaginal and anal intercourse (UVAI) that have yet to be thoroughly studied in this group: self-efficacy for sexual risk reduction and partner HIV status. Data was analyzed from 331 HIV-positive adolescent girls and women between 12 and 24 years old who reported vaginal and/or anal intercourse with a male partner in the past 3 months at fifteen sites across the United States. Results show that overall self-efficacy (B=-0.15, p=0.01), self-efficacy to discuss safe sex with one's partner (B=-0.14, p=0.01), and self-efficacy to refuse unsafe sex (B=-0.21, p=0.01) are related to UVAI episodes. Participants with only HIV-positive partners or with both HIV-positive and HIV-negative partners showed a trend towards higher percentages of UVAI episodes compared to participants with only HIV-negative partners (F(2, 319)=2.80, p=0.06). These findings point to the importance of including self-efficacy and partner HIV status in risk-reduction research and interventions developed for HIV-positive adolescent girls and young women.


Pathways for balancing CO2 emissions and sinks.
In December 2015 in Paris, leaders committed to achieve global, net decarbonization of human activities before 2100. This achievement would halt and even reverse anthropogenic climate change through the net removal of carbon from the atmosphere. However, the Paris documents contain few specific prescriptions for emissions mitigation, leaving various countries to pursue their own agendas. In this analysis, we project energy and land-use emissions mitigation pathways through 2100, subject to best-available parameterization of carbon-climate feedbacks and interdependencies. We find that, barring unforeseen and transformative technological advancement, anthropogenic emissions need to peak within the next 10 years, to maintain realistic pathways to meeting the COP21 emissions and warming targets. Fossil fuel consumption will probably need to be reduced below a quarter of primary energy supply by 2100 and the allowable consumption rate drops even further if negative emissions technologies remain technologically or economically unfeasible at the global scale.


Pattern of paediatric corneal laceration injuries in the University of Port Harcourt teaching hospital, Rivers state, Nigeria.
Corneal lacerations mostly affect younger children, commonly males, who will constitute the majority of the workforce. Clinical outcomes are reviewed and compared so that measures to reduce their occurrence and improve outcome can be proffered. Records of all children between the ages of 1-18 yrs, who presented with penetrating eye injuries at the eye clinic of the University of Port Harcourt teaching Hospital, Rivers state, Nigeria between January 2002 and December 2009 were included. Information retrieved -patient's Bio data, presenting symptoms, presenting visual acuity (VA), source of injury, surgical intervention and outcome using VA. All data analysed with EPI Info version 6 with the aid of a statistician. Folders of thirty-six children (36 eyes) between the ages of 0-18 years diagnosed with corneal laceration over a period of 8 years out of 65 cases managed within that period available. Other folders reported as missing. Male female ratio 3:1, the mean age is 8.7 years (SD ± 3.67). Only one presented within 24 hours. Objects causing injury mainly missiles with stones/catapult injuries (n = 8, 22.2%). Presenting VAs in those that could be measured, ranged from 6/24 to 6/60 (n = 4, 11%) to no light perception (NLP) (n = 5, 13.9%). Associated injuries include lid laceration, cataract, vitreous haemorrhage and retinal detachment. Twenty one patients had primary corneal repair (58.3%) carried out within 7 days of presentation. Four had endophthalmitis. After 3 months follow up, VA of 6/60 and better was achieved in 11 of 18 eyes left in follow up (6/60-6/24 in 8 eyes (22.2%), 6/18 and better in 3 eyes (8.3%). Most eye injuries in children are preventable. In this study, the prognosis was better in those whose injuries were confined to a peripheral part of the cornea, with no other associated injury, who presented within 5 days and who did not have any intraocular infection at the time of presentation. The importance of health education, adult supervision of play and application of appropriate measures that is necessary for reducing the incidence and severity of trauma is emphasized.


Ets1 was significantly activated by ERK1/2 in mutant K-ras stably transfected human adrenocortical cells.
In our previous study on the tumorigenesis of human functional adrenal tumors, we observed a high frequency of point mutation in the K-ras gene in clinical adrenal tumors. Therefore, we analyzed gene profiles of mutant K-ras transfected adrenocortical cells by DNA microarray to determine the expression pattern of genes related to cell cycle, signal transduction, apoptosis, tumorigenesis, steroidogenesis, and other expressed sequence tags (ESTs). Then we analyzed all of the significant differentially expressed genes by bioinformatics tools, "Matchminer" and "Gominer." The results revealed that expression of mutant K-ras gene induced by IPTG upregulated Ets1, which was mainly related to cell proliferation. After carefully being analyzed by software "DAVID" and "Pathart," Ets1 was found to be activated by being phosphorylated at theronine 38 by ERK1/2, and in turn, to regulate the following genes: uPA, MMP-3, and prolactin (Ling et al., 2003; Duffy and Daggan, 2004; Maupas-Schwalm et al., 2004; van Themsche et al., 2004). The result of Western blotting analysis confirmed that Ets1 was really phosphorylated when mutant K-ras was activated. On the other hand, the membrane blotting analyses indicated that the expression levels of uPA, MMP-3, and prolactin in human adrenocortical cells stably transfected with the mutant K-ras gene were significantly higher than those in normal control cells. Compared to control cells, the level of prolactin raised 1.4-fold, the level of MMP-3 raised 1.8-fold, and the level of uPA raised 2.1-fold in the transfected cells. From the results of this study, we proposed a mechanism of Ets1 in human adrenocortical cells expressing a mutated K-ras gene.


Are Nanoparticles Spherical or Quasi-Spherical?
The geometry of quasi-spherical nanoparticles is investigated. The combination of SEM imaging and electrochemical nano-impact experiments is demonstrated to allow sizing and characterization of the geometry of single silver nanoparticles.


Application of a Modified 3D-PCSI-MS Ion Source to On-Site, Trace Evidence Processing via Integrated Vacuum Collection.
Trace evidence, including hair, fibers, soil/dust, and gunshot residue (GSR), can be recovered from a crime scene to help identify or associate a suspect with illegal activities via physical, chemical, and biological testing. Vacuum collection is one technique that is employed in recovering such trace evidence but is often done so in a targeted manner, leaving other complementary, chemical-specific information unexamined. Here, we describe a modified 3D-printed cone spray ionization (3D-PCSI) source with integrated vacuum collection for on-site, forensic evidence screening, allowing the processing of targeted physical traces and nontargeted chemical species alike. The reported form factor allows sample collection, onboard extraction, filtration, and spray-based ionization in a singular vessel with minimal handling of evidence by the operator. Utilizing authentic forensic evidence types and portable MS instrumentation, this new method was characterized through systematic studies that replicate CSI applications. Reliability in the form of false positive/negative response rates was determined from a modest, user-blinded data set, and other attributes, such as collection efficacy and detection limit, were examined.


Spinal leptomeningeal invasion from intracranial glioblastoma multiforme.
The cases of 2 patients with meningeal and spinal spread of primary intracranial glioblastoma are reported. While such spinal meningeal spread of intracranial glioblastoma is considered rare, it appears that such involvement is not uncommon if specifically investigated. The incidence of meningeal seeding by primary intracranial glioblastoma may be expected to rise as new therapies are directed toward the primary tumor.


The 3' ends of the deletions of Spanish delta beta zero-thalassemia and black HPFH 1 and 2 lie within 17 kilobases.
Spanish delta beta zero-thalassemia, a mild thalassemic condition characterized by increased level of hemoglobin (Hb) F production during adult life, is known to be due to a large deletion starting within the beta globin gene cluster and extending beyond the 3' breakpoint of any other similar deletional defects so far identified. By molecular cloning and by genomic mapping we now demonstrate that the deletion of Spanish delta beta zero-thalassemia ends at approximately 11 and 17 kilobases (kb) downstream to the 3' endpoints of black hereditary persistence of fetal hemoglobin (HPFH) type 1 and 2, respectively. As suggested by the complete characterization of this and other deletional defects involving the beta globin gene cluster, the 5' and 3' breakpoints of several deletions cluster in rather restricted DNA areas, further strengthening the idea that common molecular mechanisms may operate in causing these deletions.


Comparing neural sentence encoders for topic segmentation across domains: not your typical text similarity task.
Neural sentence encoders (NSE) are effective in many NLP tasks, including topic segmentation. However, no systematic comparison of their performance in topic segmentation has been performed. Here, we present such a comparison, using supervised and unsupervised segmentation models based on NSEs. We first compare results with baselines, showing that the use of NSEs does often provide improvements, except for specific domains such as news shows. We then compare over three different datasets a range of existing NSEs and a new NSE based on ad hoc pre-training strategy. We show that existing literature documenting general performance gains of NSEs does not always conform to the results obtained by the same NSEs in topic segmentation. If Transformers-based encoders do improve over previous approaches, fine-tuning in sentence similarity tasks or even on the same topic segmentation task we aim to solve does not always equate to better performance, as results vary across method being used and domains of application. We aim to explain this phenomenon and the relative poor performance of NSEs in news shows by considering how well different NSEs encode the underlying lexical cohesion of same-topic segments; to do so, we introduce a new metric, ARP. The results from this study suggest that good topic segmentation results do not always rely on good cohesion modelling on behalf of the segmenter and that is dependent upon what kind of text we are trying to segment. Also, it appears evident that traditional sentence encoders fail to create topically cohesive clusters of segments when used on conversational data. Overall, this work advances our understanding of the use of NSEs in topic segmentation and of the general factors determining the success (or failure) of a topic segmentation system. The new proposed metric can quantify the lexical cohesion of a multi-topic document under different sentence encoders and, as such, might have many different uses in future research, some of which we suggest in our conclusions.


Public Trust in COVID-19 Prevention and Responses Between January and May 2020 in Bangladesh.
Although the Government of Bangladesh (GoB) developed some policy initiatives during the first phase of COVID-19, their efforts were questioned due to indecision, late policy decisions and implementation, and a proliferation of fake testing and fake news. As such, this research aims to examine public trust in preparedness and response measures undertaken by both the GoB and private sector organisations in Bangladesh between January and May 2020. A cross-sectional survey method was applied to a sample of Bangladeshi residents using a questionnaire distributed between April and June 2020. Three hundred and seven respondents participated in an online questionnaire that was disseminated on online outlets, such as e-mail, Facebook Messenger, and WhatsApp. The survey questionnaire was distributed to potential respondents, and continuous-chain messages were provided. Data were analyzed using exploratory factor analysis (EFA). Of the 307 participants, 77% were male and 23% were female. Findings suggest that the participants showed greater approval of private sector responses than of governmental preparedness and response activities. For preparedness activities, participants were negative about both the GoB efforts to organize and provide personal protective equipment (PPE) for doctors in time as a safeguard against COVID-19, and also the lack of coordination and informed decision-making in relation to facing COVID-19. Respondents were asked to share their perception of the suitability of GoB pandemic management plans, as evidenced by plan effectiveness during the COVID-19 pandemic. A lower level of trust was demonstrated by the Bangladeshis with regard to preparedness and response measures taken in Bangladesh. Based on participants' concerns and suggestions and a review of drawback of policy responses in the early stage, a set of recommendations are provided for future pandemics like public health emergency risk management in Bangladesh.


Rickets of prematurity. Supranormal levels of serum 1,25-dihydroxyvitamin D.
Rickets, hypocalcemia, hypophosphatemia, and hyperparathyroidism were found in a low-birth-weight premature infant. The concentration of plasma calcitriol (1,25-dihydroxyvitamin D) was 145 pg/mL. With additional exogenous calcitriol (37.5 ng/kg/24 hr) given for eight weeks, the biochemical abnormalities were corrected and healing of rickets was evident. Three months later, while receiving only 400 IU of ergocalciferal daily, the patient had normal levels of serum calcium, phosphate, and alkaline phosphatase with a serum calcitriol concentration of 36 pg/mL. These observations suggest that rickets of prematurity may involve a malabsorption of calcium and phosphorus with an elevated calcitriol level needed to overcome this inadequate absorption. Additional doses of calcitriol may be of benefit in these infants, although it must be given carefully. Furthermore, the role of phosphate supplementation in these infants requires consideration.


Nevoid malignant melanoma in an albino woman.
Albinism is a disorder of hypopigmentation affecting the skin, hair and eyes. Ultraviolet light induced cutaneous tumours are common in patients with albinism due to reduced or absent protection from melanin, with squamous cell carcinoma being the most common. Although non-melanomatous skin cancers are more frequent in patients with albinism, dysplastic nevi and melanoma present a greater diagnostic challenge in this group because of their hypopigmented appearance. Here the authors report a case of nevoid malignant melanoma in a patient who had type 1A oculocutaneous albinism.


Minor tropical fruits as a potential source of bioactive and functional foods.
Tropical fruits are defined as fruits that are grown in hot and humid regions within the Tropic of Cancer and Tropic of Capricorn, covering most of the tropical and subtropical areas of Asia, Africa, Central America, South America, the Caribbean and Oceania. Depending on the cultivation area covered, economic value and popularity these tropical fruits are divided into major and minor tropical fruits. There is an annual increment of 3.8% in terms of commercialization of the tropical fruits. In total 26 minor tropical fruits (Kiwifruit, Lutqua, Carambola, Tree Tomato, Elephant apple, Rambutan, Bay berry, Mangosteen, Bhawa, Loquat, Silver berry, Durian, Persimon, Longan, Passion fruit, Water apple, Pulasan, Indian gooseberry, Guava, Lychee, Annona, Pitaya, Sapodilla, Pepino, Jaboticaba, Jackfruit) have been covered in this work. The nutritional composition, phytochemical composition, health benefits, traditional use of these minor tropical fruits and their role in food fortification have been portrayed.


Active participation of mothers during speech therapy improved language development of children with cleft palate.
Whole language intervention uses the principles of natural language learning, which consider language not as an independent system but as a system intimately related to other cognitive and social abilities. This paper compares the outcome of speech therapy given in different settings to two groups of children with cleft palate. Those in the first group were treated by the speech pathologist alone (control group), whereas those in the second group were treated by the speech pathologist but were also accompanied by their mothers (experimental group). The purpose of this study was to find out if including the mother as an active participant in speech therapy sessions would improve the language development of children with cleft palate who also had additional language delays. Both groups were evaluated before and after treatment to evaluate the advance of each group. The patients accompanied by their mothers had significantly better language skills compared with patients treated without their mothers. The results support the statement that language development is related to mother-child mode of daily life interaction in children with cleft palate.


Spatial and temporal regularization to estimate COVID-19 reproduction number R(t): Promoting piecewise smoothness via convex optimization.
Among the different indicators that quantify the spread of an epidemic such as the on-going COVID-19, stands first the reproduction number which measures how many people can be contaminated by an infected person. In order to permit the monitoring of the evolution of this number, a new estimation procedure is proposed here, assuming a well-accepted model for current incidence data, based on past observations. The novelty of the proposed approach is twofold: 1) the estimation of the reproduction number is achieved by convex optimization within a proximal-based inverse problem formulation, with constraints aimed at promoting piecewise smoothness; 2) the approach is developed in a multivariate setting, allowing for the simultaneous handling of multiple time series attached to different geographical regions, together with a spatial (graph-based) regularization of their evolutions in time. The effectiveness of the approach is first supported by simulations, and two main applications to real COVID-19 data are then discussed. The first one refers to the comparative evolution of the reproduction number for a number of countries, while the second one focuses on French departments and their joint analysis, leading to dynamic maps revealing the temporal co-evolution of their reproduction numbers.


Mechanisms of septal lamination in the developing hippocampus analyzed by outgrowth of fibers from septal implants. II. Absence of guidance by degenerative debris.
In previous study (Lewis, E.R., and C. W. Cotman (1980) Brain Res. 96: 307--330; E. R. Lewis and C. W. Cotman, submitted for publication), we have shown that septal tissues grafted to the brain of a neonatal rat will extend fibers into special terminal laminae within the hippocampal formation of the recipient. As a consequence of the implantation surgery, neurons in the developing entorhinal cortex are ablated and it is possible that processes of implanted cells may be guided by degenerating afferent fibers in the host. In order to test this hypothesis, we have characterized the distribution of degeneration argyrophilia that results from the implant surgery and the time course of its removal and examined the growth of septal implants in a host brain devoid of observable degenerative debris. The pattern of degeneration argyrophilia shortly after the implantation surgery did not correspond to the pattern of implant-associated AChE staining in the host hippocampal formation. By 72 hr after surgery, the great majority of argyrophilic debris had been removed. Implants placed in a cavity created 72 hr after surgery demonstrated excellent viability and produced the typical pattern of AChE staining in the hippocampal formation of the host. This suggests that the presence of degenerating host axons is not necessary to guide the ingrowth of axons and establish septohippocampal laminated fields.


Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors.
Notch receptors normally play a key role in guiding a variety of cell fate decisions during development and differentiation of metazoan organisms. On the other hand, dysregulation of Notch1 signaling is associated with many different types of cancer as well as tumor angiogenesis, making Notch1 a potential therapeutic target. Here we report the in vitro activities of inhibitory Notch1 monoclonal antibodies derived from cell-based and solid-phase screening of a phage display library. Two classes of antibodies were found, one directed against the EGF-repeat region that encompasses the ligand-binding domain (LBD), and the second directed against the activation switch of the receptor, the Notch negative regulatory region (NRR). The antibodies are selective for Notch1, inhibiting Jag2-dependent signaling by Notch1 but not by Notch 2 and 3 in reporter gene assays, with EC(50) values as low as 5+/-3 nM and 0.13+/-0.09 nM for the LBD and NRR antibodies, respectively, and fail to recognize Notch4. While more potent, NRR antibodies are incomplete antagonists of Notch1 signaling. The antagonistic activity of LBD, but not NRR, antibodies is strongly dependent on the activating ligand. Both LBD and NRR antibodies bind to Notch1 on human tumor cell lines and inhibit the expression of sentinel Notch target genes, including HES1, HES5, and DTX1. NRR antibodies also strongly inhibit ligand-independent signaling in heterologous cells transiently expressing Notch1 receptors with diverse NRR "class I" point mutations, the most common type of mutation found in human T-cell acute lymphoblastic leukemia (T-ALL). In contrast, NRR antibodies failed to antagonize Notch1 receptors bearing rare "class II" or "class III" mutations, in which amino acid insertions generate a duplicated or constitutively sensitive metalloprotease cleavage site. Signaling in T-ALL cell lines bearing class I mutations is partially refractory to inhibitory antibodies as compared to cell-penetrating gamma-secretase inhibitors. Antibodies that compete with Notch1 ligand binding or that bind to the negative regulatory region can act as potent inhibitors of Notch1 signaling. These antibodies may have clinical utility for conditions in which inhibition of signaling by wild-type Notch1 is desired, but are likely to be of limited value for treatment of T-ALLs associated with aberrant Notch1 activation.


Comparisons of ambulatory blood pressure monitoring and repeated office measurements in primary care.
The accuracy of office blood pressure (BP) readings is questionable because of blood pressure variability and measurement errors. The primary aim of this study was to determine the number of office visits required to optimize the estimation of usual blood pressure in older adults in primary care. Ambulatory blood pressure monitoring was used to define usual blood pressure in an observational study of 75 randomly selected family practice patients. Each subject made six visits for office BP measurements and had 24-hour ambulatory BP monitoring done twice. Mean office BP, based on one through six visits, was compared with mean ambulatory BP. The sample consisted of 29 men and 46 women; 18 were black and 57 were white. Twenty-one subjects were taking antihypertensive medication. The mean age +/- 1/standard deviation (SD) was 60 (+/- 8) years. The correlation between mean office BP and mean ambulatory BP rose with the number of visits averaged, with most of the gain obtained within 3 visits. The maximal correlation for 24-hour ambulatory BP was r = .85/.75 (systolic/diastolic) (P < .01). However, even when using average office BP over six visits to estimate mean ambulatory BP, a discrepancy of > or = 10 mm Hg between estimated and observed ambulatory BP levels persisted in 18% to 20% of subjects. Readings from at least three office visits should be averaged to estimate usual blood pressure. It should be noted, however, that important discrepancies between estimated and observed mean ambulatory BP persist even after readings taken over six visits. Ambulatory BP monitoring probably provides unique information about usual blood pressure that cannot be captured by repeated office BP readings.


Practical clinical trials in psychopharmacology: a systematic review.
Practical clinical trials (PCTs) are randomized experiments under typical practice conditions with the aim of testing the "real-life" benefits and risks of therapeutic interventions. Influential PCTs have been conducted in cardiology, oncology, and internal medicine. Psychotropic medications are widely and increasingly used in medical practice. This review examines recent progress in conducting PCTs in psychopharmacology. The January 2000 to October 2014 MEDLINE, Scopus, and ClinicalTrials.gov databases were searched for peer-reviewed publications of PCTs with at least 100 subjects per treatment arm. Most PCTs in psychiatry evaluated mental health services or psychosocial interventions rather than specific pharmacotherapies. Of 157 PCTs in psychiatry, 30 (19%) were in psychopharmacology, with a median of 2 publications per year and no increase during the period of observation. Sample size ranged from 200 to 18,154; only 11 studies randomized 500 patients or more. Psychopharmacology PCTs were equally likely to be funded by industry as by public agencies. There were 10 PCTs of antidepressants, for a total of 4206 patients (in comparison with at least 46 PCTs of antihypertensive medications, for a total of 208,014 patients). Some psychopharmacology PCTs used suicidal behavior, treatment discontinuation, or mortality as primary outcome and produced effectiveness and safety data that have influenced both practice guidelines and regulatory decisions. Practical clinical trials can constitute an important source of information for clinicians, patients, regulators, and policy makers but have been relatively underused in psychopharmacology. Electronic medical records and integrated practice research networks offer promising platforms for a more efficient conduct of PCTs.


Herpes simplex virus 1 blocks caspase-3-independent and caspase-dependent pathways to cell death.
Earlier reports have shown that herpes simplex virus 1 (HSV-1) mutants induce programmed cell death and that wild-type HSV blocks the execution of the cell death program triggered by viral gene products, by the effectors of the immune system such as the Fas and tumor necrosis factor pathways, or by nonspecific stress agents such as either osmotic shock induced by sorbitol or thermal shock. A report from this laboratory showed that caspase inhibitors do not block DNA fragmentation induced by infection with the HSV-1 d120 mutant. To identify the events in programmed cell death induced and blocked by HSV-1, we examined cells infected with wild-type virus or the d120 mutant or cells infected and exposed to sorbitol. We report that: (i) the HSV-1 d120 mutant induced apoptosis by a caspase-3-independent pathway inasmuch as caspase 3 was not activated and DNA fragmentation was not blocked by caspase inhibitors even though the virus caused cytochrome c release and depolarization of the inner mitochondrial membrane. (ii) Cells infected with wild-type HSV-1 exhibited none of the manifestations associated with programmed cell death assayed in these studies. (iii) Uninfected cells exposed to osmotic shock succumbed to caspase-dependent apoptosis inasmuch as cytochrome c was released, the inner mitochondrial potential was lost, caspase-3 was activated, and chromosomal DNA was fragmented. (iv) Although caspase-3 was activated in cells infected with wild-type HSV-1 and exposed to sorbitol, cytochrome c outflow, depolarization of the inner mitochondrial membrane, and DNA fragmentation were blocked. We conclude that although d120 induces apoptosis by a caspase-3-independent pathway, the wild-type virus blocks apoptosis induced by this pathway and also blocks the caspase-dependent pathway induced by osmotic shock. The block in the caspase-dependent pathway may occur downstream of caspase-3 activation.


Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception.
Interstitial cystitis/painful bladder syndrome (IC/PBS), is a severely debilitating chronic condition that is frequently unresponsive to conventional pain medications. The etiology is unknown, however evidence suggests that nervous system sensitization contributes to enhanced pain in IC/PBS. In particular, central nervous system plasticity of glutamatergic signaling involving NMDA and metabotropic glutamate receptors (mGluRs) has been implicated in a variety of chronic pain conditions. Here, we test the hypothesis that mGluR5 mediates both non-inflammatory and inflammatory bladder pain or nociception in a mouse model by monitoring the visceromotor response (VMR) during graded bladder distention. Using a combination of genetic and pharmacologic approaches, we provide evidence indicating that mGluR5 is necessary for the full expression of VMR in response to bladder distention in the absence of inflammation. Furthermore, we observed that mice infected with a uropathogenic strain of Escherichia coli (UPEC) develop inflammatory hyperalgesia to bladder distention, and that the selective mGluR5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl) urea], reduces the VMR to bladder distention in UPEC-infected mice. Taken together, these data suggest that mGluR5 modulates both inflammatory and non-inflammatory bladder nociception, and highlight the therapeutic potential for mGluR5 antagonists in the alleviation of bladder pain.


Nanostructured materials for photocatalysis.
Photocatalysis is a green technology which converts abundantly available photonic energy into useful chemical energy. With a rapid rise of flow photoreactors in the last decade, the design and development of novel semiconductor photocatalysts is happening at a blistering rate. Currently, developed synthetic approaches have allowed the design of diverse modified/unmodified semiconductor materials exhibiting enhanced performances in heterogeneous photocatalysis. In this review, we have classified the so far reported highly efficient modified/unmodified semiconductor photocatalysts into four different categories based on the elemental composition, band gap engineering and charge carrier migration mechanism in composite photocatalysts. The recent synthetic developments are reported for each novel semiconductor photocatalyst within the four different categories, namely: pure semiconductors, solid solutions, type-II heterojunction nanocomposites and Z-scheme. The motivation behind the synthetic upgrading of modified/unmodified (pure) semiconductor photocatalysts along with their particular photochemical applications and photoreactor systems have been thoroughly reviewed.


Elevated FGF23 and disordered renal mineral handling with reduced bone mineralization in chronically erythropoietin over-expressing transgenic mice.
Fibroblast Growth Factor 23 (FGF23) is a phosphaturic factor causing increased renal phosphate excretion as well as suppression of 1,25 (OH)2-vitamin D3. Highly elevated FGF23 can promote development of rickets and osteomalacia. We and others previously reported that acute application of erythropoietin (EPO) stimulates FGF23 production. Considering that EPO is clinically used as chronic treatment against anemia, we used here the Tg6 mouse model that constitutively overexpresses human EPO in an oxygen-independent manner, to examine the consequences of long-term EPO therapy on mineral and bone metabolism. Six to eight weeks old female Tg6 mice showed elevated intact and C-terminal fragment of FGF23 but normal plasma levels of PTH, calcitriol, calcium and phosphate. Renal function showed moderate alterations with higher urea and creatinine clearance and mild albuminuria. Renal phosphate excretion was normal whereas mild hypercalciuria was found. Renal expression of the key proteins TRPV5 and calbindin D28k involved in active calcium reabsorption was reduced in Tg6 mice. Plasma levels of the bone turnover marker osteocalcin were comparable between groups. However, urinary excretion of deoxypyridinoline (DPD) was lower in Tg6 mice. MicroCT analysis showed reduced total, cortical, and trabecular bone mineral density in femora from Tg6 mice. Our data reveal that chronic elevation of EPO is associated with high FGF23 levels and disturbed mineral homeostasis resulting in reduced bone mineral density. These observations imply the need to study the impact of therapeutically applied EPO on bone mineralization in patients, especially those suffering from chronic kidney disease.


Pathological assessment of mismatch repair gene variants in Lynch syndrome: past, present, and future.
Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose consequences for pathogenicity cannot be easily interpreted. Such variants are designated as "variants of uncertain significance" (VUS). Management of LS can be significantly improved by identifying individuals who carry a pathogenic variant and thus benefit from screening, preventive, and therapeutic measures. Also, identifying family members that do not carry the variant is important so they can be released from the intensive surveillance. Determining which genetic variants are pathogenic and which are neutral is a major challenge in clinical genetics. The profound mechanistic knowledge on the genetics and biochemistry of MMR enables the development and use of targeted assays to evaluate the pathogenicity of variants found in suspected patients with LS. We describe different approaches for the functional analysis of MMR gene VUS and propose development of a validated diagnostic framework. Furthermore, we call attention to common misconceptions about functional assays and endorse development of an integrated approach comprising validated assays for diagnosis of VUS in patients suspected of LS.


Do We Need Basic Research in Cardiac Surgery?
Thinking about the daily practice of cardiac surgery, genetically altered mouse models, polymerase chain reactions, western blots, and other laboratory tools are the last that comes to mind. It is, therefore, not surprising that the pursuit of such basic science activities by practicing surgeons and those in training is often limited. However, there is an innate connection between these two seemingly different disciplines. To address and visualize this connection, we propose the following three hypotheses. First, cardiac surgery would not be at its present level of expertise without fundamental contributions of basic science. Second, without practicing cardiac surgeons performing basic research and translating their results to clinical practice next to their daily work, our ability to care for cardiac surgery patients would be poorer. Third, basic science training for those aiming to become practicing cardiac surgeons improves their ability to properly care for their patients. Finally, we will discuss some potentially even unexpected implications for our currently changing daily clinical practice.


A physical activity coaching intervention can improve and maintain physical activity and health-related outcomes in adult ambulatory hospital patients: the Healthy4U-2 randomised controlled trial.
The Healthy 4 U-2 study sought to evaluate the effect of a twelve-week, physical activity (PA) coaching intervention for changes and maintenance in PA, anthropometrics and health-related outcomes in adults presenting to an ambulatory hospital clinic. One hundred and twenty insufficiently active adults were recruited from an ambulatory hospital clinic and randomised to an intervention group that received an education session and five 20-min telephone sessions of PA coaching, or to a control group that received the education session only. ActiGraph GT3X accelerometers were used to measure moderate-to-vigorous physical activity (MVPA) at baseline, post-intervention (3-months) and follow-up (9-months). Secondary outcome measures (anthropometrics, PA self-efficacy, and health-related quality of life) were also assessed at the three time points. At baseline, the mean age and body mass index of participants were 53 ± 8 years and 31 ± 4 kg/m2, respectively. Relative to control, the intervention group increased objectively measured MVPA at post-intervention (p < 0.001) and 9 months follow-up (p < 0.001). At the 9-month follow-up the intervention group completed 22 min/day of MVPA (95% CI: 20 to 25 min/day), which is sufficient to meet the recommended PA guidelines. The intervention group exhibited beneficial changes in body mass (p < 0.001), waist circumference (p < 0.001), body mass index (p < 0.001), PA self-efficacy (p < 0.001), and health-related quality of life (p < 0.001) at the 9-month follow-up. This study demonstrates that a low contact PA coaching intervention results in beneficial changes in PA, anthropometrics and health-related outcomes in insufficiently active adults presenting to an ambulatory care clinic. The significant beneficial changes were measured at post-intervention and the 9-month follow-up, demonstrating a maintenance effect of the intervention. Prospectively registered on the Australian and New Zealand Clinical Trials Registry (ANZCTR, Trial registration number: ACTRN12619000036112 .


BRIDES: A New Fast Algorithm and Software for Characterizing Evolving Similarity Networks Using Breakthroughs, Roadblocks, Impasses, Detours, Equals and Shortcuts.
Various types of genome and gene similarity networks along with their characteristics have been increasingly used for retracing different kinds of evolutionary and ecological relationships. Here, we present a new polynomial time algorithm and the corresponding software (BRIDES) to provide characterization of different types of paths existing in evolving (or augmented) similarity networks under the constraint that such paths contain at least one node that was not present in the original network. These different paths are denoted as Breakthroughs, Roadblocks, Impasses, Detours, Equal paths, and Shortcuts. The analysis of their distribution can allow discriminating among different evolutionary hypotheses concerning genomes or genes at hand. Our approach is based on an original application of the popular shortest path Dijkstra's and Yen's algorithms. The C++ and R versions of the BRIDES program are freely available at: https://github.com/etiennelord/BRIDES.


A flexible pro-porous coordination polymer: non-conventional synthesis and separation properties towards CO(2)/CH(4) mixtures.
The novel coordination polymers [Cu(Hoxonic)(H(2)O)](n) (1) and [Cu(Hoxonic)(bpy)(0.5)](n)1.5 n H(2)O (2 subsetH(2)O) (H(3)oxonic: 4,6-dihydroxy-1,3,5-triazine-2-carboxylic acid; bpy: 4,4'-bipyridine) have been isolated and structurally characterised by ab initio X-ray powder diffraction. The dense phase 1 contains 1D zig-zag chains in which Hoxonic dianions bridge square-pyramidal copper(II) ions, apically coordinated by water molecules. On the contrary, 2 subsetH(2)O, prepared by solution and solventless methods, is based on 2D layers of octahedral copper(II) ions bridged by Hoxonic ligands, further pillared by bpy spacers. The resulting pro-porous 3D network possesses small hydrated cavities. The reactivity, thermal, magnetic and adsorptive properties of these materials have been investigated. Notably, the adsorption studies on 2 show that this material possesses unusual adsorption behaviour. Indeed, guest uptake is facilitated by increasing the thermal energy of both the guest and the framework. Thus, neither N(2) at 77 K nor CO(2) at 195 K are incorporated, and CH(4) is only minimally adsorbed at 273 K and high pressures (0.5 mmol g(-1) at 2500 kPa). By contrast, CO(2) is readily incorporated at 273 K (up to 2.5 mmol g(-1) at 2500 kPa). The selectivity of 2 towards CO(2) over CH(4) has been investigated by means of variable-temperature zero coverage adsorption experiments and measurement of breakthrough curves of CO(2)/CH(4) mixtures. The results show the highly selective incorporation of CO(2) in 2, which can be rationalised on the basis of the framework flexibility and polar nature of its voids.


3D deep learning based classification of pulmonary ground glass opacity nodules with automatic segmentation.
Classifying ground-glass lung nodules (GGNs) into atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC) on diagnostic CT images is important to evaluate the therapy options for lung cancer patients. In this paper, we propose a joint deep learning model where the segmentation can better facilitate the classification of pulmonary GGNs. Based on our observation that masking the nodule to train the model results in better lesion classification, we propose to build a cascade architecture with both segmentation and classification networks. The segmentation model works as a trainable preprocessing module to provide the classification-guided 'attention' weight map to the raw CT data to achieve better diagnosis performance. We evaluate our proposed model and compare with other baseline models for 4 clinically significant nodule classification tasks, defined by a combination of pathology types, using 4 classification metrics: Accuracy, Average F1 Score, Matthews Correlation Coefficient (MCC), and Area Under the Receiver Operating Characteristic Curve (AUC). Experimental results show that the proposed method outperforms other baseline models on all the diagnostic classification tasks.


Comparison between anti-reflection-coated and uncoated spectacle lenses for presbyopic highway patrol troopers.
The use of anti-reflection coatings (AR) for spectacle lenses is steadily increasing. These ultra-thin coatings reduce reflections in lenses, increasing light transmittance about 8% (from 91% to 99%). Patient reports of crisper detail and brighter environment indicate that this perceived increase in visual function would probably be of benefit to many, including highway patrolmen who must make daily judgments on the basis of fine visual detail. Nineteen presbyopic Missouri State Highway Patrolmen (MSHP) participated in this crossover study. Subjects randomly wore Varilux Comfort progressive addition lenses in CR-39 that were uncoated or AR-coated. The AR coating was Crizal. Subjects wore each lens for 1 month, then compared the lenses directly for 1 week. Data were collected for lens scoring (both general and job specific) and lens preferences. The AR-coated lens was found to be significantly better in most categories. Reduction in glare and reflections during the day, night, indoors, and in the patrol vehicle--as well as improvement in overall night vision--were highly significant. Eighty-nine percent of the subjects chose the Crizal-coated lenses as their overall preferred lens. The results of this study appear to demonstrate a noticeable subjective preference for AR-coated lenses when used by a group engaged in a visually demanding occupation.


Classical imaging theory of a microlens with super-resolution.
Super-resolution in imaging through a transparent spherical microlens has attracted lots of attention because of recent promising experimental results with remarkable resolution improvement. To provide physical insight for this super-resolution phenomenon, previous studies adopted a phenomenological explanation mainly based on the super-focusing effect of a photonic nanojet, while a direct imaging calculation with classical imaging theory has rarely been studied. Here we theoretically model the imaging process through a microlens with vectorial electromagnetic analysis, and then exclude the previously plausible explanation of super-resolution based on the super-focusing effect. The results showed that, in the context of classical imaging theory subject to the two-point resolution criterion, a microlens with a perfect spherical shape cannot achieve the experimentally verified sub-100 nm resolution. Therefore, there must be some other physical mechanisms that contribute to the reported ultrahigh resolution but have not been revealed in theory.


Health disparities in awareness of physical activity and cancer prevention: findings from the National Cancer Institute's 2007 Health Information National Trends Survey (HINTS).
This national study examines differences between racial/ethnic groups on awareness of physical activity and reduced cancer risk and explores correlates of awareness including trust, demographic, and health characteristics within racial/ethnic groups. The 2007 Health Information and National Trends Survey (HINTS) provided data for this study. After exclusions, 6,809 adults were included in analyses. Awareness of physical activity in reduced cancer risk was the main outcome. Logistic regression models tested relationships. Non-Hispanic Blacks had a 0.71 (0.54,0.93) lower odds of being aware of physical activity in reduced cancer risk than non-Hispanic Whites. Current attempts to lose weight were associated with greater odds for awareness among non-Hispanic Blacks and Hispanics (p < .01). Among non-Hispanic Blacks, trust in traditional and Internet media was associated with greater odds of awareness (p < .01). This study is the first national study to examine racial/ethnic disparities in awareness of physical activity and cancer risk. Comparisons between racial/ethnic groups found Black-White disparities in awareness. Variables associated with awareness within racial/ethnic groups identify potential subgroups to whom communication efforts to promote awareness may be targeted.


Comparison of responsiveness to methacholine, histamine, and exercise in subgroups of asthmatic children.
Nonspecific bronchial reactivity, involving inhaled challenges with methacholine and histamine and treadmill exercise challenge, were compared in 2 groups of steroid-requiring asthmatic children (9 to 15 yr of age) distinguished on the basis of marked differences in their typical time course of clinical deterioration leading to in-hospital management. Group I patients (n = 8) had rapid clinical deterioration (occurring within 8 h from the onset of respiratory symptoms), whereas in Group II patients (n = 7), clinical deterioration occurred relatively slowly (i.e., exceeding 24 h from the onset of respiratory symptoms). Pharmacologic bronchial sensitivity was evaluated as the log dose of the agonist producing a 20% fall in FEV1 (PD20 X FEV1) and a 35% fall in specific conductance (PD35 X SGaw). Exercise-induced bronchospasm was evaluated in terms of the maximal decrease in FEV1 and SGaw after 6 min of steady-state treadmill exercise at 85% of the age-predicted maximal heart rate. Group I patients had near normal baseline FEV1 and SGaw, whereas in Group II patients, the baseline values of these parameters were significantly reduced (p less than 0.02). Group I was more sensitive to methacholine than was Group II, providing significantly lower mean values of PD20 X FEV1 (p less than 0.003) and PD35 X SGaw (p less than 0.001). On the other hand, the 2 groups were not significantly different with respect to their bronchial sensitivity to either histamine or exercise challenge. Thus, asthmatic children with marked differences in clinical presentation of bronchospasm may be further distinguished on the basis of methacholine sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)


Interval estimation of familial correlations from pedigrees.
We study the estimation of familial correlations from pedigree data without the assumption of multivariate normality, using asymptotic results to obtain standard errors and confidence intervals. Two extreme weights that can be given to pairs of observations from relatives in pedigrees are pair-wise weights, in which each pair is given the same weight, and uniform weights, in which each pedigree is given the same weight. A best weighted average of these two estimates for a particular correlation as well as its standard error are derived using quadratic models for the estimates and their variances. Conclusions regarding the adequacy of the method in terms of bias, absolute bias, variance, and confidence interval coverage probabilities are presented on the basis of results from simulation studies. We determine under what circumstances the nominal 95 percent confidence intervals have excellent average coverage of the true values even for samples of small size and under what circumstances the results must be viewed with caution. We then describe a procedure by which, for both small family and large family structures, we find that the estimates we recommend provide accurate results.


[Simultaneous operations at coronary arteries and aorto-iliac zone].
Cardiac complications after operations on aorto-iliac segment take the leading place, and they are the main cause of postoperative lethality achieving 40%. Experience of 10 simultaneous operations on coronary and aorto-iliac zone with original method of aorto-femoral bypass from mini-approach is analyzed. The types and stages of simultaneous reconstructions are described. The clinical case of simultaneous operations on brachiocephal, coronary and lower limb arteries is presented with characteristics of surgical stages and the main intra- and postoperative parameters. Mini-invasive methods permit to expand the indications for simultaneous operations on different vascular segments at the patients with multifocal atherosclerosis.


Calcium Phosphate Particles as Pulmonary Delivery System for Interferon-α in Mice.
Systemically administered interferons are rapidly cleared from the circulation thus requiring frequent dosing to maintain the therapeutic levels of circulating interferon. This is particularly problematic for their use in the treatment of chronic diseases. The purpose of this study was to evaluate the potential of proprietary calcium phosphate (CaP) particles to deliver biologically active interferon alpha (IFNα) via the lungs into systemic circulation. Recombinant human IFNα-2a was formulated with proprietary CaP particles. In vitro biological activity of IFNα was assessed for its potential to activate IFN-induced cellular pathways in HEK-Blu-IFN α/β cell cultures. Antiviral activity was evaluated against vesicular stomatitis virus (VSV) infection of HeLa cells. Male BALB/c mice were used to evaluate the absorption of IFNα from CaP-IFNα across the lungs following intratracheal (IT) instillation. Serum IFNα concentrations up to 9 h post-treatment were determined. Data were analyzed to obtain pharmacokinetic (PK) parameters. Data from these studies indicated that IFNα formulated with CaP retains its biological activity, and it is transported into circulation in a dose-dependent manner. PK analysis showed larger than two-fold area under the serum concentration-time curve (AUC) for CaP-IFNα compared to non-formulated IFNα administered IT. The IFNα formulated with CaP had two-fold longer half-life (t1/2) and mean residence time (MRT) relative to IFNα alone administered by injection. Clearance of CaP-IFNα was slower than IFNα administered IM or IT. Relative bioavailability of CaP-IFNα was 1.3-fold of IFNα injection and twofold of IFNα administered IT. Furthermore, inhalation of aerosolized CaP did not indicate any lung toxicity in animals.


[Determination of diagnostic significance of nonspecific morphological signs].
For assessment of diagnostic significance of nonspecific morphological signs the authors suggest to apply calculation of their informativeness according to Kullback's formula. This qualitatively characterizes the degree of difference of crossed signs in differentiating diseases. An initial value is frequency of occurrence of a sign or a degree of its manifestation determined by a relative frequency index according to histometry findings. Calculation of informativeness may be applied only with respect to statistically significant differing aspects. The value of the informativeness index corresponds to diagnostic significance of a sign. The recommended objective method broadens the sphere of application of diagnostic biopsy and may facilitate putting into practice of pathological anatomy of methods of computer diagnosis.


Hematologic and biochemical reference ranges for captive California condors (Gymnogyps californianus).
To provide proper medical evaluation and care for the endangered California condor (Gymnogyps californianus), veterinarians need accurate hematologic and biochemical reference ranges. A retrospective study of blood samples from captive California condors housed at the San Diego Wild Animal Park assessed the samples by sex and age of condor to determine serum biochemical and hematologic reference ranges, including lead and zinc levels. Condors were grouped by age as follows: group 1 included birds less than 30 days of age; group 2 included birds between 30 days and 6 mo of age; group 3 included birds between 6 mo and 5 yr of age; group 4 included all birds greater than 5 yr of age. Significant differences between sexes included higher chloride, cholesterol, and total plasma protein concentration in males as compared to females (P < 0.05). Significant differences between age groups were identified in glucose, potassium, phosphorus, calcium, albumin, total plasma protein, globulin, cholesterol, bile acid, and zinc concentrations, as well as aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, and creatine phosphokinase activities (P < 0.05). Additionally, significant differences between age groups were noted in white blood cell count, hematocrit, heterophils, lymphocytes, and eosinophils (P < 0.05). A steady increase in glucose and a decrease in alkaline phosphatase and lactate dehydrogenase activities, as well as cholesterol, bile acid, calcium, and phosphorus concentrations, were correlated with age (P < 0.05). Following application of statistical analysis, condors less than 6 mo of age were identified as unique compared to older cohorts; therefore, two reference ranges are proposed by calculating a 90% confidence interval. Reference ranges obtained from other published avian data, including those for psittaciformes, ratites, galliformes, anseriformes, and raptors, were similar to condors in this study.


A comparison of the Bricker versus Wallace ureteroileal anastomosis in patients undergoing urinary diversion for bladder cancer.
In recent years few studies have evaluated the success and complications of the 2 most common types of ureteroenteric anastomotic techniques, the Bricker and the Wallace anastomosis. We evaluated the complications of the Bricker and Wallace techniques of ureteroenteric anastomosis in a single surgeon, single institution series. From 2001 to 2005 a total of 186 patients underwent ileal conduit or ileal neobladder after cystectomy for bladder cancer. All patients were followed for a minimum of 12 months after surgery with complete clinical information. In all cases the ureters were anastomosed to a segment of ileum in a separate (Bricker) or conjoined (Wallace) fashion. Of the 186 patients 94 underwent a Bricker (51%), 90 underwent a Wallace (48%) and 2 patients underwent both procedures (Wallace on duplicated system on 1 side, Bricker on contralateral side). Ureteral stricture developed in 5 of 186 (2.6%) patients and the overall stricture rate for all ureters was 7 of 371 (1.9%). In patients undergoing Bricker anastomosis the total stricture rate for all ureters was 3.7% (7 of 187). With the Wallace anastomosis the total stricture rate for all ureters was 0% (0 of 184). This difference in stricture rate in the Bricker vs Wallace subgroups was significant (p = 0.015). There was no difference in age, gender, creatinine, prior radiation, complications or mode of diversion between the groups. Body mass index was higher in the Bricker vs the Wallace group (29.0 vs 25.9 kg/m(2)). Of the 5 patients with strictures 1 underwent successful open repair, 1 had successful interventional radiological repair and 3 were treated with chronic ureteral stents (1 after failed open repair and 2 after failed radiological repair). Both the Bricker and the Wallace anastomoses provide acceptably low stricture rates in a single surgeon case series. Indeed, the Wallace anastomosis had no strictures in this series. The Bricker group had a higher body mass index which was likely due to the often disparate ureteral lengths in obese patients after retrosigmoidal tunneling, which would have affected the choice of technique.


Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): Implications for the risk of malignancy (ROM) in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).
The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) mostly in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories. In this multi-institutional, retrospective study, the authors investigated variations in the impact of an NIFTP diagnosis on the associated ROM for each TBSRTC category with an emphasis on the influence of pathologist and institutional diagnostic thresholds on the ROM. Baseline data on cytology and histology diagnostic categories were collected over a 3-year period at 3 academic center hospitals (institutions A, B, and C). Histology slides for all cases diagnosed as follicular variant of papillary thyroid carcinoma (FVPTC) were re-reviewed at each institution, and those that qualifying as NIFTP were separated from other PTCs. The collective case cohort from the 3 institutions included 15,973 thyroid fine-needle aspiration cytology (FNAC) specimens and 5090 thyroid surgical resection specimens. Significant differences in baseline cytology and histology data were noted among the 3 institutions. The number of cases classified as NIFTP compared with FVPTC was highly variable (institution A, 14%; institution B, 39%; and institution C, 12%). For 3250 resected thyroid nodules with a previous FNAC diagnosis, the average decrease in ROM after the exclusion of NIFTP for all TBSRTC categories was as follows: institution A, 9.8%; institution B, 3.9%; and institution C, 1.3%. The institutional frequency of NIFTP histopathology diagnosis and cytology baseline data will impact the ROM associated with specific FNAC diagnoses, especially among the indeterminate TBSRTC categories. The range of ROM for each TBSRTC diagnostic category is reflective of the inherent diagnostic thresholds and interobserver and interinstitutional variability in the diagnosis of thyroid lesions. Cancer Cytopathol 2018;126:20-6. © 2017 American Cancer Society.


Nanoneuromedicines for degenerative, inflammatory, and infectious nervous system diseases.
Interest in nanoneuromedicine has grown rapidly due to the immediate need for improved biomarkers and therapies for psychiatric, developmental, traumatic, inflammatory, infectious and degenerative nervous system disorders. These, in whole or in part, are a significant societal burden due to growth in numbers of affected people and in disease severity. Lost productivity of the patient and his or her caregiver, and the emotional and financial burden cannot be overstated. The need for improved health care, treatment and diagnostics is immediate. A means to such an end is nanotechnology. Indeed, recent developments of health-care enabling nanotechnologies and nanomedicines range from biomarker discovery including neuroimaging to therapeutic applications for degenerative, inflammatory and infectious disorders of the nervous system. This review focuses on the current and future potential of the field to positively affect clinical outcomes. From the clinical editor: Many nervous system disorders remain unresolved clinical problems. In many cases, drug agents simply cannot cross the blood-brain barrier (BBB) into the nervous system. The advent of nanomedicines can enhance the delivery of biologically active molecules for targeted therapy and imaging. This review focused on the use of nanotechnology for degenerative, inflammatory, and infectious diseases in the nervous system.


Spinal cord stimulation: the clinical application of new technology.
The use of neuromodulation for pain relief is among the fastest-growing areas of medicine, involving many diverse specialties and impacting on hundreds of thousands of patients with numerous disorders worldwide. As the evidence of efficacy improves, the interest in spinal cord stimulation (SCS) will increase because it is minimally invasive, safe, and a reversible treatment modality with limited side effect profile. While the mechanism of action evades complete understanding, the technological improvements have been considerable and current neuromodulation developments have been coupled with the rapid growth of the neuromodulation device industry resulting in the development of the next-generation neuromodulation systems. The development, the newest technicaliti and the future for the clinical application of spinal cord stimulation (SCS) are reviewed here.


Treatment considerations for posterior laboratory-fabricated composite resin restorations.
A variety of techniques are currently available to restore dentition in the posterior region, and the selection of the proper modality is dependent upon evaluation and satisfaction of numerous criteria. Direct materials provide limited strength in the posterior segment, and full-coverage indirect techniques (e.g., crown restorations) often require the destruction of sound tooth structure. When proper case selection, preparation design, and clinical protocols are utilized, a laboratory-processed composite resin (belleGlass, Kerr/Sybron, Orange, CA) can provide an optimal means by which to successfully restore posterior dentition without compromising the existing tooth structure.


Clavibacter michiganensis ssp. michiganensis: bacterial canker of tomato, molecular interactions and disease management.
Bacterial canker disease is considered to be one of the most destructive diseases of tomato (Solanum lycopersicum), and is caused by the seed-borne Gram-positive bacterium Clavibacter michiganensis ssp. michiganensis (Cmm). This vascular pathogen generally invades and proliferates in the xylem through natural openings or wounds, causing wilt and canker symptoms. The incidence of symptomless latent infections and the invasion of tomato seeds by Cmm are widespread. Pathogenicity is mediated by virulence factors and transcriptional regulators encoded by the chromosome and two natural plasmids. The virulence factors include serine proteases, cell wall-degrading enzymes (cellulases, xylanases, pectinases) and others. Mutational analyses of these genes and gene expression profiling (via quantitative reverse transcription-polymerase chain reaction, transcriptomics and proteomics) have begun to shed light on their roles in colonization and virulence, whereas the expression of tomato genes in response to Cmm infection suggests plant factors involved in the defence response. These findings may aid in the generation of target-specific bactericides or new resistant varieties of tomato. Meanwhile, various chemical and biological controls have been researched to control Cmm. This review presents a detailed investigation regarding the pathogen Cmm, bacterial canker infection, molecular interactions between Cmm and tomato, and current perspectives on improved disease management.


Moorella humiferrea sp. nov., a thermophilic, anaerobic bacterium capable of growth via electron shuttling between humic acid and Fe(III).
An anaerobic, thermophilic, spore-forming bacterium (strain 64-FGQ(T)) was isolated from a terrestrial hydrothermal spring from the Kamchatka peninsula, Russia. This strain utilized lactate as an electron donor, insoluble poorly crystalline Fe(III) oxide incorporated into alginate beads as a potential electron acceptor and 9,10-anthraquinone-2,6-disulfonate (AQDS) as an electron-shuttling compound. Vegetative cells of strain 64-FGQ(T) were Gram-stain-positive, peritrichously flagellated, motile, straight rods, 0.3-0.5 µm in diameter and 2.0-5.0 µm long, growing singly or forming short chains. Cells formed round refractive endospores in terminal swollen sporangia. The temperature range for growth was 46-70 °C, with an optimum at 65 °C. The pH range for growth was 5.5-8.5, with an optimum at pH 7.0. The substrates utilized by strain 64-FGQ(T) in the presence of AQDS as an electron acceptor included lactate, malate, succinate, glycerol and yeast extract. The strain fermented galactose, fructose, maltose, sucrose, pyruvate and peptone. Strain 64-FGQ(T) used AQDS, humic acid, thiosulfate, nitrate and perchlorate as electron acceptors for growth. Fe(III) was not directly reduced, but strain 64-FGQ(T) was able to grow and reduce Fe(III) oxide in the presence of small amounts of AQDS or humic acid as electron-shuttling compounds. The G+C content of the DNA of strain 64-FGQ(T) was 51 mol%. 16S rRNA gene sequence analysis placed the isolate in the genus Moorella, with the type strain of Moorella glycerini as its closest relative (97.2% similarity). Based on phylogenetic analysis and physiological characteristics, strain 64-FGQ(T) is considered to represent a novel species of the genus Moorella, for which the name Moorella humiferrea sp. nov. is proposed; the type strain is 64-FGQ(T) (=DSM 23265(T)=VKM B-2603(T)).


His Bundle Pacing.
Traditional right ventricular (RV) pacing for the management of bradyarrhythmias has been pursued successfully for decades, although there remains debate regarding optimal pacing site with respect to both hemodynamic and clinical outcomes. The deleterious effects of long-term RV apical pacing have been well recognized. This has generated interest in approaches providing more physiological stimulation, namely, His bundle pacing (HBP). This paper reviews the anatomy of the His bundle, early clinical observations, and current approaches to permanent HBP. By stimulating the His-Purkinje network, HBP engages electrical activation of both ventricles and may avoid marked dyssynchrony. Recent studies have also demonstrated the potential of HBP in patients with underlying left bundle branch block and cardiomyopathy. HBP holds promise as an attractive mode to achieve physiological pacing. Widespread adaptation of this technique is dependent on enhancements in technology, as well as further validation of efficacy in large randomized clinical trials.


Prenatal steroids for microcystic congenital cystic adenomatoid malformations.
The purpose of this study is to evaluate the effect of prenatal steroid treatment in fetuses with sonographically diagnosed congenital cystic adenomatoid malformations (CCAMs). This was an institutional review board-approved retrospective review of 372 patients referred to the University of California, San Francisco (UCSF), for fetal CCAM. Inclusion criteria were (1) a predominately microcystic CCAM lesion sonographically diagnosed at our institution, (2) maternal administration of a single course of prenatal corticosteroids (betamethasone), and (3) no fetal surgery. CCAM volume-to-head ratio (CVR), presence of hydrops, mediastinal shift, and diaphragm eversion were assessed before and after administration of betamethasone. The primary end points were survival to birth and neonatal discharge. Sixteen patients with predominantly microcystic CCAMs were treated with prenatal steroids. Three were excluded because of lack of follow-up information. All remaining fetuses (13/13) survived to delivery and 11/13 (84.6%) survived to neonatal discharge. At the time of steroid administration, all patients had CVR greater than 1.6, and 9 (69.2%) also had nonimmune hydrops fetalis. After a course of steroids, CVR decreased in 8 (61.5%) of the 13 patients, and hydrops resolved in 7 (77.8%) of the 9 patients with hydrops. The 2 patients whose hydrops did not resolve with steroid treatment did not survive to discharge. In high-risk fetal patients with predominantly microcystic CCAM lesions, betamethasone is an effective treatment. This series is a pilot study for a prospective randomized trial comparing treatment of CCAM with betamethasone to placebo.


Brain mitochondrial lipid abnormalities in mice susceptible to spontaneous gliomas.
Alterations in mitochondrial function have long been considered a hallmark of cancer. We compared the lipidome and electron transport chain activities of non-synaptic brain mitochondria in two inbred mouse strains, the C57BL/6J (B6) and the VM/Dk (VM). The VM strain is unique in expressing a high incidence of spontaneous brain tumors (1.5%) that are mostly gliomas. The incidence of gliomas is about 210-fold greater in VM mice than in B6 mice. Using shotgun lipidomics, we found that the mitochondrial content of ethanolamine glycerophospholipid, phosphatidylserine, and ceramide was higher, whereas the content of total choline glycerophospholipid was lower in the VM mice than in B6 mice. Total cardiolipin content was similar in the VM and the B6 mice, but the distribution of cardiolipin molecular species differed markedly between the strains. B6 non-synaptic mitochondria contained 95 molecular species of cardiolipin that were symmetrically distributed over 7 major groups based on mass charge. In contrast, VM non-synaptic mitochondria contained only 42 molecular species that were distributed asymmetrically. The activities of Complex I, I/III, and II/III enzymes were lower, whereas the activity of complex IV was higher in the mitochondria of VM mice than in B6 mice. The high glioma incidence and alterations in electron transport chain activities in VM mice compared to B6 mice could be related to the unusual composition of mitochondrial lipids in the VM mouse brain.


Pulmonary Embolism During Hepatoblastoma Resection.
Although hepatoblastoma is rare, it is the most malignant tumour of childhood. Treatment is usually done by surgical resection and chemotherapy. The mortality and morbidity have decreased due to improvements in the treatments. In this process, hepatic resection has a risk of pulmonary embolism, and this condition could be fatal. In this case, a 9-month-old patient who was treated with chemotherapy and then underwent hepatectomy was presented. We used non-invasive methods such as the perfusion index (PI), the plethysmographic variability index (PVI) (Massimo Radical 7) and non-invasive total haemoglobin measurement (SpHb) rather than invasive measurements. During closure of the surgical skin incision, the end-tidal CO2 (ETCO2) value dropped, after which arrhythmia and bradycardia resulted in cardiac arrest. Cardiopulmonary resuscitation (CPR) was initiated. However, the patient did not respond to CPR. We concluded that heparin may be administered to reduce the risk of thrombosis in patients undergoing liver surgery.


A genomics-informed, SNP association study reveals FBLN1 and FABP4 as contributing to resistance to fleece rot in Australian Merino sheep.
Fleece rot (FR) and body-strike of Merino sheep by the sheep blowfly Lucilia cuprina are major problems for the Australian wool industry, causing significant losses as a result of increased management costs coupled with reduced wool productivity and quality. In addition to direct effects on fleece quality, fleece rot is a major predisposing factor to blowfly strike on the body of sheep. In order to investigate the genetic drivers of resistance to fleece rot, we constructed a combined ovine-bovine cDNA microarray of almost 12,000 probes including 6,125 skin expressed sequence tags and 5,760 anonymous clones obtained from skin subtracted libraries derived from fleece rot resistant and susceptible animals. This microarray platform was used to profile the gene expression changes between skin samples of six resistant and six susceptible animals taken immediately before, during and after FR induction. Mixed-model equations were employed to normalize the data and 155 genes were found to be differentially expressed (DE). Ten DE genes were selected for validation using real-time PCR on independent skin samples. The genomic regions of a further 5 DE genes were surveyed to identify single nucleotide polymorphisms (SNP) that were genotyped across three populations for their associations with fleece rot resistance. The majority of the DE genes originated from the fleece rot subtracted libraries and over-representing gene ontology terms included defense response to bacterium and epidermis development, indicating a role of these processes in modulating the sheep's response to fleece rot. We focused on genes that contribute to the physical barrier function of skin, including keratins, collagens, fibulin and lipid proteins, to identify SNPs that were associated to fleece rot scores. We identified FBLN1 (fibulin) and FABP4 (fatty acid binding protein 4) as key factors in sheep's resistance to fleece rot. Validation of these markers in other populations could lead to vital tests for marker assisted selection that will ultimately increase the natural fleece rot resistance of Merino sheep.


Hair Stylists as Lay Health Workers: Perspectives of Black Women on Salon-Based Health Promotion.
Lay health workers (LHWs) have been effective in delivering health promotion to underserved, vulnerable populations. Hair stylists are well positioned to serve as LHWs in addressing health disparities among Black women in the U.S. The purpose of this qualitative study was to explore the extent to which hair stylists influence their Black female clients and clients' preferences for their stylist's role in salon-based health promotion programming. Eight virtual platform focus groups were conducted with Black women (n = 39) who receive hair care services from a licensed hair stylist across the U.S. Most participants had a college degree (89.8%), health insurance (92.3%), a primary care provider (89.7%), and the majority had at least one chronic disease (56.4%). Participants reported higher potential for influence related to level of trust in the stylists and for stylists they find relatable and credible. Trust, relatability, and credibility were further determined by racial and gender congruence. Client interviewees felt stylists should model healthy behaviors and reported they may not be receptive to stylist-delivered health promotion out of the context of a hair-health connection. In this sample of well-educated clients, there was an expressed preference for stylists to provide referral to healthcare professionals or solicit experts for health topics out of the scope of haircare rather than guide the health promotion efforts themselves. Findings from this study can inform future development of acceptable salon-based, stylist-led health promotion programs that partner stylists with health experts to deliver health promotion.


Electrochemical enzyme-linked immunosorbent assay (e-ELISA) for parasitic nematode Ostertagia ostertagi (brown stomach worm) infections in dairy cattle.
A sensitive electrochemical immunoassay (e-ELISA) has been developed for the detection of the gastrointestinal parasitic nematode Ostertagia ostertagi (brown stomach worm) in infected and control serum samples. An antigen-indirect immunoassay format was employed to detect the presence of O. ostertagi antibodies, coupled with an anti-species monoclonal horseradish peroxidase (HRP) conjugate. ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)) and TMB (3,3',5,5'-tetramethylbenzidine/hydrogen peroxide) were investigated as both chromogenic visualising reagents for optical ELISA and electroactive substrates for electrochemical ELISA in the HRP catalysed oxidation reaction. Coulometry was applied for the detection of O. ostertagi antibodies (via TMB electrochemistry) and compared with the commercial optical ELISA (ABTS based SVANOVIR® O. ostertagi-Ab ELISA kit). Cost-effective in-house sensors were designed and fabricated using polyester and chemical adhesive materials with the aid of stencil printing and laser machining techniques. The performance of the electrochemical ELISA and sensor was evaluated by investigating redox mediators (ABTS vs. TMB), stop solutions (sodium dodecyl sulfate vs. sulfuric acid) and incubation times (150 min vs. 70 min vs. 25 min). For a total assay incubation time of 70 minutes, the TMB/H2SO4 based e-ELISA was able to differentiate between positive (P) and negative (N) control serum samples, with a P/N70 control ratio 1.6 times higher than that of optical ELISA (TMB/H2SO4 combination) and 2.9 times higher than that of the commercial ELISA kit (ABTS/SDS combination). Furthermore, the e-ELISA approach is quicker and required only 25 min (total incubation time) with even better response (P/N25 = 14.7), which is approximately 4-fold higher than the optical immunoassay (P/N25 = 3.8). The proposed e-ELISA is specific (selective Ab-Ag interactions) and highly sensitive - capable of detecting up to 16-fold dilutions of a positive control serum sample. The electrochemical ELISA approach has the potential for rapid sample screening in a portable, disposable format, contributing to the quest for effective prevention and control of parasitic Ostertagia ostertagi infections in cattle.


Pure arterial malformation of the posterior inferior cerebellar artery with interspersed adipose tissue: case report.
Incidental vascular lesions are being discovered at an increasing frequency due to widespread noninvasive brain imaging studies. One of these lesions has recently been termed a "pure arterial malformation" (PAM), which is defined as dilated, overlapping, and tortuous arteries forming a mass of arterial loops with a coil-like appearance in the absence of arteriovenous shunting. The pathogenesis of these lesions is not known, but a congenital etiology is suspected. The authors report the case of a 17-year-old female who was found to have a PAM of the posterior inferior cerebellar artery with adipose tissue interspersed within the arterial loops. The authors believe that this abnormal intracranial association between blood vessel and adipose tissue lends further support to the theory that PAMs are the result of a congenital malformation and are therefore safe to manage conservatively given their presumed benign natural history. Far from offering conclusive evidence, this unique case report adds to the growing body of PAM literature and strengthens an increasingly supported congenital theory of genesis.


Dynamics and phylogenetic relationships of HIV-1 transmitted drug resistance according to subtype in Italy over the years 2000-14.
Transmitted drug-resistance (TDR) remains a critical aspect for the management of HIV-1-infected individuals. Thus, studying the dynamics of TDR is crucial to optimize HIV care. In total, 4323 HIV-1 protease/reverse-transcriptase sequences from drug-naive individuals diagnosed in north and central Italy between 2000 and 2014 were analysed. TDR was evaluated over time. Maximum-likelihood and Bayesian phylogenetic trees with bootstrap and Bayesian-probability supports defined transmission clusters. Most individuals were males (80.2%) and Italian (72.1%), with a median (IQR) age of 37 (30-45) years. MSM accounted for 42.2% of cases, followed by heterosexuals (36.4%). Non-B subtype infections accounted for 30.8% of the overall population and increased over time (<2005-14: 19.5%-38.5%, P < 0.0001), particularly among Italians (<2005-14: 6.5%-28.8%, P < 0.0001). TDR prevalence was 8.8% and increased over time in non-B subtypes (<2005-14: 2%-7.1%, P = 0.018). Overall, 467 transmission clusters (involving 1207 individuals; 27.9%) were identified. The prevalence of individuals grouping in transmission clusters increased over time in both B (<2005-14: 12.9%-33.5%, P = 0.001) and non-B subtypes (<2005-14: 18.4%-41.9%, P = 0.006). TDR transmission clusters were 13.3% within the overall cluster observed and dramatically increased in recent years (<2005-14: 14.3%-35.5%, P = 0.005). This recent increase was mainly due to non-B subtype-infected individuals, who were also more frequently involved in large transmission clusters than those infected with a B subtype [median number of individuals in transmission clusters: 7 (IQR 6-19) versus 4 (3-4), P = 0.047]. The epidemiology of HIV transmission changed greatly over time; the increasing number of transmission clusters (sometimes with drug resistance) shows that detection and proper treatment of the multi-transmitters is a major target for controlling HIV spread.


Candida albicans SH3-domain proteins involved in hyphal growth, cytokinesis, and vacuolar morphology.
This report describes the analyses of three Candida albicans genes that encode Src Homology 3 (SH3)-domain proteins. Homologs in Saccharomyces cerevisiae are encoded by the SLA1, NBP2, and CYK3 genes. Deletion of CYK3 in C. albicans was not feasible, suggesting it is essential. Promoter shutdown experiments of CaCYK3 revealed cytokinesis defects, which are in line with the localization of GFP-tagged Cyk3 at septal sites. Deletion of SLA1 resulted in strains with decreased ability to form hyphal filaments. The number of cortical actin patches was strongly reduced in Deltasla1 strains during all growth stages. Sla1-GFP localizes in patches that are found concentrated at the hyphal tip. Deletion of the first two SH3-domains of Sla1 still resulted in cortical localization of the truncated protein. However, the actin cytoskeleton in this strain was aberrant like in the Deltasla1 deletion mutant indicating a function of these SH3 domains to recruit actin nucleation to sites of endocytosis. Deletion of NBP2 resulted in a defect in vacuolar fusion in hyphae. Germ cells of Deltanbp2 strains lacked a large vacuole but initiated several germ tubes. The mutant phenotypes of Deltanbp2 and Deltasla1 could be corrected by reintegration of the wild-type genes.


Activation and functional characterization of the mosaic receptor SorLA/LR11.
We previously isolated and sequenced the approximately 250-kDa type 1 receptor sorLA/LR11, a mosaic protein with elements characterizing the Vps10p domain receptor family as well as the low density lipoprotein receptor family. The N terminus of the Vps10p domain comprises a consensus sequence for cleavage by furin ((50)RRKR(53)) that precedes a truncation found in sorLA isolated from human brain. Here we show that sorLA, like sortilin-1/neurotensin receptor-3, whose lumenal domain consists of a Vps10p domain only, is synthesized as a proreceptor that is cleaved by furin in late Golgi compartments. We show that the truncation conditions the Vps10p domain for propeptide inhibitable binding of neuropeptides and the receptor-associated protein. We further demonstrate that avid binding of the receptor-associated protein, apolipoprotein E, and lipoprotein lipase not inhibited by propeptide occurs to sites located in other lumenal domains. In transfected cells, about 10% of full-length sorLA were expressed on the cell surface capable of mediating endocytosis. However, the major pool of receptors was found in late Golgi compartments, suggesting possible interaction with newly synthesized ligands. The results show that sorLA, following activation by truncation, binds multiple ligands and may mediate both endocytosis and sorting.


Upper Thermal Tolerance Indicated by CTmax Fails to Predict Migration Strategy and Timing, Growth, and Predation Vulnerability in Juvenile Brown Trout (Salmo trutta).
AbstractPartial migration is common in a variety of taxa and has important ecological and evolutionary implications, yet the underlying factors that lead to different migratory strategies are not clearly understood. Given the importance of temperature in serving as a cue for migration, along with its role in regulating metabolism, growth, reproduction, and survival, we examined how intraspecific variation in critical thermal maximum (CTmax) values influenced migratory strategy (residency vs. migration), timing of migration, growth, and predation vulnerability in a wild population of partially anadromous juvenile brown trout (Salmo trutta). Using passive integrated transponder telemetry and mark-recapture techniques, we identified individuals that out-migrated to sea, assumed residency, and were predated by cormorants several months later. Acute thermal stress induced by conducting CTmax trials did not affect the final fate of assayed fish compared with controls. We found that mass and body condition predicted CTmax and migration timing, but CTmax failed to predict migratory strategy or timing, growth (of resident fish), or predation vulnerability. Although there may be links between mass, thermal tolerance, and migration strategy, the relationship between CTmax and migration remains unclear. The role of upper thermal tolerance in influencing life-history strategies should not be neglected, however, as alternative indicators of thermal tolerance could be further explored. The high degree of variation in CTmax estimates warrants additional investigation of how increasingly prevalent high-temperature events might drive selection toward thermally tolerant extremes, which is particularly relevant in a rapidly warming world.


Saponins from soy and chickpea: stability during beadmaking and in vitro bioaccessibility.
This study investigated the stability of saponins during the making and simulated digestion of soy and soy-chickpea breads and the bioaccessibility of saponins in digested breads. Recovery of saponins in soy bread exceeded that in soy-chickpea breads, and recovery of type A and B saponins was greater than for type E and DDMP saponins. Simulated digestion of breads resulted in greater relative losses of type A and DDMP saponins than type B and E saponins due in part to conversion of DDMP. Bioaccessibility of type B, E, and DDMP saponins in aqueous fraction of chyme exceeded 50%, but was ∼30% for type A saponins. Caco-2 cells accumulated 0.8-2.8% of saponins from apical compartment containing diluted aqueous fraction of chyme. These findings suggest that saponin structure and food matrix affect the stability of saponins during processing and digestion and that uptake of saponins by enterocyte-like cells is poor despite moderate apparent bioaccessibility.