Performance of a three dimensional transformation-optical-flattened Lüneburg lens.
We demonstrate both the beam-forming and imaging capabilities of an X-band (8-12 GHz) operational Lüneburg lens, one side of which has been flattened via a coordinate transformation optimized using quasi-conformal transformation optics (QCTO) procedures. Our experimental investigation includes benchmark performance comparisons between the QCTO Lüneburg lens and a commensurate conventional Lüneburg lens. The QCTO Lüneburg lens is made from a metamaterial comprised of inexpensive plastic and fiberglass, and manufactured using fast and versatile numerically controlled water-jet machining. Looking forward towards the future and advanced TO designs, we discuss inevitable design trade-offs between affordable scalable manufacturing and rigorous adherence to the full TO solution, as well as possible paths to mitigate performance degradation in realizable designs.


The allometry of patch selection in ruminants.
An axiomatic feature of food consumption by animals is that intake rate and prey abundance are positively related. While this has been demonstrated rigorously for large herbivores, it is apparent from patch selection trials that grazers paradoxically tend to prefer short, sparse swards to tall, dense swards. Indeed, migratory herbivores often shift from areas of high to low sward biomass during the growing season. As nutritional quality is an inverse function of grass abundance, herbivores appear to sacrifice short-term intake for nutritional gains obtainable by eating sparse forage of higher quality. Explicit models of this trade-off suggest that individual ruminants maximize daily rates of energy gain by choosing immature swards of intermediate biomass. As body mass is related positively to both ruminant cropping rates and digestibility, there should be an allometric link between grass abundance and energy maximization, providing a tool for predicting patterns of herbivore habitat selection. We used previously published studies to develop a synthetic model of trade-offs between forage abundance and quality predicting that optimal sward biomass should scale allometrically with body size. The model predicts size-related variation in habitat selection observed in a guild of grazing ungulates in the Serengeti ecosystem.


Insanity and ethnicity in New Zealand: Māori encounters with the Auckland Mental Hospital, 1860-1900.
This article examines Māori patients at the Auckland Mental Hospital between 1860 and 1900.We argue that the patient case notes reveal 'European' categories in which Māori were situated, and demonstrate the extent to which the authorities at the hospital grappled with their appearance, their language and their culture, all of which were elements of their ethnicity. We argue that the use of institutional case records is highly suggestive of some of the historical meanings of insanity for Māori, including the lack of detailed or sustained collection of information about patients' tribal affiliations, the interest shown in their rights to land in maintenance payment inquiries, the experiences of cultural alienation or mate Māori, and the sad outcomes for Māori.


Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia.
Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (mIDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition-related differentiation and apoptosis. This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed mIDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922). Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). mIDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving mIDH1 mutation clearance.


Creation of a cardiotropic adeno-associated virus: the story of viral directed evolution.
Adeno-associated virus (AAV) is an important vector system for human gene therapy. Although use of AAV serotypes can result in efficient myocardial gene transfer, improvements in the transduction efficiency and specificity are still required. As a method for artificial modification and selection of gene function, directed evolution has been used for diverse applications in genetic engineering of enzymes and proteins. Since 2000, pioneering work has been performed on directed evolution of viral vectors. We further attempted to evolve the AAV using DNA shuffling and in vivo biopanning in a mouse model. An AAVM41 mutant was characterized, which was found to have improved transduction efficiency and specificity in myocardium, an attribute unknown for any natural AAV serotypes. This review focuses on the development of AAV vector for cardiac gene transfer, the history of directed evolution of viral vectors, and our creation of a cardiotropic AAV, which might have implications for the future design and application of viral vectors.


Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing.
Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.


Increases in ductal carcinoma in situ (DCIS) of the breast in relation to mammography: a dilemma.
The increased use of screening mammography has resulted in a marked increase in detected cases of ductal carcinoma in situ (DCIS) of the breast since the early 1980s. In 1993, there were an estimated 23,275 newly diagnosed cases of DCIS in the United States, of which 4,676 were in women aged 40-49. DCIS accounted for 14.7% of all newly diagnosed breast cancers in women aged 40-49 in 1993, and perhaps 40% of all mammographically detected breast cancers in this age group are DCIS. Among women aged 40-49, an estimated 1,890 mastectomies and 2,707 lumpectomies (with or without radiation) were performed for DCIS in 1993. There is an urgent need to better understand the relationship of mammographically detected DCIS to invasive and potentially life-threatening breast cancer. Better information about the appropriate treatment of DCIS is also needed to reduce the confusion and uncertainty many women and their physicians currently experience in the face of a DCIS diagnosis. For the present, women considering screening mammography should be told the likelihood of being diagnosed with DCIS and that only some DCIS cases may be clinically significant but almost all will be treated surgically.


Magnetic resonance imaging features of orbital inflammation with intracranial extension in four dogs.
This retrospective study describes the clinical and magnetic resonance (MR) imaging features of chronic orbital inflammation with intracranial extension in four dogs (two Dachshunds, one Labrador, one Swiss Mountain). Intracranial extension was observed through the optic canal (n=1), the orbital fissure (n=4), and the alar canal (n=1). On T1-weighted images structures within the affected skull foramina could not be clearly differentiated, but were all collectively isointense to hypointense compared with the contralateral, unaffected side, or compared with gray matter. On T2-, short tau inversion recovery (STIR)-, or fluid-attenuated inversion recovery (FLAIR)-weighted images structures within the affected skull foramina appeared hyperintense compared with gray matter, and extended with increased signal into the rostral cranial fossa (n=1) and middle cranial fossa (n=4). Contrast enhancement at the level of the affected skul foramina as well as at the skull base in continuity with the orbital fissure was observed in all patients. Brain edema or definite meningeal enhancement could not be observed, but a close anatomic relationship of the abnormal tissue to the cavernous sinus was seen in two patients. Diagnosis was confirmed in three dogs (one cytology, two biopsy, one necropsy) and was presumptive in one based on clinical improvement after treatment. This study is limited by its small sample size, but provides evidence for a potential risk of intracranial extension of chronic orbital inflammation. This condition can be identified best by abnormal signal increase at the orbital fissure on transverse T2-weighted images, on dorsal STIR images, or on postcontrast transverse or dorsal images.


Reporting quality of nursing home care to consumers: the Maryland experience.
To design and implement a reporting system for quality of long-term care to empower consumers and to create incentives for quality improvement. To identify a model to approach this technically and politically difficult task. Establishment of a credible and transparent decision process using a public forum. Development of the system based on: (1) review of the literature and existing systems, and discussions with stakeholders about strengths and weaknesses; (2) focus on consumer preferences in the design; and (3) responsiveness to industry concerns in the implementation. None of the existing systems appeared to be a suitable model. We decided to develop an entirely new system based on three key design principles that allowed us to tailor the system to consumer needs: (1) designing a decision tool rather than a database; (2) summarizing rather than simplifying information; and (3) accounting for the target audience in the creative execution. Industry concerns focused on the burden of the system, the potential for errors, and the possible communication of a negative impression of the industry. As methodological and data limitations prevented us from resolving those concerns, we addressed them by using cautionary language in the presentation and by making a commitment to incorporate improvements in the future. All stakeholders regarded the final design as an acceptable compromise. Despite its potentially controversial nature and many methodological challenges, the system has been well received by both the public and the industry. We attribute this success to two key factors: a collaborative decision process, in which all critical design and execution choices were laid out explicitly and debated with stakeholders in a public forum, and realism and honesty regarding the limitations of the system.


Posttraumatic stress disorder in patients with bipolar disorder: a review of prevalence, correlates, and treatment strategies.
In this article, we review the evidence for, and implications of, a high rate of comorbid posttraumatic stress disorder (PTSD) in individuals with bipolar disorder. We reviewed studies providing comorbidity data on patients with bipolar disorder, and also examined the PTSD literature for risk factors and empirically supported treatment options for PTSD. Studies of bipolar patients have documented elevated rates of PTSD. Based on our review, representing 1214 bipolar patients, the mean prevalence of PTSD in bipolar patients is 16.0% (95% CI: 14-18%), a rate that is roughly double the lifetime prevalence for PTSD in the general population. Risk factors for PTSD that are also characteristic of bipolar samples include the presence of multiple axis I disorders, greater trauma exposure, elevated neuroticism and lower extraversion, and lower social support and socio-economic status. These findings are discussed in relation to the cost of PTSD symptoms to the course of bipolar disorder. Pharmacological and cognitive-behavioral treatment options are reviewed, with discussion of modifications to current cognitive-behavioral protocols for addressing PTSD in individuals at risk for mood episodes.


Improvement of the experimental setup to assess cutaneous bioavailability on human skin models: dynamic protocol.
Human skin models, such as EpiDerm and Episkin, are not easily mounted into static or dynamic diffusion cells that are commonly used to perform bioavailability studies with human skin ex vivo. For various reasons, such as fragility, small sample size, and other morphological constraints, skin absorption studies with human skin models are often carried out on the delimited skin surface obtained by gluing a ring onto the reconstituted epidermis and manually exchanging the receptor solution. However, such an experimental setup is prone to artifacts. Discontinuous removal of the receptor fluid leads to alternating sink conditions, and an area of application smaller than the area in contact with the receptor fluid, as well as imperfect seal of the glued ring, may result in inaccurate penetration rates. Human skin models were shown to be relatively easily mounted into In-Line cells (PermeGear Inc.), vertical diffusion cells which appear to be appropriately designed for such a purpose. In-Line cells allowed accurate determination of solute penetration as well as automated sampling of receptor fluid. Excised human skin can be mounted into these cells as well, making it possible to compare penetration rates through different types of skin samples under identical conditions. Using mannitol as a reference compound, penetration profiles and epidermal distribution similar to those obtained with human skin ex vivo were obtained both with EpiDerm and Episkin. Under the present conditions, human skin models were more permeable to mannitol than excised human skin, which was only slightly permeable to mannitol. Due to these experimental innovations and to the good agreement with the absorption characteristics through human skin ex vivo, EpiDerm and Episkin seem to be promising human skin models for testing the cutaneous bioavailability of topical products in vitro.


Time-resolved diffusing wave spectroscopy beyond 300 transport mean free paths.
We presented theoretical and experimental demonstrations of the possibilities of performing time-resolved diffusing wave spectroscopy: We successfully registered field fluctuations for selected photon path lengths that can surpass 300 transport mean free paths. Such performance opens new possibilities for biomedical optics applications.


Banana leaves as an alternative wound dressing.
There is a need for cheap and efficacious wound dressings in developing countries. Banana leaves have been described as an excellent, inexpensive, easily available dressing material in tropical countries. As a natural product, banana leaves are heavily contaminated with various pathogens that must be removed before they can be used as wound dressings, but effective sterilization methods that do not affect the beneficial wound-dressing properties of banana leaves have not been described. To study different sterilization methods and determine which can be used on banana leaves without affecting their beneficial wound-dressing properties. We first compared the use of different decontamination techniques to reduce the natural microflora of the leaves and then tested the wound-dressing properties of the leaves in a mouse model of skin transplantation and in postsurgical patients in Uganda, Africa. Steam sterilization proved to be the optimal sterilization technique. Banana leaves displayed wound-dressing properties that equaled those of petroleum jelly gauze dressings and were tested successfully in a clinical setting in postsurgical patients in Uganda, Africa. We found banana leaves to be an excellent alternative wound dressing, combining the desirable properties of modern wound-dressing material with low cost.


Tailoring diffraction of light carrying orbital angular momenta.
A unified approach to controlling the diffraction of light carrying orbital angular momenta (OAM) is developed and experimentally verified in this Letter. This approach allows one to specify not only the number of diffraction maxima, their spatial frequencies, and the intensity distribution between them, but also the OAM in each maximum. It is verified that the approach can be used for structuring both single and multiple beams carrying OAMs. Simulations reveal phase singularities in structured beams. In addition, the approach makes it possible to shape the light in regular and irregular two-dimensional arrays with addressing the OAMs at each site. This approach offers new opportunities for singular optics.


Outcome Determinants of Decompressive Craniectomy in Patients with Traumatic Brain Injury; A Single Center Experience from Southern Iran.
To investigate the determinants of outcome in patients with traumatic brain injury (TBI) undergoing decompressive craniectomy (DC) in a large level I trauma center in southern Iran. This retrospective cross-sectional study was conducted during an 18-month period from 2013 to 2014 in Shahid Rajaei hospital, a Level I trauma center in Southern Iran. Patients with TBI who had undergone DC were included and the medical charts were reviewed regarding demographics, clinical, radiological and outcome characteristics. The outcome was determined by extended Glasgow outcome scale (GOS-E) after one year of surgery. The variables were compared between those with favorable and unfavorable outcome to investigate the outcome determinants. Overall 142 patients with mean age of 34.8 ± 15.5 (ranging from 15 to 85) years were included. There were 127 (89.4%) men and 15 (10.6%) women among the patients. After 1-year, the mortality rate was 58 (40.8%) and 8 (5.6%) patients were persistent vegetative state. The final outcome was found to be unfavorable in 77 (54.2%) patients. Unfavorable outcome was associated with lower GCS on admission (p<0.001) as well as occurrence of postoperative hydrocephalus (p=0.011). Formation of the postoperative subdural hygroma after the operation was found to be associated with favorable outcome (p=0.019). DC in patients with TBI is associated with favorable outcome in most of them. On admission GCS, postoperative hydrocephalus and presence of postoperative subdural hygroma are among the important predictors of outcome in TBI patients undergoing DC.


Formulation and evaluation of niosomes.
Span 20-based niosome was prepared by lipid film hydration technique and loaded with Newcastle disease vaccine. Three batches with Span 20, cholesterol and dicetyl phosphate in micro molar ratios of 10:10:1; 15:15:1 and 20:20:1 were prepared and evaluated for encapsulation efficiency using haemagglutination test. The morphology of the vesicles was studied by means of transmission electron microscopy. Particle size, zeta potential and polydispersity index were determined by photon correlation spectroscopy using a nanosizer. Adjuvanticity was assessed using haemagglutination inhibition test. The vesicles of Span 20-based niosomes were distinct, near spherical large unilamellar vesicles. The vesicles were of varied sizes (<1000 nm) with the entrapped Newcastle disease vaccine in the core of the vaccine. The zeta potential had a peak at -50 mV. The polydispersity index was 0.68. Haemagglutination inhibition test showed a 71% increment in immune response over that of the marketed La Sota(®) vaccine which had a 60% increment in immune response. The niosomal vaccine did not alter but rather enhanced the immunogenicity of the Newcastle disease vaccine.


Doctor and patient awareness of treatment options for cervical intraepithelial neoplasia 1 (CIN 1): a survey questionnaire approach.
The purpose of this study was to investigate doctors' and patients' perceptions of cervical intraepithelial neoplasia 1 (CIN 1) and its treatment methods. A survey questionnaire was offered to obstetrics and gynaecology doctors and patients with CIN 1 in 2017. Only 43% of patients knew of this disease. Regarding perceptions of its aetiology, 64% of the patients perceived human papillomavirus infection to be the main cause of CIN 1. Patients' most preferred treatments were medication (20%), followed by alternative treatment (14%). Among doctors, regular follow-up was the most preferred method for managing CIN 1. The survey showed that current treatment modalities for CIN 1 were satisfactory to only half of doctors (50%) and patients (53%). Overall, 70% of doctors responded that new drug development for CIN 1 is needed. Although, CIN 1 is a low-grade lesion, doctors and patients expressed the desire for new therapeutic agents to manage it.IMPACT STATEMENTWhat is already known on this subject? In general, treatment is not recommended for CIN 1 because lesions are considered indicative of transient HPV infection and spontaneously regress in most patients.What do the results of this study add? Regular follow-up for CIN 1 were satisfactory to only half of doctors and patients. Thirty-six percent of patients wanted active treatment instead of regular follow-up. In addition, 70% of doctors responded that new drug development for CIN 1 is needed.What are the implications of these findings for clinical practice and/or further research? Our results support the need for therapeutic agents for CIN 1.


Infantile systemic hyalinosis in siblings: clinical report, biochemical and ultrastructural findings, and review of the literature.
A boy presented at age 3.5 months with joint contractures, restlessness, and pain on handling. His skin was thickened and there were livid-red macular lesions over bony prominences. Infantile systemic hyalinosis (ISH) was diagnosed, a presumably autosomal recessive, progressive, and painful disorder of as yet unknown pathogenesis. Observation over three years confirmed the diagnosis as typical changes, such as nodules on both ears, pearly papules in the perinasal folds and on the neck, fleshy nodules in the perianal region, and gingival hypertrophy, developed. Skin lesions and painful joint contractures progressed in spite of intense physiotherapy, and at age 3, the child had marked motor disability. The central nervous system (CNS) appeared to be intact and the infant showed normal mental development. Radiologic findings included marked generalized osteopenia, osteolytic erosions in the metaphyses of the long bones, and cortical thinning. Electron microscopy of two skin biopsies demonstrated deposition of floccular amorphous substance that was abundant around, and appeared to originate from, small blood vessels in the dermis, partially interfering with collagen fiber formation. Lysosomal inclusions were not seen. Serum acid hyaluronidase activity was within the normal range, and the synthesis of hyaluronic acid and proteoglycans in cultured skin fibroblasts was similar to that of control cells. A younger sister presented at age two months with painful joint contractures and discrete livid-red macules over both malleoli, and showed a similar progression of the disorder over the first year of life. The diagnosis of ISH should be considered in infants and children presenting with painful joint contractures and skin lesions. The pathogenesis of this disabling and disfiguring disorder remains unclear. Our data confirm probable autosomal recessive inheritance, and do not support lysosomal storage, hyaluronidase deficiency, or a primary collagen disorder, but indicate that the amorphous material accumulating in the skin and articular soft tissues may originate from the blood circulation.


Preconception and prenatal cannabis use and the risk of behavioural and emotional problems in the offspring; a multi-informant prospective longitudinal study.
Studies of the long-term consequences of maternal cannabis use on child development beyond the neonatal period are sparse. In the current study, we use a multi-information approach to assess the association of prenatal cannabis exposure and child behavioural and emotional functioning. To explore the possible causal nature of the association, we investigated whether maternal tobacco and paternal cannabis use during pregnancy were also associated with child problems. The study population included children of a population-based birth cohort in The Netherlands (n = 5903). Information on parental cannabis use was collected using questionnaires; urine of mothers was analysed for the presence of cannabis metabolites. Child behavioural and emotional problems at approximately 7-10 years were measured using validated teacher-, child- and mother-reports. Our findings show associations of maternal cannabis use during pregnancy with offspring externalising problems (B = 0.53; 95% CI: 0.29-0.77), but not with internalising problems (B = -0.10; 95% CI: -0.31-0.11). However, maternal cannabis use before pregnancy was also associated with offspring externalising problems (B = 0.27; 95% CI: 0.02-0.52). Further, cannabis use by the father was associated with child externalising problems (B = 0.36; 95% CI: 0.22-0.49) but not internalising problems. Prenatal exposure to maternal cannabis use is specifically associated with offspring behavioural problems, but not emotional problems. This association is probably not due to an effect of intrauterine cannabis exposure on fetal development, because both maternal and paternal cannabis exposure during pregnancy were related to offspring externalising problems. Our findings suggest that the association can be explained through residual confounding, most likely through shared genetic vulnerabilities for parental cannabis use and offspring behavioural problems.


Hormone suppression with GnRH antagonist promotes spermatogenic recovery from transplanted spermatogonial stem cells in irradiated cynomolgus monkeys.
Hormone suppression given before or after cytotoxic treatment stimulates the recovery of spermatogenesis from endogenous and transplanted spermatogonial stem cells (SSC) and restores fertility in rodents. To test whether the combination of hormone suppression and transplantation could enhance the recovery of spermatogenesis in primates, we irradiated (7 Gy) the testes of 12 adult cynomolgus monkeys and treated six of them with gonadotropin-releasing hormone antagonist (GnRH-ant) for 8 weeks. At the end of this treatment, we transfected cryopreserved testicular cells with green fluorescent protein-lentivirus and autologously transplanted them back into one of the testes. The only significant effect of GnRH-ant treatment on endogenous spermatogenesis was an increase in the percentage of tubules containing differentiated germ cells (tubule differentiation index; TDI) in the sham-transplanted testes of GnRH-ant-treated monkeys compared with radiation-only monkeys at 24 weeks after irradiation. Although transplantation alone after irradiation did not significantly increase the TDI, detection of lentiviral DNA in the spermatozoa of one radiation-only monkey indicated that some transplanted cells colonized the testis. However, the combination of transplantation and GnRH-ant clearly stimulated spermatogenic recovery as evidenced by several observations in the GnRH-ant-treated monkeys receiving transplantation: (i) significant increases (~20%) in the volume and weight of the testes compared with the contralateral sham-transplanted testes and/or to the transplanted testes of the radiation-only monkeys; (ii) increases in TDI compared to the transplanted testes of radiation-only monkeys at 24 weeks (9.6% vs. 2.9%; p = 0.05) and 44 weeks (16.5% vs. 6.1%, p = 0.055); (iii) detection of lentiviral sequences in the spermatozoa or testes of five of the GnRH-ant-treated monkeys and (iv) significantly higher sperm counts than in the radiation-only monkeys. Thus hormone suppression enhances spermatogenic recovery from transplanted SSC in primates and may be a useful tool in conjunction with spermatogonial transplantation to restore fertility in men after cancer treatment.


Stress modulation of hippocampal activity--spotlight on the dentate gyrus.
The effects of stress on learning and memory are diverse, ranging from impairment to facilitation. Many studies emphasize the major role of the hippocampus, mainly its CA1 and CA3 areas, in the process of memory formation under emotional and stressful conditions. In the current review, we summarize work which suggests that the dentate gyrus (DG) of the hippocampus is likely to play a pivotal role in defining the impact of stress on hippocampal functioning. We describethe effects of stress on long term potentiation (LTP) and local circuit activity in the DG and the role of the amygdala in mediating these effects. As one of the brain regions known to have a high rate of adult neurogenesis, the effects of stress on DG neurogenesis will also be reviewed. Finally, we discuss exposure to stress during juvenility and its influence on the adult DG. The DG is a dynamic structure which is susceptible to stress. Under stressful conditions, its response is variable and complex, much like the behavioral outcomes of such circumstances. It is likely to significantly contribute to the diverse effects of stress on memory formation.


Neuraminidase inhibitory activities of flavonols isolated from Rhodiola rosea roots and their in vitro anti-influenza viral activities.
Five flavonols (3, 5, and 9-11) were isolated from Rhodiola rosea, and compared with commercially available flavonoids (1, 2, 4, 6-8, and 12-14) to facilitate analysis of their structure-activity relationship (SAR). All compounds (1-14) showed neuraminidase inhibitory activities with IC(50) values ranging from 0.8 to 56.9 microM. The in vitro anti-influenza virus activities of flavonoids 1-6, 8-12, and 14 were evaluated using two influenza viral strains, H1N1 (A/PR/8/34) and H9N2 (A/Chicken/Korea/MS96/96), testing their ability to reduce virus-induced cytopathic effect (CPE) in MDCK cells. We found that the activity of these compounds ranged from 30.2 to 99.1 microM against H1N1- and 18.5 to 133.6 microM against H9N2-induced CPE. Of compounds 1-14, gossypetin (6) exhibited the most potent inhibitory activity, with IC(50) values of 0.8 and 2.6 microM on neuraminidases from Clostridium perfringens and recombinant influenza virus A (rvH1N1), respectively. In contrast, kaempferol (3) exhibited the highest activity against two influenza viruses, H1N1 and H9N2 with EC(50) values of 30.2 and 18.5 microM, respectively. Activity depended on the position and number of hydroxy groups on the flavonoids backbone. In kinetic studies, all isolated compounds behaved as noncompetitive inhibitors.


Efficient solution of Poisson's equation using discrete variable representation basis sets for Car-Parrinello ab initio molecular dynamics simulations with cluster boundary conditions.
An efficient computational approach to perform Car-Parrinello ab initio molecular dynamics (CPAIMD) simulations under cluster (free) boundary conditions is presented. The general approach builds upon a recent real-space CPAIMD formalism using discrete variable representation (DVR) basis sets [Y. Liu et al., Phys. Rev. B 12, 125110 (2003); H.-S. Lee and M. E. Tuckerman, J. Phys. Chem. A 110, 5549 (2006)]. In order to satisfy cluster boundary conditions, a DVR based on sinc functions is utilized to expand the Kohn-Sham orbitals and electron density. Poisson's equation is solved in order to calculate the Hartree potential via an integral representation of the 1/r singularity. Excellent convergence properties are achieved with respect to the number of grid points (or DVR functions) and the size of the simulation cell. A straightforward implementation of the present approach leads to near linear scaling [O(N(4/3))] of the computational cost with respect to the system size (N) for the solution of Poisson's equation. The accuracy and stability of CPAIMD simulations based on sinc DVR are tested for a model problem as well as for N(2) and a water dimer.


Alterations of larval photo-dependent swimming responses (PDR): New endpoints for rapid and diagnostic screening of aquatic contamination.
Detection and toxicity assessment of waterborne contaminants are crucial for protecting human health and the environment. Development of easy-to-implement, rapid and cost-effective tools to measure anthropogenic effects on watersheds are critical for responsible management, particularly in times of increasing development and urbanization. Traditionally, environmental toxicology has focused on limited endpoints, such as lethality and fertility, which are directly affecting population levels. However, more sensitive readings are needed to assess sub-lethal effects. Monitoring of contaminant-induced behavior alterations was proposed before, but is difficult to implement in the wild and performing it in aquatic laboratory models seem more suited. For this purpose, we adapted a photo-dependent swimming response (PDR) that was previously described in zebrafish larva. We first asked if PDR was present in other aquatic animals. We measured PDR in larvae from two freshwater prawn species (Macrobrachium rosenbergii, MR, and Macrobrachium carcinus, MC) and from another fish the fathead minnow (FHM, Pimephales promelas). In all, we found a strong and reproducible species-specific PDR, which is arguing that this behavior is important, therefore an environmental relevant endpoint. Next, we measured PDR in fish larvae after acute exposure to copper, a common waterborne contaminant. FHM larvae were hyperactive at all tested concentrations in contrast to ZF larvae, which exhibited a concentration-dependent hyperactivity. In addition to this well-accepted anxiety-like behavior, we examined two more: photo-stimulated startle response (PSSR) and center avoidance (CA). Both were significantly increased. Therefore, PDR measures after acute exposure to this waterborne contaminant provided as sensitive readout for its detection and toxicity assessment. This approach represents an opportunity to diagnostically examine any substance, even when present in complex mixtures like ambient surface waters. Mechanistic studies of toxicity using the extensive molecular tool kit of ZF could be a direct extension of such approaches.


Phylogenetic relationships and regional spread of meningococcal strains in the meningitis belt, 2011-2016.
Historically, the major cause of meningococcal epidemics in the meningitis belt of sub-Saharan Africa has been Neisseria meningitidis serogroup A (NmA), but the incidence has been substantially reduced since the introduction of a serogroup A conjugate vaccine starting in 2010. We performed whole-genome sequencing on isolates collected post-2010 to assess their phylogenetic relationships and inter-country transmission. A total of 716 invasive meningococcal isolates collected between 2011 and 2016 from 11 meningitis belt countries were whole-genome sequenced for molecular characterization by the three WHO Collaborating Centers for Meningitis. We identified three previously-reported clonal complexes (CC): CC11 (n = 434), CC181 (n = 62) and CC5 (n = 90) primarily associated with NmW, NmX, and NmA, respectively, and an emerging CC10217 (n = 126) associated with NmC. CC11 expanded throughout the meningitis belt independent of the 2000 Hajj outbreak strain, with isolates from Central African countries forming a distinct sub-lineage within this expansion. Two major sub-lineages were identified for CC181 isolates, one mainly expanding in West African countries and the other found in Chad. CC10217 isolates from the large outbreaks in Nigeria and Niger were more closely related than those from the few cases in Mali and Burkina Faso. Whole-genome based phylogenies revealed geographically distinct strain circulation as well as inter-country transmission events. Our results stress the importance of continued meningococcal molecular surveillance in the region, as well as the development of an affordable vaccine targeting these strains. FUND: Meningitis Research Foundation; CDC's Office of Advanced Molecular Detection; GAVI, the Vaccine Alliance.


Dysfunctional maltreatment-related cognitions in children and adolescents.
Dysfunctional trauma-related cognitions correlate highly with chronic stress. Studies on maltreatment-related cognitions and their predictors in children and adolescents are rare. The study sample consisted of 231 children aged 8-17 years who had experienced maltreatment including domestic violence, emotional abuse, neglect, physical, and sexual abuse. Using multiple linear regression analysis, gender, age, index-event, multi-type maltreatment, out-of-home-care, and migration background were investigated as possible predictors of dysfunctional maltreatment-related cognitions. Additionally, the associations between dysfunctional cognitions and posttraumatic stress symptoms (PTSS) as well as further internalizing and externalizing symptoms were calculated. Gender emerged as a significant predictor of dysfunctional maltreatment-related cognitions. Moreover, there was an interaction effect of gender and age, with female adolescents showing most dysfunctional cognitions. Furthermore, experiencing five different maltreatment types had an impact, leading to more dysfunctional cognitions compared to single-type maltreatment. Dysfunctional maltreatment-related cognitions correlated highly with PTSS and internalizing symptoms, and moderately with externalizing symptoms. Dysfunctional maltreatment-related cognitions are associated with psychological symptoms after maltreatment and, therefore, need to be addressed in assessment and treatment. Trial registration DRKS00003979. Registered 03 July 2012.


Image statistics of American Sign Language: comparison with faces and natural scenes.
Several lines of evidence suggest that the image statistics of the environment shape visual abilities. To date, the image statistics of natural scenes and faces have been well characterized using Fourier analysis. We employed Fourier analysis to characterize images of signs in American Sign Language (ASL). These images are highly relevant to signers who rely on ASL for communication, and thus the image statistics of ASL might influence signers' visual abilities. Fourier analysis was conducted on 105 static images of signs, and these images were compared with analyses of 100 natural scene images and 100 face images. We obtained two metrics from our Fourier analysis: mean amplitude and entropy of the amplitude across the image set (which is a measure from information theory) as a function of spatial frequency and orientation. The results of our analyses revealed interesting differences in image statistics across the three different image sets, setting up the possibility that ASL experience may alter visual perception in predictable ways. In addition, for all image sets, the mean amplitude results were markedly different from the entropy results, which raises the interesting question of which aspect of an image set (mean amplitude or entropy of the amplitude) is better able to account for known visual abilities.


Comprehensive classification system for multirod constructs across three-column osteotomies: a reliability study.
In this study, the authors' goal was to determine the intra- and interobserver reliability of a new classification system that allows the description of all possible constructs used across three-column osteotomies (3COs) in terms of rod configuration and density. Thirty-five patients with multirod constructs (MRCs) across a 3CO were classified by two spinal surgery fellows according to the new system, and then were reclassified 2 weeks later. Constructs were classified as follows: the number of rods across the osteotomy site followed by a letter corresponding to the type of rod configuration: "M" is for a main rod configuration, defined as a single rod spanning the osteotomy. "L" is for linked rod configurations, defined as 2 rods directly connected to each other at the osteotomy site. "S" is for satellite rod configurations, which were defined as a short rod independent of the main rod with anchors above and below the 3CO. "A" is for accessory rods, defined as an additional rod across the 3CO attached to main rods but not attached to any anchors across the osteotomy site. "I" is for intercalary rod configurations, defined as a rod connecting 2 separate constructs across the 3CO, without the intercalary rod itself attached to any anchors across the osteotomy site. The intra- and interobserver reliability of this classification system was determined. A sample estimation for validation assuming two readers and 35 subjects results in a two-sided 95% confidence interval with a width of 0.19 and a kappa value of 0.8 (SD 0.3). The Fleiss kappa coefficient (κ) was used to calculate the degree of agreement between interrater and intraobserver reliability. The interrater kappa coefficient was 0.3, and the intrarater kappa coefficient was 0.63 (good reliability). This scenario represents a high degree of agreement despite a low kappa coefficient. Correct observations by both observers were 34 of 35 and 33 of 35 at both time points. Misclassification was related to difficulty in determining connectors versus anchors. MRCs across 3COs have variable rod configurations. Currently, no classification system or agreement on nomenclature exists to define the configuration of rods across 3COs. The authors present a new, comprehensive MRC classification system with good inter- and intraobserver reliability and a high degree of agreement that allows for a standardized description of MRCs across 3COs.


Tracking of fetal growth characteristics during different trimesters and the risks of adverse birth outcomes.
Fetal growth characteristics are used to identify influences of several maternal characteristics and to identify individuals at increased risk of adverse outcomes. The extent to which fetal growth characteristics track in different trimesters is not known. In a population-based prospective cohort study among 8636 pregnant women, we examined the extent to which fetal growth characteristics track, are influenced by maternal socio-demographic and lifestyle related determinants and are associated with birth outcomes. Fetal growth was assessed in each trimester and at birth. Correlation coefficient between first-trimester crown-rump length and birthweight was r = 0.12 (P-value < 0.05). Correlation coefficients for fetal-head circumference, (femur) length and (estimated) fetal weight ranged from r = 0.16 to r = 0.30 (all P-values < 0.05) between second trimester and birth and from r = 0.36 to r = 0.58 (all P-values < 0.05) between third trimester and birth, and were highest for (estimated) fetal weight. Correlation coefficients for (estimated) fetal weight tended to be lower among overweight mothers, as compared with normal weight mothers, but were not influenced by other maternal characteristics. First, second and third-trimester fetal growth characteristics were associated with risks of preterm birth and small size for gestational age at birth,with the strongest associations present in third trimester. Fetal growth characteristics track moderately throughout gestation, with stronger tracking coefficients present in later pregnancy. Tracking coefficients were not materially influenced by maternal socio-demographic and lifestyle characteristics. First, second and third trimester fetal growth characteristics were associated with the risk of adverse birth outcomes.


Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A-dependent mechanism.
A dozen clinical trials examining a combination of temsirolimus and cetuximab in treating metastatic colon cancer are currently underway. We investigated the role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in the synergism between temsirolimus and cetuximab in colon cancer. Five colon cancer cell lines were used for in vitro studies. Signal transduction pathways were assessed by immunoblotting. The synergism between studied drugs was analyzed with combination indexes. Gene silencing was performed using small interfering RNAs. The efficacies of temsirolimus and cetuximab were tested in nude mice with colon cancer xenografts. Transcriptional activity was assessed using a reporter assay. The inhibitors leupeptin, chloroquine, and MG132 were used to assess protein degradation. The association between CIP2A, clinicopathological parameters, and survival was examined by immunohistochemical staining using a tumor tissue microarray. Temsirolimus decreased the resistance of cells to cetuximab by both inhibiting transcription of CIP2A and increasing degradation of CIP2A through the lysosomal-autophagy pathway. The mammalian target of rapamycin (mTOR) protein immunoprecipitated along with CIP2A. Temsirolimus decreased expression of phosphorylated extracellular regulated protein kinase (pErk) and phosphorylated v-akt murine thymoma viral oncogene (pAKT) and decreased the interaction of CIP2A and mTOR in cell lines without the K-ras codon 12 mutation. CIP2A was a prognostic marker only in colon cancer patients with weak expression of pErk or pAKT. Temsirolimus decreases cellular resistance to cetuximab by regulating CIP2A expression in colon cancer cells. Potential biomarkers for CIP2A inhibitors include pErk and pAKT.


The interactive-alignment model: Developments and refinements.
The interactive-alignment model of dialogue provides an account of dialogue at the level of explanation normally associated with cognitive psychology. We develop our claim that interlocutors align their mental models via priming at many levels of linguistic representation, explicate our notion of automaticity, defend the minimal role of "other modeling," and discuss the relationship between monologue and dialogue. The account can be applied to social and developmental psychology, and would benefit from computational modeling.


Building a Contextually-Relevant Understanding of Resilience among African American Youth Exposed to Community Violence.
Studies consistently demonstrate that African American youth experience disproportionate levels of community violence, which is associated with negative health and well-being outcomes among these youth. The frequency and severity of community violence exposure is a unique challenge for these youth and requires tailored approaches to promote resilience after community violence exposure. However, limited research exists that operationalizes resilience after community violence based on the unique context and lived experience of African American youth. Developing a more contextually relevant understanding of resilience is critical to reducing health inequities experienced by African American youth and promoting their well-being. Five focus groups were conducted with 39 African American adolescents (ages 13-18) exposed to community violence. Participants also completed a brief survey that included questions on demographics, adverse childhood experiences, social capital, and resilience. Focus-group transcripts were independently coded by two members of the research team and analyzed using an inductive approach. Youth highlighted key indicators of resilience including the ability to persevere, self-regulate, and change to adapt/improve. Youth also described family, peer, and cultural contexts that impact how resilience is produced and manifested, highlighting trust, perceived burdensomeness, self-determination, connectedness, and mental health stigma as key factors within these contexts. Results of this qualitative study support the development of health promotion programs for African American youth exposed to community violence that address unique risks and build on existing protective factors within family, peer, and cultural contexts.


Pathophysiology and implications of intradialytic hypertension.
Intradialytic hypertension occurs regularly in 10--15% of hemodialysis patients. A large observational study recently showed that intradialytic hypertension of any magnitude increased mortality risk comparable to the most severe degrees of intradialytic hypotension. The present review review discusses the most recent evidence underlying the pathophysiology of intradialytic hypertension and implications for its management. Patients with intradialytic hypertension typically have small interdialytic weight gains, but bioimpedance spectroscopy shows these patients have significant chronic extracellular volume excess. Intradialytic hypertension patients have lower albumin and predialysis urea nitrogen levels, which may contribute to small reductions in osmolarity that prevents blood pressure decreases. Intradialytic vascular resistance surges remain implicated as the driving force for blood pressure increases, but mediators other than endothelin-1 may be responsible. Beyond dry weight reduction, the only controlled intervention shown to interrupt the blood pressure increase is lowering dialysate sodium. Patients with recurrent intradialytic hypertension should be identified as high-risk patients. Dry weight should be re-evaluated, even if patients do not clinically appear volume overloaded. Antihypertensive drugs should be prescribed because of the persistently elevated ambulatory blood pressure. Dialysate sodium reduction should be considered, although the long term effects of this intervention are uncertain.


Notes from the Field: Cluster of Lymphogranuloma Venereum Cases Among Men Who Have Sex with Men - Michigan, August 2015-April 2016.
Lymphogranuloma venereum (LGV) is a sexually transmitted disease (STD) caused by infection with invasive Chlamydia trachomatis serovars L1-L3 (1). LGV is characterized by inguinal and/or femoral lymphadenopathy, typically following a transient, self-limited genital ulcer or papule that might go unnoticed. Rectal infection can result in proctocolitis that can present with mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and tenesmus, and signs of granulomas and/or ulcerations on anoscopy (1,2). LGV can be an invasive, systemic infection, and if it is not treated early, LGV proctocolitis can lead to chronic colorectal fistulas and strictures (2). In Europe, outbreaks of LGV have been reported among men who have sex with men (MSM), often in association with human immunodeficiency virus (HIV) coinfection (3-5). The prevalence of LGV in the United States is unknown (1), because diagnostic tests to differentiate LGV from non-LGV Chlamydia trachomatis are not widely available (6), and providers might not know that they should report cases that are presumptively treated.


Interleukin-1-beta changes the expression of metalloproteinases in the vitreous humor and induces membrane formation in eyes containing preexisting retinal holes.
Proliferative vitreoretinopathy occurs when cells migrate into the vitreous humor, where they proliferate and produce a membrane composed of extracellular matrix. Interleukin-1-beta (IL-1-beta) may be involved in these processes because it is chemotactic and mitogenic, and it stimulates metalloproteinase production. In the present study, the effects of intravitreally injected IL-1-beta on retinal membrane formation and the associated changes in metalloproteinase content of vitreous humor were examined. Rabbit eyes were injected with IL-1-beta in a buffer, with or without the prior creation of retinal holes. Control eyes received the buffer alone or no injection, with or without retinal holes. Animals were examined by slit lamp biomicroscopy and indirect ophthalmoscopy for 1 month. Zymography was performed on a portion of vitreous humor to assess collagenase content, and the remaining tissue was subjected to histologic analysis. Intraocular IL-1-beta induced perilimbal vessel engorgement, keratic precipitates, synechiae, flare, lens deposits, optic disk hyperemia, and granulomatous formations that gradually subsided during the first week. Intravitreal injection of IL-1-beta in eyes with preexisting retinal holes additionally induced membrane formation. Zymographic analysis of vitreous humor from animals sacrificed 24 hours after IL-1-beta injection showed a 100-kd and a 65-kd gelatinase, whereas control vitreous humor contained predominantly a single gelatinase species of approximately 65 kd. Retinal holes did not affect IL-1-beta induction of the 100-kd gelatinase. IL-1-beta induces a 100-kd gelatinase in the vitreous humor and epiretinal membrane formation in eyes containing preexisting retinal holes. The presence of retinal holes and abnormal production of cytokines may lead to a cascade of events, including aberrant extracellular matrix remodeling, that result in proliferative diseases of the eye.


Dose-related effects of selective 5-HT2 receptor antagonists on slow wave sleep in humans.
The effects of the selective 5-HT2 receptor antagonists, ritanserin (1, 5 and 10 mg) and ICI 169.369 (50 and 100 mg), were studied on the sleep EEG of healthy volunteers using home-based Medilog 9000 cassette monitoring. Ritanserin (5 and 10 mg) produced a significant increase in slow wave sleep (SWS) while ICI 169,369 also increased SWS but only at a dose of 100 mg. These findings are consistent with the proposal that selective 5-HT2 receptor blockade increases SWS in humans; however, the data cannot exclude involvement of the closely related 5-HT1c receptor in this effect.


Partial correction of cystic fibrosis defects with PLGA nanoparticles encapsulating curcumin.
Cystic fibrosis (CF) is a common life threatening genetic disease (incidence: approximately 1 in 2500 live births). CF is caused by mutations in CFTR, a chloride channel involved in epithelial secretion of fluid and electrolytes. The most common mutation entails the deletion of a phenylalanine in position 508 that causes protein misfolding and abnormal CFTR processing. The DeltaF508 mutation accounts for approximately 70% of all CF alleles, and about 90% of CF patients carry at least one copy of DeltaF508 CFTR. Curcumin, a natural constituent of Curcuma longa (turmeric spice), is a nontoxic low-affinity SERCA (sarco (endo)plasmic reticulum calcium ATPase) pump inhibitor thought to permit DeltaF508 CFTR escape from the ER. The compound has been shown to be capable of correcting the defect in cell lines and mice expressing DeltaF508 CFTR. In this work, poly lactic-co-glycolic acid (PLGA) nanoparticles encapsulating curcumin were synthesized and used to treat two different CF mouse strains in an effort to correct the defects associated with CF by improving bioavailability of the compound, which has previously been a challenge in treatment with curcumin. Our results suggest that oral administration of PLGA nanoparticles encapsulating curcumin enhances the effects of curcumin therapy in CF mice, as compared to delivery of nonencapsulated curcumin.


Molecular approaches to improvement of Jatropha curcas Linn. as a sustainable energy crop.
With the increase in crude oil prices, climate change concerns and limited reserves of fossil fuel, attention has been diverted to alternate renewable energy sources such as biofuel and biomass. Among the potential biofuel crops, Jatropha curcas L, a non-domesticated shrub, has been gaining importance as the most promising oilseed, as it does not compete with the edible oil supplies. Economic relevance of J. curcas for biodiesel production has promoted world-wide prospecting of its germplasm for crop improvement and breeding. However, lack of adequate genetic variation and non-availability of improved varieties limited its prospects of being a successful energy crop. In this review, we present the progress made in molecular breeding approaches with particular reference to tissue culture and genetic transformation, genetic diversity assessment using molecular markers, large-scale transcriptome and proteome studies, identification of candidate genes for trait improvement, whole genome sequencing and the current interest by various public and private sector companies in commercial-scale cultivation, which highlights the revival of Jatropha as a sustainable energy crop. The information generated from molecular markers, transcriptome profiling and whole genome sequencing could accelerate the genetic upgradation of J. curcas through molecular breeding.


Energy requirements for waste water treatment.
The actual mathematical models describing global climate closely link the detected increase in global temperature to anthropogenic activity. The only energy source we can rely on in a long perspective is solar irradiation which is in the order of 10,000 kW/inhabitant. The actual primary power consumption (mainly based on fossil resources) in the developed countries is in the range of 5 to 10 kW/inhabitant. The total power contained in our nutrition is in the range of 0.11 kW/inhabitant. The organic pollution of domestic waste water corresponds to approximately 0.018 kW/inhabitant. The nutrients contained in the waste water can also be converted into energy equivalents replacing market fertiliser production. This energy equivalent is in the range of 0.009 kW/inhabitant. Hence waste water will never be a relevant source of energy as long as our primary energy consumption is in the range of several kW/inhabitant. The annual mean primary power demand of conventional municipal waste water treatment with nutrient removal is in the range of 0.003-0.015 kW/inhabitant. In principle it is already possible to reduce this value for external energy supply to zero. Such plants should be connected to an electrical grid in order to keep investment costs low. Peak energy demand will be supported from the grid and surplus electric energy from the plant can be is fed to the grid. Zero 'carbon footprint' will not be affected by this solution. Energy minimisation must never negatively affect treatment efficiency because water quality conservation is more important for sustainable development than the possible reduction in energy demand. This argument is strongly supported by economical considerations as the fixed costs for waste water infrastructure are dominant.


Functional significance of the uncinate processes in birds.
The functional significance of the uncinate processes to the ventilatory mechanics of birds was examined by combining analytical modeling with morphological techniques. A geometric model was derived to determine the function of the uncinate processes and relate their action to morphological differences associated with locomotor specializations. The model demonstrates that uncinates act as levers, which improve the mechanical advantage for the forward rotation of the dorsal ribs and therefore lowering of the sternum during respiration. The length of these processes is functionally important; longer uncinate processes increasing the mechanical advantage of the Mm. appendicocostales muscle during inspiration. Morphological studies of four bird species showed that the uncinate process increased the mechanical advantage by factors of 2-4. Using canonical variate analysis and analysis of variance we then examined the variation in skeletal parameters in birds with different primary modes of locomotion (non-specialists, walking and diving). Birds clustered together in distinct groups, indicating that uncinate length is more similar in birds that have the same functional constraint, i.e. specialization to a locomotor mode. Uncinate processes are short in walking birds, long in diving species and of intermediate length in non-specialist birds. These results demonstrate that differences in the breathing mechanics of birds may be linked to the morphological adaptations of the ribs and rib cage associated with different modes of locomotion.


A propensity-matched comparison of long-term disability worsening in patients with multiple sclerosis treated with dimethyl fumarate or fingolimod.
Although the aggregate of data among patients with multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY), most studies have not assessed long-term worsening of disability. We compared long-term disability worsening over 5 years, as assessed by the Patient-Determined Disease Steps (PDDS), among participants with MS treated with DMF or FTY. We identified individuals in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry who had relapsing-remitting MS (RRMS), residing in the United States (Spring 2011 to Spring 2018), who initiated treatment with DMF (n = 689) or FTY (n = 565) and had ⩾1 year follow-up on index treatment. Participants receiving DMF who were previously treated with FTY and those on FTY previously treated with DMF were excluded. Propensity score matching at baseline was used to match FTY-treated to DMF-treated participants. Time to 6-month confirmed disability worsening (⩾1-point increase on PDDS, sustained for ⩾6 months) was estimated using Cox regression. A sensitivity analysis was conducted to account for differences in the duration of index exposure between DMF and FTY groups. After propensity score matching, 468 DMF-treated participants were matched with 468 FTY-treated participants. Median treatment duration was 3.0 years for DMF and 4.0 years for FTY. At 5 years, 68.3% [95% confidence interval (CI): 62.4-73.5] of DMF-treated participants and 63.3% (95% CI: 59.6-70.1) treated with FTY were free from 6-month confirmed PDDS worsening [hazard ratio (HR) 1.01 (95% CI: 0.79-1.28); p = 0.95]. Results were similar in the sensitivity analysis: 70.5% (95% CI: 61.8-77.6) of DMF-treated participants and 72.7% (95% CI: 65.4-78.6) of FTY-treated participants were free from 6-month confirmed PDDS worsening [HR: 1.04 (95% CI: 0.71-1.51); p = 0.84]. In participants with MS from the NARCOMS registry, there was no significant difference in confirmed disability (PDDS) worsening over 5 years between those treated with DMF versus FTY.


Mitochondrial proton conductance and H+/O ratio are independent of electron transport rate in isolated hepatocytes.
In this paper we examine the non-linearity of the relationship between the proton electrochemical gradient across the mitochondrial inner membrane (delta p) and oxygen consumption of non-phosphorylating mitochondria in situ in hepatocytes. Models proposing to explain the non-linear relationship were tested experimentally. It was shown that the mitochondrial proton conductance and the number of protons pumped to the cytosolic side of the mitochondrial inner membrane by the electron transport complexes per oxygen atom consumed (H+/O ratio) are independent of electron transport rate in mitochondria in isolated hepatocytes. The non-linearity of the plot of delta p against the non-phosphorylating oxygen consumption is due to either a potential-dependent slippage of the proton pumps of the mitochondrial inner membrane and/or a potential-dependent leakage of protons back across the mitochondrial inner membrane.


Etomidate: a new intravenous anesthetic induction agent.
Currently available anesthetic induction agents provide adequate hypnosis but are not ideal, particularly in the high risk patient (ASA class III-V), because most cause myocardial and/or respiratory depression and some have other important side effects. Etomidate was recently marketed as an intravenous anesthetic induction agent. It is a non-barbiturate hypnotic without analgesic properties that has less cardiovascular and respiratory depressant actions than sodium thiopental, even in patients with minimal cardiovascular reserve. Laboratory studies indicate that etomidate is approximately 25 times more potent and has a therapeutic index six times greater than sodium thiopental. In contrast to most other induction agents, etomidate does not cause histamine release. Furthermore, tolerance does not occur with repeated administration. Etomidate's rapid distribution half life (t 1/2 alpha = 2.81 +/- 1.64 min), short elimination half life 1/2 beta = 3.88 +/- 1.11 hr) and rapid clearance (954 +/- 178 ml/min) explain its rapid onset and short duration of action. The compound produces electroencephalographic changes and effects on cerebral blood flow, metabolism and intracranial pressure that are similar to sodium thiopental, suggesting that it may have a place in neurosurgery and as a "brain protective" agent in patients at risk of a brain hypoxic insult. Etomidate did not affect hepatorenal and hematologic function after repeated injections in animal toxicology studies, but few investigations addressing its effects on hepatic, renal, and neuromuscular function in man have been accomplished. The most noticeable side effects of etomidate include myoclonia, pain on injection and postoperative nausea and vomiting.(ABSTRACT TRUNCATED AT 250 WORDS)


Prehospital emergency medical services.
Our primary objectives were to estimate how frequently emergency medical technicians with defibrillation skills (EMT-Ds) are forced to deal with prehospital do-not-resuscitate (DNR) orders, to assess their comfort in doing so, and to describe the prehospital care provided to patients with DNR orders in a system without a prehospital DNR policy (i.e., where resuscitation is mandatory). Using Dillman methodology, the authors developed a 13-item survey and mailed it to 382 of 764 EMT-Ds in the metropolitan Toronto area. Responses were evaluated using 5-point Likert scales, limited-option and open-ended questions. Narrative responses were categorized. Two authors independently categorized narrative responses from 20 surveys, and kappa values for agreement beyond chance were determined. Among 382 EMT-Ds surveyed, 236 (62%) responded, of whom 221 (94%) answered the questionnaire. Overall, 126 of 219 (58%) indicated that they were called to resuscitate patients with DNR orders "sometimes," "frequently," or "all the time." In such situations, 22 of 207 (11%) stated they would honour the DNR order and 55 of 207 (27%) would honour the order but appear to provide basic resuscitation, in order to adhere to mandatory resuscitation regulations. Willingness to honour a DNR order did not vary by years of emergency medical service. EMT-Ds cited concern for the family and the patient, fear of repercussions and conflict with personal ethics as key factors contributing to this ethical dilemma. If legally allowed to honour DNR orders, 212 of 221 (96%) respondents would be comfortable with a written order and 137 of 220 (62%) with a verbal order. Prehospital DNR orders are common, and a significant number of EMT-Ds disregard current regulations by honouring them. EMT-Ds would be more comfortable with written than verbal DNR orders. An ethical prehospital DNR policy should be developed and applied.


Modeling the impact of COPD on the brain.
Previous studies have shown that COPD adversely affects distant organs and body systems, including the brain. This pilot study aims to model the relationships between respiratory insufficiency and domains related to brain function, including low mood, subtly impaired cognition, systemic inflammation, and brain structural and neurochemical abnormalities. Nine healthy controls were compared with 18 age- and education-matched medically stable-COPD patients, half of whom were oxygen-dependent. Measures included depression, anxiety, cognition, health status, spirometry, oximetry at rest and during 6-minute walk, and resting plasma cytokines and soluble receptors, brain MRI, and MR spectroscopy in regions relevant to mood and cognition. ANOVA was used to compare controls with patients and with COPD subgroups (oxygen users [n = 9] and nonusers [n = 9]), and only variables showing group differences at p < or = 0.05 were included in multiple regressions controlling for age, gender, and education to develop the final model. Controls and COPD patients differed significantly in global cognition and memory, mood, and soluble TNFR1 levels but not brain structural or neurochemical measures. Multiple regressions identified pathways linking disease severity with impaired performance on sensitive cognitive processing measures, mediated through oxygen dependence, and with systemic inflammation (TNFR1), related through poor 6-minute walk performance. Oxygen desaturation with activity was related to indicators of brain tissue damage (increased frontal choline, which in turn was associated with subcortical white matter attenuation). This empirically derived model provides a conceptual framework for future studies of clinical interventions to protect the brain in patients with COPD, such as earlier oxygen supplementation for patients with desaturation during everyday activities.


An experimental study on fabricating an inverted mesa-type quartz crystal resonator using a cheap wet etching process.
In this study, a miniaturized high fundamental frequency quartz crystal microbalance (QCM) is fabricated for sensor applications using a wet etching technique. The vibration area is reduced in the fabrication of the high frequency QCM with an inverted mesa structure. To reduce the complexity of the side wall profile that results from anisotropic quartz etching, a rectangular vibration area is used instead of the conventional circular structure. QCMs with high Q values exceeding 25,000 at 47 MHz, 27,000 at 60 MHz, 24,000 at 73 MHz and 25,000 at 84 MHz are fabricated on 4 × 4 mm2 chips with small vibration areas of 1.2 × 1.4 mm2. A PMMA-based flow cell is designed and manufactured to characterize the behavior of the fabricated QCM chip in a liquid. Q values as high as 1,006 at 47 MHz, 904 at 62 MHz, 867 at 71 MHz and 747 at 84 MHz are obtained when one side of the chip is exposed to pure water. These results show that fabricated QCM chips can be used for bio- and chemical sensor applications in liquids.


Systematic, Multimethod Assessment of Adaptations Across Four Diverse Health Systems Interventions.
Many health outcomes and implementation science studies have demonstrated the importance of tailoring evidence-based care interventions to local context to improve fit. By adapting to local culture, history, resources, characteristics, and priorities, interventions are more likely to lead to improved outcomes. However, it is unclear how best to adapt evidence-based programs and promising innovations. There are few guides or examples of how to best categorize or assess health-care adaptations, and even fewer that are brief and practical for use by non-researchers. This study describes the importance and potential of assessing adaptations before, during, and after the implementation of health systems interventions. We present a promising multilevel and multimethod approach developed and being applied across four different health systems interventions. Finally, we discuss implications and opportunities for future research. The four case studies are diverse in the conditions addressed, interventions, and implementation strategies. They include two nurse coordinator-based transition of care interventions, a data and training-driven multimodal pain management project, and a cardiovascular patient-reported outcomes project, all of which are using audit and feedback. We used the same modified adaptation framework to document changes made to the interventions and implementation strategies. To create the modified framework, we started with the adaptation and modification model developed by Stirman and colleagues and expanded it by adding concepts from the RE-AIM framework. Our assessments address the intuitive domains of Who, How, When, What, and Why to classify and organize adaptations. For each case study, we discuss how the modified framework was operationalized, the multiple methods used to collect data, results to date and approaches utilized for data analysis. These methods include a real-time tracking system and structured interviews at key times during the intervention. We provide descriptive data on the types and categories of adaptations made and discuss lessons learned. The multimethod approaches demonstrate utility across diverse health systems interventions. The modified adaptations model adequately captures adaptations across the various projects and content areas. We recommend systematic documentation of adaptations in future clinical and public health research and have made our assessment materials publicly available.


Maternal BCG scar is associated with increased infant proinflammatory immune responses.
Prenatal exposures such as infections and immunisation may influence infant responses. We had an opportunity to undertake an analysis of innate responses in infants within the context of a study investigating the effects of maternal mycobacterial exposures and infection on BCG vaccine-induced responses in Ugandan infants. Maternal and cord blood samples from 29 mother-infant pairs were stimulated with innate stimuli for 24h and cytokines and chemokines in supernatants were measured using the Luminex® assay. The associations between maternal latent Mycobacterium tuberculosis infection (LTBI), maternal BCG scar (adjusted for each other's effect) and infant responses were examined using linear regression. Principal Component Analysis (PCA) was used to assess patterns of cytokine and chemokine responses. Gene expression profiles for pathways associated with maternal LTBI and with maternal BCG scar were examined using samples collected at one (n=42) and six (n=51) weeks after BCG immunisation using microarray. Maternal LTBI was positively associated with infant IP-10 responses with an adjusted geometric mean ratio (aGMR) [95% confidence interval (CI)] of 5.10 [1.21, 21.48]. Maternal BCG scar showed strong and consistent associations with IFN-γ (aGMR 2.69 [1.15, 6.17]), IL-12p70 (1.95 [1.10, 3.55]), IL-10 (1.82 [1.07, 3.09]), VEGF (3.55 [1.07, 11.48]) and IP-10 (6.76 [1.17, 38.02]). Further assessment of the associations using PCA showed no differences for maternal LTBI, but maternal BCG scar was associated with higher scores for principal component (PC) 1 (median level of scores: 1.44 in scar-positive versus -0.94 in scar-negative, p=0.020) in the infants. PC1 represented a controlled proinflammatory response. Interferon and inflammation response pathways were up-regulated in infants of mothers with LTBI at six weeks, and in infants of mothers with a BCG scar at one and six weeks after BCG immunisation. Maternal BCG scar had a stronger association with infant responses than maternal LTBI, with an increased proinflammatory immune profile.


Plasmonic sensing using metallic nano-sculptured thin films.
Nano-sculptured thin films (nSTFs) is a group of meterials prepared by the oblique or the glancing angle deposition technique. They take the form of rods having different shapes such as nanocolumns, nanoscrews, nanozigzags and many other nanoshapes. Their potential for biosensing is highlighted in this review particularly the metallic ones due to their remarkable plasmonic properties. The techniques that have been shown so far to be of high potential are: extended surface plasmon resonance (SPR), localised SPR, surface enhanced flourescence (SEF) and Raman scattering (SERS). The use of metal nSTFs in SPR biosensors with Kretschmann-Raether configuration enhances both the angular and the spectral sensitivities due to the porosity and adds more degrees of freedom in designing evanescent waves based techniques. The metallic nSTFs, exhibit remarkable localised plasmonic properties that make them a promising substrate for enhanced spectroscopies. Their long term stability in water environment makes them suitable candidates for biosensing in water as it is already demonstrated for several water pollutants. The influences of the nanostructures' size, topology, the substrate features, and the preparation conditions on the enhancement of SEF and SERS are highlighted with emphases on the unresolved issues and future trends.


Where the lake meets the sea: strong reproductive isolation is associated with adaptive divergence between lake resident and anadromous three-spined sticklebacks.
Contact zones between divergent forms of the same species are often characterised by high levels of phenotypic diversity over small geographic distances. What processes are involved in generating such high phenotypic diversity? One possibility is that introgression and recombination between divergent forms in contact zones results in greater phenotypic and genetic polymorphism. Alternatively, strong reproductive isolation between forms may maintain distinct phenotypes, preventing homogenisation by gene flow. Contact zones between divergent freshwater-resident and anadromous stickleback (Gasterosteus aculeatus L.) forms are numerous and common throughout the species distribution, offering an opportunity to examine these contrasting hypotheses in greater detail. This study reports on an interesting new contact zone located in a tidally influenced lake catchment in western Ireland, characterised by high polymorphism for lateral plate phenotypes. Using neutral and QTL-linked microsatellite markers, we tested whether the high diversity observed in this contact zone arose as a result of introgression or reproductive isolation between divergent forms: we found strong support for the latter hypothesis. Three phenotypic and genetic clusters were identified, consistent with two divergent resident forms and a distinct anadromous completely plated population that migrates in and out of the system. Given the strong neutral differentiation detected between all three morphotypes (mean FST = 0.12), we hypothesised that divergent selection between forms maintains reproductive isolation. We found a correlation between neutral genetic and adaptive genetic differentiation that support this. While strong associations between QTL linked markers and phenotypes were also observed in this wild population, our results support the suggestion that such associations may be more complex in some Atlantic populations compared to those in the Pacific. These findings provide an important foundation for future work investigating the dynamics of gene flow and adaptive divergence in this newly discovered stickleback contact zone.


Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease.
The effect of bacterial colonization of the bronchi on the progress of airflow limitation is not well known. Therefore, the pattern of airway inflammation in smokers and patients with stable chronic obstructive pulmonary disease (COPD) and its relation to bronchial microbial colonization was assessed. Eight nonsmoking and 18 smoking controls as well as 52 patients with COPD (28 mild, 11 moderate and 13 severe) were studied. All subjects were investigated by means of flexible bronchoscopy including protected specimen brush and bronchoalveolar lavage (BAL) sampling. Differential cell counts, cytokine (interleukin (IL)-1beta, IL-6, IL-8, IL-10 and tumour necrosis factor-alpha(TNF-alpha) concentrations and microbial patterns were determined in BAL fluid. Forced expiratory volume in one second (FEV1) % of the predicted value was inversely correlated with pack-yrs of cigarette smoking (r=-0.47, p<0.0001), the percentage of neutrophil (p=-0.56, p<0.0001) and IL-6 (p=-0.37, p=0.01) and IL-8 concentration (p=-0.43, p=0.004) in BAL fluid. Accordingly, pk-yrs of cigarette smoking (p=0.39, p=0.01) and IL-8 (p=0.69, p<0.0001) and TNFalpha (p=0.4, p<0.005) were positively correlated with the percentage of neutrophils in BAL fluid. Smoking controls and COPD patients were mainly colonized in the bronchial tree (33%) by community endogenous potentially pathogenic micro-organisms (PPMs). Colonization rates and patterns of PPMs were not affected by severity of airflow obstruction. The presence of PPMs was significantly associated with higher percentages of neutrophils (33.2+/-10.4% versus 10.1+/-3.5%, p=0.02) and TNF-alpha concentration (29.9+/-10.8 versus 6.3+/-2.1 pg x mL(-1), p=0.01) in BAL fluid. In conclusion, bronchial neutrophilia is a key inflammatory pattern in chronic obstructive pulmonary disease patients. Bronchial colonization with potentially pathogenic micro-organisms may represent an independent stimulus for additional airway inflammation.


Relationship between the excited state relaxation paths of rhodopsin and isorhodopsin.
The pigment Isorhodopsin, an analogue of the visual pigment Rhodopsin, is investigated via quantum-mechanics/molecular-mechanics computations based on an ab initio multiconfigurational quantum chemical treatment. The limited <5 kcal mol(-1) error found for the spectral parameters allows for a nearly quantitative analysis of the excited-state structure and reactivity of its 9-cis-retinal chromophore. We demonstrate that, similar to Rhodopsin, Isorhodopsin features a shallow photoisomerization path. However, the structure of the reaction coordinate appears to be reversed. In fact, while the coordinate still corresponds to an asynchronous crankshaft motion, the dominant isomerization component involves a counterclockwise, rather than clockwise, twisting of the 9-cis bond. Similarly, the minor component involves a clockwise, rather than counterclockwise, twisting of the 11-trans bond. Ultimately, these results indicate that Rhodopsin and Isorhodopsin relax along a common excited-state potential energy valley starting from opposite ends. The fact that the central and lowest energy region of such valley runs along a segment of the intersection space between the ground and excited states of the protein explains why the pigments decay at distinctive conical intersection structures.


High Tech Aids Low Vision: A Review of Image Processing for the Visually Impaired.
Recent advances in digital image processing provide promising methods for maximizing the residual vision of the visually impaired. This paper seeks to introduce this field to the readership and describe its current state as found in the literature. A systematic search revealed 37 studies that measure the value of image processing techniques for subjects with low vision. The techniques used are categorized according to their effect and the principal findings are summarized. The majority of participants preferred enhanced images over the original for a wide range of enhancement types. Adapting the contrast and spatial frequency content often improved performance at object recognition and reading speed, as did techniques that attenuate the image background and a technique that induced jitter. A lack of consistency in preference and performance measures was found, as well as a lack of independent studies. Nevertheless, the promising results should encourage further research in order to allow their widespread use in low-vision aids.


mRNA regulation by Puf domain proteins.
Puf domain proteins bind specific sequences in mRNAs to regulate their translation or stability, or both. Neither the mechanism of their action nor the identities of targeted mRNAs have been well defined. Recent work suggests that Puf proteins generally act by recruiting Pop2, a deadenylation enzyme that is part of a large complex. Recent work from a separate group defines a subset of the Drosophila transcriptome that is bound by the fly Puf protein, Pumilio. Together, these papers substantially increase our understanding of the biology of the Puf family of mRNA regulators.


Mitochondrial Efflux of Citrate and Isocitrate Is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function.
The defining feature of pancreatic islet β-cell function is the precise coordination of changes in blood glucose levels with insulin secretion to regulate systemic glucose homeostasis. While ATP has long been heralded as a critical metabolic coupling factor to trigger insulin release, glucose-derived metabolites have been suggested to further amplify fuel-stimulated insulin secretion. The mitochondrial export of citrate and isocitrate through the citrate-isocitrate carrier (CIC) has been suggested to initiate a key pathway that amplifies glucose-stimulated insulin secretion, though the physiological significance of β-cell CIC-to-glucose homeostasis has not been established. Here, we generated constitutive and adult CIC β-cell knockout (KO) mice and demonstrate that these animals have normal glucose tolerance, similar responses to diet-induced obesity, and identical insulin secretion responses to various fuel secretagogues. Glucose-stimulated NADPH production was impaired in β-cell CIC KO islets, whereas glutathione reduction was retained. Furthermore, suppression of the downstream enzyme cytosolic isocitrate dehydrogenase (Idh1) inhibited insulin secretion in wild-type islets but failed to impact β-cell function in β-cell CIC KO islets. Our data demonstrate that the mitochondrial CIC is not required for glucose-stimulated insulin secretion and that additional complexities exist for the role of Idh1 and NADPH in the regulation of β-cell function.


Circadian clocks: from stem cells to tissue homeostasis and regeneration.
The circadian clock is an evolutionarily conserved timekeeper that adapts body physiology to diurnal cycles of around 24 h by influencing a wide variety of processes such as sleep-to-wake transitions, feeding and fasting patterns, body temperature, and hormone regulation. The molecular clock machinery comprises a pathway that is driven by rhythmic docking of the transcription factors BMAL1 and CLOCK on clock-controlled output genes, which results in tissue-specific oscillatory gene expression programs. Genetic as well as environmental perturbation of the circadian clock has been implicated in various diseases ranging from sleep to metabolic disorders and cancer development. Here, we review the origination of circadian rhythms in stem cells and their function in differentiated cells and organs. We describe how clocks influence stem cell maintenance and organ physiology, as well as how rhythmicity affects lineage commitment, tissue regeneration, and aging.


Surfactant effects on amyloid aggregation kinetics.
There is strong experimental evidence of the influence of surfactants (e.g., fatty acids) on the kinetics of amyloid fibril formation. However, the structures of mixed assemblies and interactions between surfactants and fibril-forming peptides are still not clear. Here, coarse-grained simulations are employed to study the aggregation kinetics of amyloidogenic peptides in the presence of amphiphilic lipids. The simulations show that the lower the fibril formation propensity of the peptides, the higher the influence of the surfactants on the peptide self-assembly kinetics. In particular, the lag phase of weakly aggregating peptides increases because of the formation of mixed oligomers, which are promoted by hydrophobic interactions and favorable entropy of mixing. A transient peak in the number of surfactants attached to the growing fibril is observed before reaching the mature fibril in some of the simulations. This peak originates from transient fibrillar defects consisting of exposed hydrophobic patches on the fibril surface, which provide a possible explanation for the temporary maximum of fluorescence observed sometimes in kinetic traces of the binding of small-molecule dyes to amyloid fibrils.


Synaptic transmission between pairs of retinal amacrine cells in culture.
We have examined synaptic transmission between isolated pairs of chick GABAergic amacrine cells, maintained in sparse culture and identified by their binding of an amacrine cell-selective antibody. Using the perforated-patch method to whole-cell clamp both cells of a pair, postsynaptic currents were examined for step depolarizations of the "presynaptic" cell. Synaptic transmission, frequently reciprocal, was calcium dependent and reversibly blocked by bicuculline. Post-synaptic currents, excluding those due to ohmic electrical coupling, were elicited only for presynaptic voltage steps positive to about -40 mV and were always very noisy, suggesting that they were summed from relatively small numbers of quanta. Postsynaptic currents continued well after the termination of the 100 msec presynaptic voltage step when the step was to -10 mV, or positive to this value. This result is interpreted to imply that presynaptic calcium concentration remains elevated after the membrane is returned to its holding potential. When presynaptic voltages were kept low or else presynaptic voltage was uncontrolled, spontaneous quantal events mediated by GABAA receptors could often be seen. Quanta rose quickly (less than 4 msec) and decayed with a mean time constant of 19.3 msec. The amplitude distributions of quantal currents were positively skewed, sometimes showing rare quanta of exceptionally large amplitude. Peak conductance per quantum was about 300 pS, corresponding to the simultaneous opening of only 17 GABAA channels and corresponding to a net flux of only 32 x 10(3) Cl- ions per millivolt of driving force. Estimates of the maximum sustained release rate at individual release sites suggest an upper bound of between 19 and 42 quanta per second.


Role of Interleukin-37 in Inflammatory and Autoimmune Diseases.
Interleukin-1 family 7 (IL-1F7) is a novel member of IL-1F cytokines. IL-1F7 is more commonly known as IL-37. IL-37 can join the α-subunit of the IL-18 receptor, or IL-18 binding protein (IL-18BP), and binding of these proteins can enhance the IL-18 suppression. IL-37 also translocates to the cell nucleus and affects gene transcription. IL-37 inhibits the phosphorylation of p38 mitogen-activated protein kinases. Almost all reports showed that IL-37 has remarkable anti-inflammatory activity. IL-37 plays an important role in a variety of inflammatory and autoimmune diseases, as well. Recently, studies demonstrated that the expression of IL-37 is abnormal in many diseases such as inflammatory bowel diseases, inflammatory respiratory diseases, atherosclerosis, hepatitis, obesity, contact hypersensitivity, Graves' disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, and Behcet's disease. Here, we will review the biological characteristics of IL-37 and its key roles in various inflammatory and autoimmune diseases.


[Evaluation of training on the programs to optimize antimicrobial use in medical residents of the province of Las Palmas].
Antibiotic resistance is a threat to global public health. This situation makes essential to establish programs to optimize antimicrobial use (PROA). Training needs are identified in the PROA of resident physicians and the results of the analysis of the associations between study variables and training in the rational and prudent use of antibiotics are presented in this analysis. Cross-sectional and analytical study through a self-administered questionnaire to a group of 506 medical residents of the province of Las Palmas. The association between resident's characteristics and PROA training was calculated through logistic regression. The associations between response variance and speciality were observed in most of the core component analysis (opportunity p=0.003, training p=0.007, motivation p=0.055 and hand hygiene p=0.044), followed by variance according to sex (capacity p=0.028, theoretical knowledge p=0.013, hand hygiene p=0.002). Very few differences were associated with age (capacity p=0.051 and hand hygiene p=0.054) or the year of expertise (hand hygiene p=0.032). The main training needs of resident physicians include one health, motivation, training, hand hygiene and information. The type of speciality followed by sex are the most important determinants on antibiotic use and resistance for resident physicians.


Comparison of U.S. Environmental Protection Agency's CAP88 PC Versions 3.0 and 4.0.
The Savannah River National Laboratory (SRNL) with the assistance of Georgia Regents University, completed a comparison of the U.S. Environmental Protection Agency's (U.S. EPA) environmental dosimetry code CAP88 PC V3.0 with the recently developed V4.0. CAP88 is a set of computer programs and databases used for estimation of dose and risk from radionuclide emissions to air. At the U.S. Department of Energy's Savannah River Site, CAP88 is used by SRNL for determining compliance with U.S. EPA's National Emission Standards for Hazardous Air Pollutants (40 CFR 61, Subpart H) regulations. Using standardized input parameters, individual runs were conducted for each radionuclide within its corresponding database. Some radioactive decay constants, human usage parameters, and dose coefficients changed between the two versions, directly causing a proportional change in the total effective dose. A detailed summary for select radionuclides of concern at the Savannah River Site (60Co, 137Cs, 3H, 129I, 239Pu, and 90Sr) is provided. In general, the total effective doses will decrease for alpha/beta emitters because of reduced inhalation and ingestion rates in V4.0. However, for gamma emitters, such as 60Co and 137Cs, the total effective doses will increase because of changes U.S. EPA made in the external ground shine calculations.


Melatonin rescues impaired penetration ability of human spermatozoa induced by mitochondrial dysfunction.
Fertilization failure often occurs during in vitro fertilization (IVF) cycles despite apparently normal sperm and oocytes. Accumulating evidence suggests that mitochondria play crucial roles in the regulation of sperm function and male fertility. 3-Nitrophthalic acid (3-NPA) can induce oxidative stress in mitochondria, and melatonin, as an antioxidant, can improve mitochondrial function by reducing mitochondrial oxidative stress. The role of sperm mitochondrial dysfunction in fertilization failure during IVF is unclear. The present study revealed that spermatozoa with low, or poor, fertilization rates had swollen mitochondria, increased mitochondria-derived ROS, and attenuated mitochondrial respiratory capacity. 3-NPA treatment enhanced mitochondrial dysfunction in sperm. Spermatozoa with poor fertilization rates, and spermatozoa treated with 3-NPA, had reduced penetration ability. The concentration of melatonin was decreased in semen samples with low and poor fertilization rates. Melatonin, not only decreased excessive mitochondria-derived ROS, but also 'rescued' the reduced penetration capacity of spermatozoa treated with 3-NPA. Taken together, the study suggested that mitochondria-derived ROS and mitochondrial respiratory capacity are independent bio-markers for sperm dysfunction, and melatonin may be useful in improving sperm quality and overall male fertility.


Laboratory mouse housing conditions can be improved using common environmental enrichment without compromising data.
Animal welfare requires the adequate housing of animals to ensure health and well-being. The application of environmental enrichment is a way to improve the well-being of laboratory animals. However, it is important to know whether these enrichment items can be incorporated in experimental mouse husbandry without creating a divide between past and future experimental results. Previous small-scale studies have been inconsistent throughout the literature, and it is not yet completely understood whether and how enrichment might endanger comparability of results of scientific experiments. Here, we measured the effect on means and variability of 164 physiological parameters in 3 conditions: with nesting material with or without a shelter, comparing these 2 conditions to a "barren" regime without any enrichments. We studied a total of 360 mice from each of 2 mouse strains (C57BL/6NTac and DBA/2NCrl) and both sexes for each of the 3 conditions. Our study indicates that enrichment affects the mean values of some of the 164 parameters with no consistent effects on variability. However, the influence of enrichment appears negligible compared to the effects of other influencing factors. Therefore, nesting material and shelters may be used to improve animal welfare without impairment of experimental outcome or loss of comparability to previous data collected under barren housing conditions.


Bone mineral density in people living with HIV: a narrative review of the literature.
Bone health status is largely absent in South Africa, the main reasons being the absence and cost-effectiveness of specific screening equipment for assessing bone mineral density (BMD). Various risk factors seem to play a role, some of which can be modified to change bone health status. Urbanisation is also a public health concern. Changing nutritional, as well as social behaviour, play integral roles in the prevalence and incidence of decreased BMD. Furthermore, human immunodeficiency virus (HIV) specifically, has a negative impact on BMD and although highly active antiretroviral therapy increases the prognosis for HIV-infected individuals, BMD still seem to decrease further. Dual energy X-ray absorptiometry is considered the gold standard for BMD assessment; however, recent developments have provided more cost-effective screening methods, among which heel quantitative ultrasound appears to be the most widely used in resource limited countries such as South Africa.