A hierarchical phosphorylation cascade that regulates the timing of PERIOD nuclear entry reveals novel roles for proline-directed kinases and GSK-3beta/SGG in circadian clocks.
The daily timing of when PERIOD (PER) proteins translocate from the cytoplasm to the nucleus is a critical step in clock mechanisms underpinning circadian rhythms in animals. Numerous lines of evidence indicate that phosphorylation plays a prominent role in regulating various aspects of PER function and metabolism, including changes in its daily stability and subcellular distribution. In this report, we show that phosphorylation of serine 661 (Ser661) by a proline-directed kinase(s) is a key phospho-signal on the Drosophila PER protein (dPER) that regulates the timing of its nuclear accumulation. Mutations that block phosphorylation at Ser661 do not affect dPER stability but delay its nuclear entry in key pacemaker neurons, yielding longer behavioral rhythms. Intriguingly, abolishing phosphorylation at Ser661 also attenuates the extent of dPER hyperphosphorylation in vivo, suggesting the phosphorylated state of Ser661 regulates phosphorylation at other sites on dPER. Indeed, we identify Ser657 as a site that is phosphorylated by the glycogen synthase kinase GSK-3β (SHAGGY; SGG) in a manner dependent on priming at Ser661. Although not as dramatic as mutating Ser661, mutations that abolish phosphorylation at Ser657 also lead to longer behavioral periods, suggesting that a multi-kinase hierarchical phosphorylation module regulates the timing of dPER nuclear entry. Together with evidence in mammalian systems, our findings implicate proline-directed kinases in clock mechanisms and suggest that PER proteins are key downstream targets of lithium therapy, a potent inhibitor of GSK-3β used to treat manic depression, a disorder associated with clock malfunction in humans.


A Research Agenda for Emergency Medicine-based Adolescent Sexual and Reproductive Health.
The objective was to identify key questions for emergency medicine (EM)-based adolescent sexual and reproductive health and to develop an evidence-based research agenda. We recruited national content experts to serve as advisory group members and used a modified Delphi technique to develop consensus around actionable research questions related to EM-based adolescent reproductive and sexual health care. Author subgroups conducted literature reviews and developed the initial list of research questions, which were iteratively refined with advisory members. External stakeholders then independently rated each item for its importance in expanding the evidence base (1 = not important to 5 = very important) via electronic survey. Our final list of 24 research questions included items that intersected all sexual and reproductive health topics as well as questions specific to human immunodeficiency virus/sexually transmitted infections (HIV/STIs), pregnancy prevention, confidentiality/consent, public health, and barriers and facilitators to care. External stakeholders rated items related to HIV/STI, cost-effectiveness, brief intervention for sexual risk reduction, and implementation and dissemination as most important. We identified critical questions to inform EM-based adolescent sexual and reproductive health research. Because evidence-based care has potential to improve health outcomes while reducing costs associated with HIV/STI and unintended pregnancy, funders and researchers should consider increasing attention to these key questions.


Landscapes for Energy and Wildlife: Conservation Prioritization for Golden Eagles across Large Spatial Scales.
Proactive conservation planning for species requires the identification of important spatial attributes across ecologically relevant scales in a model-based framework. However, it is often difficult to develop predictive models, as the explanatory data required for model development across regional management scales is rarely available. Golden eagles are a large-ranging predator of conservation concern in the United States that may be negatively affected by wind energy development. Thus, identifying landscapes least likely to pose conflict between eagles and wind development via shared space prior to development will be critical for conserving populations in the face of imposing development. We used publically available data on golden eagle nests to generate predictive models of golden eagle nesting sites in Wyoming, USA, using a suite of environmental and anthropogenic variables. By overlaying predictive models of golden eagle nesting habitat with wind energy resource maps, we highlight areas of potential conflict among eagle nesting habitat and wind development. However, our results suggest that wind potential and the relative probability of golden eagle nesting are not necessarily spatially correlated. Indeed, the majority of our sample frame includes areas with disparate predictions between suitable nesting habitat and potential for developing wind energy resources. Map predictions cannot replace on-the-ground monitoring for potential risk of wind turbines on wildlife populations, though they provide industry and managers a useful framework to first assess potential development.


[Direct-to-consumer genetic tests in the consulting room].
Rapid developments in genome technology and a growing interest in personalized healthcare have led to a large rise in the range and use of commercial DNA tests, the so-called direct-to-consumer genetic tests (DTC-GT). DTC-GT can be of a non-medical (e.g. for external characteristics) or medical nature; medical tests mostly indicate relative risks of disease e.g. Alzheimer's disease or certain forms of cancer. Low clinical validity and frequently unknown analytical validity of DTC-GT make it difficult to estimate the clinical usefulness of test results. From an ethical perspective, an increase in autonomy and possible health benefits must be weighed against loss of privacy, inadequate provision of information and the risk of misinterpretation of results, over-diagnosis, overtreatment and higher healthcare costs. It is unclear whether providing and implementing DTC-GT require authorisation under Dutch law in the Population Screening Act (Wet op het Bevolkingsonderzoek) or the Special Medical Procedures Act (Wet op BijzondereMedischeVerrichtingen). Clinical utility of DTC-GT can only increase if there is greater clarity on interpretation and scope of the law and regulations, when DTC-GT companies provide better information and guidance for consumers and when there is more focus on DTC-GT in education and training programmes for healthcare professionals.


Negative electron transfer dissociation of glycosaminoglycans.
Structural characterization of glycosaminoglycans (GAGs) has been a challenge in the field of mass spectrometry, and the application of electron detachment dissociation (EDD) Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) has shown great promise to GAG oligosaccharide characterization in a single tandem mass spectrometry experiment. In this work, we apply the technique of negative electron transfer dissociation (NETD) to GAGs on a commercial ion trap mass spectrometer. NETD of GAGs, using fluoranthene or xenon as the reagent gas, produces fragmentation very similar to previously observed EDD fragmentation. Using fluoranthene or xenon, both glycosidic and cross-ring cleavages are observed, as well as even- and odd-electron products. The loss of SO(3) can be minimized and an increase in cross-ring cleavages is observed if a negatively charged carboxylate is present during NETD, which can be controlled by the charge state or the addition of sodium. NETD effectively dissociates GAGs up to eight saccharides in length, but the low resolution of the ion trap makes assigning product ions difficult. Similar to EDD, NETD is also able to distinguish the epimers iduronic acid from glucuronic acid in heparan sulfate tetrasaccharides and suggests that a radical intermediate plays an important role in distinguishing these epimers. These results demonstrate that NETD is effective at characterizing GAG oligosaccharides in a single tandem mass spectrometry experiment on a widely available mass spectrometry platform.


Nucleosome eviction from MHC class II promoters controls positioning of the transcription start site.
Nucleosome depletion at transcription start sites (TSS) has been documented genome-wide in multiple eukaryotic organisms. However, the mechanisms that mediate this nucleosome depletion and its functional impact on transcription remain largely unknown. We have studied these issues at human MHC class II (MHCII) genes. Activation-induced nucleosome free regions (NFR) encompassing the TSS were observed at all MHCII genes. Nucleosome depletion was exceptionally strong, attaining over 250-fold, at the promoter of the prototypical HLA-DRA gene. The NFR was induced primarily by the transcription factor complex that assembles on the conserved promoter-proximal enhancer situated upstream of the TSS. Functional analyses performed in the context of native chromatin demonstrated that displacing the NFR without altering the sequence of the core promoter induced a shift in the position of the TSS. The NFR thus appears to play a critical role in transcription initiation because it directs correct TSS positioning in vivo. Our results provide support for a novel mechanism in transcription initiation whereby the position of the TSS is controlled by nucleosome eviction rather than by promoter sequence.


Volumetric ultrasound imaging using 2-D CMUT arrays.
Recently, capacitive micromachined ultrasonic transducers (CMUTs) have emerged as a candidate to overcome the difficulties in the realization of 2-D arrays for real-time 3-D imaging. In this paper, we present the first volumetric images obtained using a 2-D CMUT array. We have fabricated a 128 x 128-element 2-D CMUT array with through-wafer via interconnects and a 420-microm element pitch. As an experimental prototype, a 32 x 64-element portion of the 128 x 128-element array was diced and flip-chip bonded onto a glass fanout chip. This chip provides individual leads from a central 16 x 16-element portion of the array to surrounding bondpads. An 8 x 16-element portion of the array was used in the experiments along with a 128-channel data acquisition system. For imaging phantoms, we used a 2.37-mm diameter steel sphere located 10 mm from the array center and two 12-mm-thick Plexiglas plates located 20 mm and 60 mm from the array. A 4 x 4 group of elements in the middle of the 8 x 16-element array was used in transmit, and the remaining elements were used to receive the echo signals. The echo signal obtained from the spherical target presented a frequency spectrum centered at 4.37 MHz with a 100% fractional bandwidth, whereas the frequency spectrum for the echo signal from the parallel plate phantom was centered at 3.44 MHz with a 91% fractional bandwidth. The images were reconstructed by using RF beamforming and synthetic phased array approaches and visualized by surface rendering and multiplanar slicing techniques. The image of the spherical target has been used to approximate the point spread function of the system and is compared with theoretical expectations. This study experimentally demonstrates that 2-D CMUT arrays can be fabricated with high yield using silicon IC-fabrication processes, individual electrical connections can be provided using through-wafer vias, and flip-chip bonding can be used to integrate these dense 2-D arrays with electronic circuits for practical 3-D imaging applications.


Pairing experimentation and computational modeling to understand the role of tissue inducer cells in the development of lymphoid organs.
The use of genetic tools, imaging technologies and ex vivo culture systems has provided significant insights into the role of tissue inducer cells and associated signaling pathways in the formation and function of lymphoid organs. Despite advances in experimental technologies, the molecular and cellular process orchestrating the formation of a complex three-dimensional tissue is difficult to dissect using current approaches. Therefore, a robust set of simulation tools have been developed to model the processes involved in lymphoid tissue development. Specifically, the role of different tissue inducer cell populations in the dynamic formation of Peyer's patches has been examined. Utilizing approaches from systems engineering, an unbiased model of lymphoid tissue inducer cell function has been developed that permits the development of emerging behaviors that are statistically not different from that observed in vivo. These results provide the confidence to utilize statistical methods to explore how the simulator predicts cellular behavior and outcomes under different physiological conditions. Such methods, known as sensitivity analysis techniques, can provide insight into when a component part of the system (such as a particular cell type, adhesion molecule, or chemokine) begins to have an influence on observed behavior, and quantifies the effect a component part has on the end result: the formation of lymphoid tissue. Through use of such a principled approach in the design, calibration, and analysis of a computer simulation, a robust in silico tool can be developed which can both further the understanding of a biological system being explored, and act as a tool for the generation of hypotheses which can be tested utilizing experimental approaches.


Audio-computerized self-interviewing versus face-to-face interviewing for research data collection at drug abuse treatment programs.
To assess audio computer-assisted self-interviewing (A-CASI) as a mode of data collection with injecting drug users (IDUs) entering two drug treatment programs in New York City. A-CASI has been found to increase reporting of sensitive items among a variety of population subgroups. A field test of A-CASI data collection conducted within an ongoing cross-sectional study of drug use and HIV risk behaviors among IDUs entering drug treatment. Participants were assigned without bias to either a computer-assisted interviewer-administered personal interview (CAPI) or to a mixed CAPI/A-CASI interview. In the latter, 'sensitive' portions (dealing with stigmatized behavior) of the questionnaire were self-administered through A-CASI, while the remaining portions were interviewer-administered. The Detoxification Program and the Methadone Maintenance Treatment Program (MMTP) at Beth Israel Medical Center in New York City. Seven hundred and eighty-three IDUs entering drug treatment. Odds ratios and adjusted odds ratios (controlling for demographic differences) for comparison of A-CASI versus CAPI responses on 111 sensitive questions. Twenty-three statistically significant differences (each at P < 0.05), all in the direction of more reporting of the behaviors by the A-CASI group. Forty-one per cent of A-CASI participants said they would prefer any subsequent interviews to be fully A-CASI and 46% said they would prefer the mixed CAPI/A-CASI mode. A-CASI was associated with greater reporting of potentially stigmatized drug, sex and HIV risk behaviors on a moderate number of questions. Moreover, a large majority of participants who used A-CASI would like to be assigned to this method of data collection in future interviews.


Japan as the front-runner of super-aged societies: Perspectives from medicine and medical care in Japan.
The demographic structure of a country changes dramatically with increasing trends toward general population aging and declining birth rates. In Japan, the percentage of the elderly population (aged ≥65 years) reached 25% in 2013; it is expected to exceed 30% in 2025 and reach 39.9% in 2060. The national total population has been decreasing steadily since its peak reached in 2008, and it is expected to fall to the order of 80 million in 2060. Of the total population, those aged ≥75 years accounted for 12.3% as of 2013, and this is expected to reach 26.9% in 2060. As the demographic structure changes, the disease structure changes, and therefore the medical care demand changes. To accommodate the medical care demand changes, it is necessary to secure a system for providing medical care. Japan has thus far attained remarkable achievements in medical care, seeking a better prognosis for survival; however, its medical care demand is anticipated to change both qualitatively and quantitatively. As diseases in the elderly, particularly in the old-old population, are often intractable, conventional medical care must be upgraded to one suitable for an aged society. What is required to this end is a shift from "cure-seeking medical care" focusing on disease treatment on an organ-specific basis to "cure and support-seeking medical care" with treatments reprioritized to maximize the quality of life (QOL) for the patient, or a change from "hospital-centered medical care" to "community-oriented medical care" in correlation with nursing care and welfare. (1) Necessity for a paradigm shift to "cure-and-support seeking medical care" In addition to the process of aging with functional deterioration of multiple organs, the elderly often suffer from systemically disordering diseases, such as lifestyle-related diseases, as well as geriatric syndrome and daily activity dysfunction; therefore, integrated and comprehensive medical care is required. In addition, with regard to diseases in the elderly, not only their acute stage, but also their chronic and intermediate stages must be emphasized in their treatment. Aiming to achieve a complete cure of disease by exploring the cause and implementing radical treatment, the conventional medical care model is difficult to apply to the medical care of the elderly; medical care suitable for the elderly is required. (2) Spread of home-based care and the necessity for human resources development Many elderly people want to continue to live in their house and their community where they have been living for a long time, even with disease. There are increasing needs for QOL-emphasizing home-based care for patients in the intermediate stage after completion of acute stage treatment, or for end-of-life care. Hence, there is a demand for a shift to "community-oriented medical care" for providing comprehensive care supported with medical and nursing resources available in the community. As the percentage of the elderly population (aged ≥65 years) and the availability of medical care resources vary considerably among different regions, it is important that specialists in the fields of public health, medical care, nursing care, and welfare work on establishing a collaborative system suitable for the local characteristics of each region by making the best use of their own specialties. (3) Necessity for establishing a department of gerontology or geriatric medicine at each medical school In line with the increasing number of elderly people, it is necessary to upgrade the systems for educating and nurturing physicians engaged in healthcare and nursing care for the elderly. It is also necessary to develop the organic cooperation with other medical and nursing care professionals, such as registered nurses and care workers. At present, just approximately 30% of medical schools in Japan have a department specializing in medical care for the elderly and relevant medical education; there is an urgent need to improve the situation, as the majority of universities do not provide any such education. (4) Necessity for establishing a medical center for promoting medical care provider collaboration, multidisciplinary training and a means to increase public awareness In the medical care for the elderly, comprehensive care must be provided from the viewpoints of both healthcare and nursing care; to improve the quality of such care services, multidisciplinary collaboration and team-based medicine are indispensable. Therefore, physicians, nurses, therapists, pharmacists, dieticians, care managers, and other health care professionals who have thorough knowledge about medical care for the elderly are of utmost necessity. In reality, however, the collaboration of these health care professionals is unsatisfactory, and the degree of understanding of team-based medicine by each medical professional is low. Therefore, as in the case of the establishment of cancer centers within individual regions to promote medical care for cancer, there is a demand to nurture professionals engaged in medical care for the elderly, and to establish a core facility for the promotion of multidisciplinary collaboration and team-based medicine for each region. (5) Do the people understand the paradigm shift? Currently, not only healthcare professionals, but also many citizens seek "cure-seeking medical care" aiming at a restoration of organ function; however, surveys of the elderly often show that they want to restore independent daily activity, rather than to achieve a "cure." In contrast, in the actual medical care setting, contradictory situations prevail in which the public awareness of the shift to "cure-and-support seeking medical care" is unsatisfactory, including the fact that the majority of recipients of tertiary emergency care are elderly patients. The Science Council of Japan has the task to propose future visions for the Japanese aging society not only from the viewpoint of the health of each individual, but also from a broader perspective, taking into account the relationship between humans and society. Various issues related to general population aging are posing serious problems, which require prompt resolution. Although we made a number of proposals at the 21st Subcommittee for Aging, the situation has not changed satisfactorily. Accordingly, the present proposals on specific solutions were designed. (1) In a super-aged society, a paradigm shift to "cure-and-support seeking medical care" should be implemented A super-aged society will consist of an unprecedented demographic structure in which the percentage of only those people aged ≥75 years will increase in the entire population. Therefore, there is an urgent need to prepare for increasing populations of persons in need of long-term care and those who are likely to become in need of long-term care. Given the consideration that "patients are not merely sick persons, but rather living persons," a paradigm shift from conventional "cure-seeking medical care" to "cure and support-seeking medical care" must be implemented. (2) Facilitate a paradigm shift to community-oriented medical care, and promote the activity of female physicians in the medical care for the elderly A paradigm shift should be promptly facilitated by reorganizing hospital functions and establishing a community comprehensive care system for home-based care to promote the participation of the elderly by themselves in care-supporting society. To further promote the collaboration of medical care and welfare, not only persons in charge of actual regional settings, but also university schools of medicine and regional core medical institutions experienced in medical care for the elderly should take the initiative to promote home-based care and facilitate a paradigm shift to community-oriented medical care. In addition, programs should also be developed to re-educate female physicians who became housewives in order to nurture them to become facilitators of geriatric medicine. (3) Physicians who are required at local medical facilities must be nurtured through the establishment of a department of gerontology or geriatric medicine at each medical school To facilitate efficient medical care services, medical education and research, and human resources development in support of expected paradigm shifts, it is considered that a department of gerontology or geriatric medicine should be established at each medical school. Furthermore, it is necessary to allocate dedicated teachers of medical care for the elderly to all medical schools, as well as to upgrade practice-participatory drills and to collaborate with a broad range of entities, including local medical institutions, and welfare and nursing care facilities. Efforts must be made to nurture locally wanted physicians through specific efforts concerning team-based medicine. (4) Promote the establishment of centers for geriatrics and gerontology (provisional name) for medical care collaboration, multidisciplinary training, and a means to increase public awareness To promote the uniform accessibility of expertise on efficient medical care that is best suited for a super-aged society, it is necessary to build a post-graduation educational system under the initiatives of the Japan Geriatrics Society and the National Center for Geriatrics and Gerontology across the nation in cooperation with regional medical schools and the Japan Medical Association. Furthermore, at least one hospital serving as a center for geriatrics and gerontology should be established in each regional block (Hokkaido, Tohoku, Koshinetsu, Hokuriku/Tokai, Kinki, Chushikoku and Kyushu/Okinawa) by making the best use of existing hospitals. By establishing these centers, uniform accessibility for the quality of medical care for the elderly in each region is expected. (ABSTRACT TRUNCATED).


Cutting-edge issues in celiac disease and in gluten intolerance.
Celiac disease (CD) is a gluten-dependent immune-mediated disease with a prevalence in the general population estimated between 0.3% and 1.2%. Large-scale epidemiological studies have shown that only 10-20% of cases of CD are identified on the basis of clinical findings and that laboratory tests are crucial to identify subjects with subtle or atypical symptoms. The correct choice and clinical use of these diagnostic tools may enable accurate diagnosis and early recognition of silent CD cases. In this review, we have considered some relevant aspects related to the laboratory diagnosis of CD and, more extensively, of gluten intolerance, such as the best combination of tests for early and accurate diagnosis, the diagnostic role of new tests for detecting antibodies against neoepitopes produced by the transglutaminase-gliadin complex, the forms of non-celiac gluten intolerance (gluten sensitivity), and the use and significance of measuring cytokines in CD.


Hexa helix: modified quad helix appliance to correct anterior and posterior crossbites in mixed dentition.
Among the commonly encountered dental irregularities which constitute developing malocclusion is the crossbite. During primary and mixed dentition phase, the crossbite is seen very often and if left untreated during these phases then a simple problem may be transformed into a more complex problem. Different techniques have been used to correct anterior and posterior crossbites in mixed dentition. This case report describes the use of hexa helix, a modified version of quad helix for the management of anterior crossbite and bilateral posterior crossbite in early mixed dentition. Correction was achieved within 15 weeks with no damage to the tooth or the marginal periodontal tissue. The procedure is a simple and effective method for treating anterior and bilateral posterior crossbites simultaneously.


Prevalence and Determinants of Vitamin D Deficiency in 1825 Cape Town Primary Schoolchildren: A Cross-Sectional Study.
Vitamin D deficiency (25-hydroxyvitamin D[25(OH)D] <50 nmol/L) is common among adults in Cape Town, South Africa, but studies investigating vitamin D status of children in this setting are lacking. We conducted a cross-sectional study to determine the prevalence and determinants of vitamin D deficiency in 1825 Cape Town schoolchildren aged 6−11 years. Prevalence of vitamin D deficiency was 7.6% (95% Confidence Interval [CI] 6.5% to 8.9%). Determinants of vitamin D deficiency included month of sampling (adjusted odds ratio [aOR] for July−September vs. January−March 10.69, 95% CI 5.02 to 22.77; aOR for October−December vs. January−March 6.73, 95% CI 2.82 to 16.08), older age (aOR 1.25 per increasing year, 95% CI: 1.01−1.53) and higher body mass index (BMI; aOR 1.24 per unit increase in BMI-for-age Z-score, 95% CI: 1.03−1.49). In a subset of 370 participants in whom parathyroid hormone (PTH) concentrations were measured; these were inversely related to serum 25(OH)D concentrations (p < 0.001). However, no association between participants with hyperparathyroidism (PTH >6.9 pmol/L) and vitamin D deficiency was seen (p = 0.42). In conclusion, we report that season is the major determinant of vitamin D status among Cape Town primary schoolchildren, with prevalence of vitamin D deficiency ranging from 1.4% in January−March to 22.8% in July−September.


Youth-friendly primary-care services: how are we doing and what more needs to be done?
For developmental as well as epidemiological reasons, young people need youth-friendly models of primary care. Over the past two decades, much has been written about barriers faced by young people in accessing health care. Worldwide, initiatives are emerging that attempt to remove these barriers and help reach young people with the health services they need. In this paper, we present key models of youth-friendly health provision and review the evidence for the effect of such models on young people's health. Unfortunately, little evidence is available, since many of these initiatives have not been appropriately assessed. Appropriate controlled assessments of the effect of youth-friendly health-service models on young people's health outcomes should be the focus of future research agendas. Enough is known to recommend that a priority for the future is to ensure that each country, state, and locality has a policy and support to encourage provision of innovative and well assessed youth-friendly services.


Prophylactic effect of intravenous moxifloxacin in a rabbit model of Staphylococcus epidermidis endophthalmitis.
To compare the prophylactic effects of intravenous moxifloxacin and vancomycin for Staphylococcus epidermidis endophthalmitis in a rabbit model. Albino rabbits (n = 60) were divided into three groups. Intravenous moxifloxacin was injected into 20 animals (group 1), and intravenous vancomycin was injected into 20 animals (group 2). In group 3, 20 animals received 0.9% normal saline. After these prophylactic intravenous injections, the right eyes of the 60 rabbits were injected intravitreally with 10(5) colony-forming units of S. epidermidis. Intravenous antibiotic injection was repeated on days 1, 2, and 3 after infection. Clinical features were evaluated on days 1, 3, 5, and 7 after infection, and 10 eyes per group were then enucleated for histopathologic examination. Vitreous aspirates were obtained for bacterial culture on days 1, 3, 5, and 7 after infection from the other 10 eyes per group. The moxifloxacin group showed significant clinical effects at days 1, 3, 5, and 7 (P = 0.019, < 0.001, < 0.001, and < 0.001, respectively); bacteriologic results at days 1, 3, 5, and 7 (P = 0.001, 0.002, 0.01, and 0.002, respectively); and histopathologic results, with less severe inflammation and relatively well-preserved retinal architecture. However, no difference was detected between the vancomycin group and control group in any aspect examined. Intravenously administered moxifloxacin showed a significant prophylactic effect against S. epidermidis endophthalmitis. Thus, intravenous moxifloxacin may be a useful prophylactic medication against postoperative endophthalmitis.


Fractional free space, fractional lenses, and fractional imaging systems.
Continuum extensions of common dual pairs of operators are presented and consolidated, based on the fractional Fourier transform. In particular, the fractional chirp multiplication, fractional chirp convolution, and fractional scaling operators are defined and expressed in terms of their common nonfractional special cases, revealing precisely how they are interpolations of their conventional counterparts. Optical realizations of these operators are possible with use of common physical components. These three operators can be interpreted as fractional lenses, fractional free space, and fractional imaging systems, respectively. Any optical system consisting of an arbitrary concatenation of sections of free space and thin lenses can be interpreted as a fractional imaging system with spherical reference surfaces. As a special case, a system departing from the classical single-lens imaging condition can be interpreted as a fractional imaging system.


Management of full-thickness duodenal laceration in the damage control era: evolution to primary repair without diversion or decompression.
The management of duodenal laceration (DL) is controversial. We sought to determine the influence of damage control (DC) on the use of decompression/diversion/exclusion (DDE) techniques and the risk of duodenal-related complications (DRC). We conducted a retrospective review of all patients with full-thickness DL surviving more than 72 hours in the years 1989 to 2009. Forty-one patients with a median duodenal organ injury scale of 3 and a mean abdominal trauma index (ATI) of 45 ± 24 underwent laparotomy. Twenty-five patients (61%) were treated with DC and 16 (39%) with fascial closure (FC). Although the ATI of the patients treated with DC was greater than the ATI of the patients treated with FC (56 ± 23 vs 28 ± 17, P < 0.001), DRCs were equivalent (two vs three, nonsignificant). Twenty-one patients were treated in the first decade and 20 in the second decade. Between the first and second decades, there were trends toward an increased use of DC (52 to 70%, nonsignificant) and a decreased use of DDE (52 to 35%, nonsignificant) with a significant reduction in DRC (5 vs 0, P = 0.04). Among the 18 patients (44%) who underwent DDE procedures there were 2 DRCs (11%) related to DDE. Among the 23 patients who did not have DDE, there were three DRCs (13%), including two obstructions, one partial and one complete. When DC is used after DL, DDE may be unnecessary. Diversion is recommended, however, when the duodenum is at risk for obstruction after primary repair.


Septin-dependent compartmentalization of the endoplasmic reticulum during yeast polarized growth.
Polarized cells frequently use diffusion barriers to separate plasma membrane domains. It is unknown whether diffusion barriers also compartmentalize intracellular organelles. We used photobleaching techniques to characterize protein diffusion in the yeast endoplasmic reticulum (ER). Although a soluble protein diffused rapidly throughout the ER lumen, diffusion of ER membrane proteins was restricted at the bud neck. Ultrastructural studies and fluorescence microscopy revealed the presence of a ring of smooth ER at the bud neck. This ER domain and the restriction of diffusion for ER membrane proteins through the bud neck depended on septin function. The membrane-associated protein Bud6 localized to the bud neck in a septin-dependent manner and was required to restrict the diffusion of ER membrane proteins. Our results indicate that Bud6 acts downstream of septins to assemble a fence in the ER membrane at the bud neck. Thus, in polarized yeast cells, diffusion barriers compartmentalize the ER and the plasma membrane along parallel lines.


Dopamine receptor reappearance after irreversible receptor blockade: effect of chronic estradiol treatment of ovariectomized rats.
It is well established that estrogen modulates central dopamine functions; however, the mechanism of this interaction is still poorly understood. We have used peripheral N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) administration to induce irreversible blockade of dopamine receptors in ovariectomized female rats, which were pretreated with estradiol (10 micrograms, twice each day for 2 weeks) or its vehicle, in order to investigate the effect of estradiol on dopamine receptor repopulation kinetics. As previously observed, chronic estradiol treatment increased both striatal D1 and D2 dopamine receptor densities and left affinities unchanged. Anterior pituitary D2 dopamine receptor density remained unchanged. One day after EEDQ administration, a similar decrease (80%) of [3H]SCH 23390 and [3H]spiperone binding to striatum of estradiol- and vehicle-treated animals was observed. Anterior pituitary D2 dopamine receptor specific binding was reduced by about 50% the day after EEDQ. Recovery after EEDQ administration showed that both receptor production rate and degradation rate constants of anterior pituitary D2 and striatal D1 receptors were slowed after chronic estradiol treatment, whereas recovery rates for striatal D2 dopamine receptors were unaffected. EEDQ administration in vehicle-treated rats did not significantly affect plasma prolactin levels, whereas the combination of estradiol pretreatment and EEDQ administration led to increased plasma prolactin levels, compared with estradiol-treated animals that did not receive EEDQ. This suggests that only a fraction of anterior pituitary dopamine receptors are required for a maximal inhibition of prolactin secretion. Estradiol affected both striatal D1 and D2 dopamine receptor densities but only D1 dopamine receptor repopulation kinetics, suggesting that it may act by different mechanisms on each dopamine receptor. Alternatively, estradiol may affect dopamine receptor interaction. Thus, the present study raises the possibility that a biochemical D1/D2 receptor interaction affects dopamine receptor biosynthesis, turnover, and/or gene expression and that estradiol may influence this dopamine receptor interaction in the striatum.


Propolis reduces oxidative stress in l-NAME-induced hypertension rats.
The inhibition in the synthesis or bioavailability of nitric oxide (NO) has an important role in progress of hypertension. The blocking of nitric oxide synthase activity may cause vasoconstriction with the formation of reactive oxygen species (ROS). Propolis is a resinous substance collected by honey bees from various plants. Propolis has biological and pharmacological properties. The aim of this study was to examine the effect of propolis on catalase (CAT) activity, malondialdehyde (MDA) and NO levels in the testis tissues of hypertensive rats by Nω-nitro-l-arginine methyl ester (l-NAME). Rats have received nitric oxide synthase inhibitor (l-NAME, 40 mg kg(-1) , intraperitoneally) for 15 days to produce hypertension and propolis (200 mg kg(-1) , by gavage) during the last 5 days. MDA level in l-NAME-treated group significantly increased compared with control group (P < 0.01). MDA level of l-NAME + propolis-treated rats significantly reduced (P < 0.01) compared with l-NAME-treated group. CAT activity and NO level significantly reduced (P < 0.01) in l-NAME group compared with control group. There were no statistically significant increases in the CAT activity and NO level of the l-NAME + propolis group compared with the l-NAME-treated group (P > 0.01). These results suggest that propolis changes CAT activity, NO and MDA levels in testis of l-NAME-treated animals, and so it may modulate the antioxidant system.


NK Cell-Based Immunotherapy for Hematological Malignancies.
Natural killer (NK) lymphocytes are an integral component of the innate immune system and represent important effector cells in cancer immunotherapy, particularly in the control of hematological malignancies. Refined knowledge of NK cellular and molecular biology has fueled the interest in NK cell-based antitumor therapies, and recent efforts have been made to exploit the high potential of these cells in clinical practice. Infusion of high numbers of mature NK cells through the novel graft manipulation based on the selective depletion of T cells and CD19+ B cells has resulted into an improved outcome in children with acute leukemia given human leucocyte antigen (HLA)-haploidentical hematopoietic transplantation. Likewise, adoptive transfer of purified third-party NK cells showed promising results in patients with myeloid malignancies. Strategies based on the use of cytokines or monoclonal antibodies able to induce and optimize NK cell activation, persistence, and expansion also represent a novel field of investigation with remarkable perspectives of favorably impacting on outcome of patients with hematological neoplasia. In addition, preliminary results suggest that engineering of mature NK cells through chimeric antigen receptor (CAR) constructs deserve further investigation, with the goal of obtaining an "off-the-shelf" NK cell bank that may serve many different recipients for granting an efficient antileukemia activity.


Performance analysis of coherent optical 8-star QAM systems using decision-aided maximum likelihood phase estimation.
An approximate bit-error rate (BER) expression of 8-star quadrature amplitude modulation (QAM) in the presence of a phase estimation error is derived. The accuracy of the approximate BER is verified via numerical integration of the conditional BER and the Monte-Carlo (MC) simulations. This approximation allows quick estimation of the BER performance and prediction of laser linewidth tolerance, and also facilitates optimization of the ring ratio.


Inhibition of phosphatidylinositol 3-kinase stimulates activity of the small-conductance K channel in the CCD.
We used Western blotting to examine the expression of phosphatidylinositol 3-kinase (PI3K) in the renal cortex and outer medulla and employed the patch-clamp technique to study the effect of PI3K on the ROMK-like small-conductance K (SK) channels in the cortical collecting duct (CCD). Low K intake increased the expression of the 110-kDa alpha-subunit (p110alpha) of PI3K compared with rats on a normal-K diet. Because low K intake increases superoxide levels (2), the possibility that increases in superoxide anions may be responsible for the effect of low K intake on the expression of PI3K is supported by finding that addition of H(2)O(2) stimulates the expression of p110alpha in M1 cells. Inhibition of PI3K with either wortmannin or LY-294002 significantly increased channel activity in the CCD from rats on a K-deficient (KD) diet or on a normal-K diet. The stimulatory effect of wortmannin on ROMK channel activity cannot be mimicked by inhibition of phospholipase C with U-73122. This suggests that the effect of inhibiting PI3K was not the result of increasing the phosphatidylinositol 4,5-bisphosphate level. Moreover, application of the exogenous phosphatidylinositol 3,4,5-trisphosphate analog had no effect on channel activity in excised patches. Because low K intake has been shown to increase the activity of protein tyrosine kinase (PTK), we explored the role of the interaction between PTK and PI3K in the regulation of the SK channel activity. Inhibition of PTK increased SK channel activity in the CCD from rats on a KD diet. However, addition of wortmannin did not further increase ROMK channel activity. Also, the effect of wortmannin was abolished by treatment of CCD with phalloidin. We conclude that PI3K is involved in mediating the effect of low K intake on ROMK channel activity in the CCD and that the effect of PI3K on SK channels requires the involvement of PTK and the cytoskeleton.


Baseline reward processing and ventrostriatal dopamine function are associated with pramipexole response in depression.
The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function. However, an important question is whether dopamine agonists are most beneficial for patients with reward-based deficits. This study evaluated whether measures of reward processing and ventrostriatal dopamine function predicted response to the dopamine agonist, pramipexole (ClinicalTrials.gov Identifier: NCT02033369). Individuals with major depressive disorder (n = 26) and healthy controls (n = 26) (mean ± SD age = 26.5 ± 5.9; 50% female) first underwent assessments of reward learning behaviour and ventrostriatal prediction error signalling (measured using functional MRI). 11C-(+)-PHNO PET before and after oral amphetamine was used to assess ventrostriatal dopamine release. The depressed group then received open-label pramipexole treatment for 6 weeks (0.5 mg/day titrated to a maximum daily dose of 2.5 mg). Symptoms were assessed weekly, and reward learning was reassessed post-treatment. At baseline, relative to controls, the depressed group showed lower reward learning (P = 0.02), a trend towards blunted reward-related prediction error signals (P = 0.07), and a trend towards increased amphetamine-induced dopamine release (P = 0.07). Despite symptom improvements following pramipexole (Cohen's d ranging from 0.51 to 2.16 across symptom subscales), reward learning did not change after treatment. At a group level, baseline reward learning (P = 0.001) and prediction error signalling (P = 0.004) were both associated with symptom improvement, albeit in a direction opposite to initial predictions: patients with stronger pretreatment reward learning and reward-related prediction error signalling improved most. Baseline D2/3 receptor availability (P = 0.02) and dopamine release (P = 0.05) also predicted improvements in clinical functioning, with lower D2/3 receptor availability and lower dopamine release predicting greater improvements. Although these findings await replication, they suggest that measures of reward-related mesolimbic dopamine function may hold promise for identifying depressed individuals likely to respond favourably to dopaminergic pharmacotherapy.


PMMA/SWCNT Composites with Very Low Electrical Percolation Threshold by Direct Incorporation and Masterbatch Dilution and Characterization of Electrical and Thermoelectrical Properties.
In the present study, Poly(methyl methacrylate) (PMMA)/single-walled carbon nanotubes (SWCNT) composites were prepared by melt mixing to achieve suitable SWCNT dispersion and distribution and low electrical resistivity, whereby the SWCNT direct incorporation method was compared with masterbatch dilution. An electrical percolation threshold of 0.05-0.075 wt% was found, the lowest threshold value for melt-mixed PMMA/SWCNT composites reported so far. The influence of rotation speed and method of SWCNT incorporation into the PMMA matrix on the electrical properties and the SWCNT macro dispersion was investigated. It was found that increasing rotation speed improved macro dispersion and electrical conductivity. The results showed that electrically conductive composites with a low percolation threshold could be prepared by direct incorporation using high rotation speed. The masterbatch approach leads to higher resistivity values compared to the direct incorporation of SWCNTs. In addition, the thermal behavior and thermoelectric properties of PMMA/SWCNT composites were studied. The Seebeck coefficients vary from 35.8 µV/K to 53.4 µV/K for composites up to 5 wt% SWCNT.


Inland treatment of the brine generated from reverse osmosis advanced membrane wastewater treatment plant using epuvalisation system.
The reverse osmosis (RO) brine generated from the Al-Quds University wastewater treatment plant was treated using an epuvalisation system. The advanced integrated wastewater treatment plant included an activated sludge unit, two consecutive ultrafiltration (UF) membrane filters (20 kD and 100 kD cutoffs) followed by an activated carbon filter and a reverse osmosis membrane. The epuvalisation system consisted of salt tolerant plants grown in hydroponic channels under continuous water flowing in a closed loop system, and placed in a greenhouse at Al-Quds University. Sweet basil (Ocimum basilicum) plants were selected, and underwent two consecutive hydroponic flowing stages using different brine-concentrations: an adaptation stage, in which a 1:1 mixture of brine and fresh water was used; followed by a functioning stage, with 100% brine. A control treatment using fresh water was included as well. The experiment started in April and ended in June (2012). At the end of the experiment, analysis of the effluent brine showed a remarkable decrease of electroconductivity (EC), PO43-, chemical oxygen demand (COD) and K+ with a reduction of 60%, 74%, 70%, and 60%, respectively, as compared to the influent. The effluent of the control treatment showed 50%, 63%, 46%, and 90% reduction for the same parameters as compared to the influent. Plant growth parameters (plant height, fresh and dry weight) showed no significant difference between fresh water and brine treatments. Obtained results suggest that the epuvalisation system is a promising technique for inland brine treatment with added benefits. The increasing of channel number or closed loop time is estimated for enhancing the treatment process and increasing the nutrient uptake. Nevertheless, the epuvalisation technique is considered to be simple, efficient and low cost for inland RO brine treatment.


Petrocodon wenshanensis, a new species of Gesneriaceae from southwestern China.
A new species of Petrocodon, P. wenshanensis from Yunnan province of southwestern China, is described and illustrated here. P. wenshanensis morphologically closely resembles P. jingxiensis and P. lithophilus, but differs in vegetative and generative characters. Differences between the new species and others Petrocodon species occurring in Yunnan Province are also shown in the identification key.


Reduced brown adipose tissue thermogenesis during environmental interactions in transgenic rats with ataxin-3-mediated ablation of hypothalamic orexin neurons.
Thermogenesis in brown adipose tissue (BAT) contributes to substantial increases in body temperature evoked by threatening or emotional stimuli. BAT thermogenesis also contributes to increases in body temperature that occur during active phases of the basic rest-activity cycle (BRAC), as part of normal daily life. Hypothalamic orexin-synthesizing neurons influence many physiological and behavioral variables, including BAT and body temperature. In conscious unrestrained animals maintained for 3 days in a quiet environment (24-26°C) with ad libitum food and water, we compared temperatures in transgenic rats with ablation of orexin neurons induced by expression of ataxin-3 (Orx_Ab) with wild-type (WT) rats. Both baseline BAT temperature and baseline body temperature, measured at the onset of BRAC episodes, were similar in Orx_Ab and WT rats. The time interval between BRAC episodes was also similar in the two groups. However, the initial slopes and amplitudes of BRAC-related increases in BAT and body temperature were reduced in Orx_Ab rats. Similarly, the initial slopes and amplitudes of the increases in BAT temperatures induced by sudden exposure to an intruder rat (freely moving or confined to a small cage) or by sudden exposure to live cockroaches were reduced in resident Orx_Ab rats. Constriction of the tail artery induced by salient alerting stimuli was also reduced in Orx_Ab rats. Our results suggest that orexin-synthesizing neurons contribute to the intensity with which rats interact with the external environment, both when the interaction is "spontaneous" and when the interaction is provoked by threatening or salient environmental events.


Robust trypsin coating on electrospun polymer nanofibers in rigorous conditions and its uses for protein digestion.
An efficient protein digestion in proteomic analysis requires the stabilization of proteases such as trypsin. In the present work, trypsin was stabilized in the form of enzyme coating on electrospun polymer nanofibers (EC-TR), which crosslinks additional trypsin molecules onto covalently attached trypsin (CA-TR). EC-TR showed better stability than CA-TR in rigorous conditions, such as at high temperatures of 40 and 50°C, in the presence of organic co-solvents, and at various pH's. For example, the half-lives of CA-TR and EC-TR were 1.42 and 231 h at 40°C, respectively. The improved stability of EC-TR can be explained by covalent linkages on the surface of trypsin molecules, which effectively inhibits the denaturation, autolysis, and leaching of trypsin. The protein digestion was performed at 40°C by using both CA-TR and EC-TR in digesting a model protein, enolase. EC-TR showed better performance and stability than CA-TR by maintaining good performance of enolase digestion under recycled uses for a period of 1 week. In the same condition, CA-TR showed poor performance from the beginning and could not be used for digestion at all after a few usages. The enzyme coating approach is anticipated to be successfully employed not only for protein digestion in proteomic analysis but also for various other fields where the poor enzyme stability presently hampers the practical applications of enzymes.


Lateral cerebral ventricular enlargement in chronic schizophrenia.
To investigate if cerebral ventricular enlargement is associated with chronic schizophrenia, computerized tomography scans from 73 psychiatric patients were compared with 56 asymptomatic volunteers all less than 50 years old. Ventricular size was significantly greater in the subgroup of 58 chronic schizophrenic patients than in the controls. Of the chronic schizophrenic patients, 40% were outside the control range; 53% exceeded 2 SDs of the control mean. Neither duration of illness nor length of hospitalization correlated with ventricular size. The 44 chronic schizophrenic patients who had never been treated with electroshock therapy (EST) had larger ventricles than controls. A group of seven nonchronic schizophrenic patients also had enlarged ventricles; the eight patients who were either schizoaffective or nonschizophrenic did not differ from controls. This study shows that lateral cerebral ventricular enlargement is associated with chronic schizophrenia; it suggests that this is not a result of treatment.


Mood state moderates the role of serotonin in cognitive biases.
Reduction of the monoamine serotonin (5-HT) via the dietary manipulation of tryptophan (acute tryptophan depletion; ATD) has been shown to induce negative cognitive biases similar to those found in depression in healthy individuals. However, evidence also indicates that there can be positive effects of ATD on both mood and reinforcement processing. Here, we present two separate studies, with remarkably similar findings, which may help explain these discrepancies. In both experiments, we assessed cognitive biases following experimentally induced mood states under both a balanced amino acid drink (BAL) and ATD. A significant interaction between treatment, mood state and cognitive bias was observed in both experiments. In the first experiment, subjects undergoing positive mood induction demonstrated a positive cognitive bias on BAL, which was abolished by ATD. The same effect was observed in subjects undergoing neutral mood induction in the second experiment. These effects replicate findings in healthy individuals undergoing ATD. Subjects undergoing negative mood induction, by contrast, demonstrated the opposite pattern of results; in both experiments, they showed no bias under BAL but induction of a positive cognitive bias by ATD. These results mimic previous findings in currently depressed patients undergoing ATD. We therefore suggest that mood state moderates the effect of ATD on cognitive biases. This, in turn, has important implications for the understanding of the role of 5-HT in psychiatric disorders.


Bypassing Iron Storage in Endodermal Vacuoles Rescues the Iron Mobilization Defect in the natural resistance associated-macrophage protein3natural resistance associated-macrophage protein4 Double Mutant.
To improve seed iron (Fe) content and bioavailability, it is crucial to decipher the mechanisms that control Fe storage during seed development. In Arabidopsis (Arabidopsis thaliana) seeds, most Fe is concentrated in insoluble precipitates, with phytate in the vacuoles of cells surrounding the vasculature of the embryo. NATURAL RESISTANCE ASSOCIATED-MACROPHAGE PROTEIN3 (AtNRAMP3) and AtNRAMP4 function redundantly in Fe retrieval from vacuoles during germination. When germinated under Fe-deficient conditions, development of the nramp3nramp4 double mutant is arrested as a consequence of impaired Fe mobilization. To identify novel genes involved in seed Fe homeostasis, we screened an ethyl methanesulfonate-mutagenized population of nramp3nramp4 seedlings for mutations suppressing their phenotypes on low Fe. Here, we report that, among the suppressors, two independent mutations in the VACUOLAR IRON TRANSPORTER1 (AtVIT1) gene caused the suppressor phenotype. The AtVIT1 transporter is involved in Fe influx into vacuoles of endodermal and bundle sheath cells. This result establishes a functional link between Fe loading in vacuoles by AtVIT1 and its remobilization by AtNRAMP3 and AtNRAMP4. Moreover, analysis of subcellular Fe localization indicates that simultaneous disruption of AtVIT1, AtNRAMP3, and AtNRAMP4 limits Fe accumulation in vacuolar globoids.


Analytical subcellular fractionation of jejunal biopsy specimens: methodology and characterization of the organelles in normal tissue.
1. Portions of closed jejunal biopsies were gently homogenized in isotonic sucrose or sorbitol and centrifuged at 800 g for 10 min to prepare a cell extract. 2. The extract was fractionated in a single-step procedure by isopycnic centrifugation on a continuous sucrose or sorbitol density gradient with the Beaufay automatic zonal rotor. 3. The subcellular organelles were located in the density gradient by assay of marker enzymes and previously unassigned enzymes were localized to particular organelles. 4. The following organelles were characterized by their modal equilibrium densities in sucrose density gradients: brush borders (1.21), peroxisomes (1.18), mitochondria (1.16), endoplasmic reticulum (1.16), basal-lateral membranes (1.12). At least three distinct populations of lysosomes with different modal densities and enzyme content were demonstrated. 5. This analytical fraction technique can be used to study the subcellular pathology of human jejunum.


Keeping an eye on the truth? Pupil size changes associated with recognition memory.
During recognition memory tests participants' pupils dilate more when they view old items compared to novel items. We sought to replicate this "pupil old/new effect" and to determine its relationship to participants' responses. We compared changes in pupil size during recognition when participants were given standard recognition memory instructions, instructions to feign amnesia, and instructions to report all items as new. Participants' pupils dilated more to old items compared to new items under all three instruction conditions. This finding suggests that the increase in pupil size that occurs when participants encounter previously studied items is not under conscious control. Given that pupil size can be reliably and simply measured, the pupil old/new effect may have potential in clinical settings as a means for determining whether patients are feigning memory loss.


Reduced hair cortisol after maltreatment mediates externalizing symptoms in middle childhood and adolescence.
The enduring impact of childhood maltreatment on biological systems and ensuing psychopathology remains incompletely understood. Long-term effects of stress may be reflected in cumulative cortisol secretion over several months, which is now quantifiable via hair cortisol concentrations (HCC). We conducted a first comprehensive investigation utilizing the potential of hair cortisol analysis in a large sample of maltreated and nonmaltreated children and adolescents. Participants included 537 children and adolescents (3-16 years; 272 females) with maltreatment (n = 245) or without maltreatment histories (n = 292). Maltreated subjects were recruited from child protection services (CPS; n = 95), youth psychiatric services (n = 56), and the community (n = 94). Maltreatment was coded using the Maltreatment Classification System drawing on caregiver interviews and complemented with CPS records. Caregivers and teachers reported on child mental health. HCC were assessed in the first 3 cm hair segment. Analyses uniformly supported that maltreatment coincides with a gradual and dose-dependent reduction in HCC from 9 to 10 years onwards relative to nonmaltreated controls. This pattern emerged consistently from both group comparisons between maltreated and nonmaltreated subjects (27.6% HCC reduction in maltreated 9-16-year-olds) and dimensional analyses within maltreated subjects, with lower HCC related to greater maltreatment chronicity and number of subtypes. Moreover, both group comparisons and dimensional analyses within maltreated youth revealed that relative HCC reduction mediates the effect of maltreatment on externalizing symptoms. From middle childhood onwards, maltreatment coincides with a relative reduction in cortisol secretion, which, in turn, may predispose to externalizing symptoms.


Contraceptive Failure in the United States: Estimates from the 2006-2010 National Survey of Family Growth.
Contraceptive failure rates measure a woman's probability of becoming pregnant while using a contraceptive. Information about these rates enables couples to make informed contraceptive choices. Failure rates were last estimated for 2002, and social and economic changes that have occurred since then necessitate a reestimation. To estimate failure rates for the most commonly used reversible methods in the United States, data from the 2006-2010 National Survey of Family Growth were used; some 15,728 contraceptive use intervals, contributed by 6,683 women, were analyzed. Data from the Guttmacher Institute's 2008 Abortion Patient Survey were used to adjust for abortion underreporting. Kaplan-Meier methods were used to estimate the associated single-decrement probability of failure by duration of use. Failure rates were compared with those from 1995 and 2002. Long-acting reversible contraceptives (the IUD and the implant) had the lowest failure rates of all methods (1%), while condoms and withdrawal carried the highest probabilities of failure (13% and 20%, respectively). However, the failure rate for the condom had declined significantly since 1995 (from 18%), as had the failure rate for all hormonal methods combined (from 8% to 6%). The failure rate for all reversible methods combined declined from 12% in 2002 to 10% in 2006-2010. These broad-based declines in failure rates reverse a long-term pattern of minimal change. Future research should explore what lies behind these trends, as well as possibilities for further improvements.


Molecular characterization of rotavirus strains from children with diarrhea in Italy, 2007-2009.
The surveillance network RotaNet-Italia was established in 2007 in order to investigate the diversity of co-circulating rotavirus strains in Italy, and to provide a baseline for future assessment of possible effects of vaccine implementation in selecting novel versus common rotavirus strains. A total of 2,645 rotavirus strains from pediatric patients with acute diarrhea were collected over three consecutive seasons from September 2006 through August 2009, and partially characterized by standardized multiplex RT-PCR. Most of strains (89.1%) belonged to genotypes G1-G4, and G9, associated with either P[8] or P[4], commonly found in humans worldwide. However, in at least 2.0% of cases, viruses exhibited either a G or P type typical of animal viral strains, suggesting gene reassortment events between rotaviruses of different origin. Mixed infections with two or more rotavirus strains were observed frequently (7.6% of patients), and depended on the frequencies of co-circulating rotaviruses of one particular genotype. The numbers and genotypes of likely natural reassortants of common genotype rotaviruses were found to be correlated with the observed numbers and genotypes of mixed infections. Large variation in the relative frequency of different rotavirus genotypes was observed between different seasons and/or areas of Italy, suggesting independent evolution or differential introduction of viral strains with respect to both time and space.


Identification of suitable reference genes for gene expression studies by qRT-PCR in the blister beetle Mylabris cichorii.
The blister beetle Mylabris cichorii L. (Coleoptera: Meloidae) is a traditional medicinal insect recorded in the Chinese Pharmacopoeia. It synthesizes cantharidin, which kills cancer cells efficiently. Only males produce large amounts of cantharidin. Reference genes are required as endogenous controls for the analysis of differential gene expression in M. cichorii. Our study chose 10 genes as candidate reference genes. The stability of expression of these genes was analyzed by quantitative PCR and determined with two algorithms, geNorm and Normfinder. We recommend UBE3A and RPL22e as suitable reference genes in females and UBE3A, TAF5, and RPL22e in males.


Effect of organizational models of provider-initiated testing and counseling (PITC) in health facilities on adult HIV testing coverage in sub-Saharan Africa.
The purpose of this paper is to identify which Provider-Initiated HIV Testing and Counseling (PITC) organizational models are the most efficient to maximize testing coverage. We conducted a systematic literature review to identify published articles that evaluated routine PITC programs implemented in adult health facilities in Sub-Saharan Africa. We considered only articles measuring PITC offer, PITC acceptability and PITC coverage. Adjusted meta-regression models were performed to measure the association between PITC offer, acceptability and coverage with PITC organizational model. A total of 30 articles were included in the meta-analysis. Overall, 85.4% [95%CI: 77.2-93.5] of patients were offered a test, and 87.1% [82.4-91.7] accepted the test resulting in a PITC coverage of 74.3% [66-82.6]. Four types of PITC organizational models were identified: PITC initiated and performed during the consultation (model A), PITC initiated before consultation (model B), PITC referred on-site (model C) and PITC referred off-site (model D). Compared to model A, model B had a similar coverage (aOR: 1.02 [0.82-1.26]). However, coverage was lower for model C (aOR: 0.81 [0.68-0.97]) and model D (aOR: 0.58 [0.44-0.77]). Initiating the testing process before or during medical consultation is recommended for maximizing testing coverage among patients.


Explicating alcohol's role in acquaintance sexual assault: complementary perspectives and convergent findings.
This article summarizes the proceedings of a symposium presented at the 2004 meeting of the Research Society on Alcoholism (RSA) in Vancouver, British Columbia, Canada. There were four presentations and a discussant. The symposium was co-chaired by Tina Zawacki and Jeanette Norris. The first presentation was made by Jeanette Norris, who found that alcohol consumption and preexisting alcohol expectancies affected women's hypothetical responses to a vignette depicting acquaintance sexual aggression. The second presentation was made by Joel Martell, who reported that alcohol-induced impairment of executive cognitive functioning mediated the effect of intoxication on men's perceptions of a sexual assault vignette. In the third presentation, Antonia Abbey found that the experiences of women whose sexual assault involved intoxication or force were more negative than were the experiences of women whose sexual assault involved verbal coercion. The fourth presentation was made by Tina Zawacki, who reported that men who perpetrated sexual assault only in adolescence differed from men who continued perpetration into adulthood in terms of their drinking patterns and attitudes toward women. William H. George discussed these findings in terms of their implications for theory development and prevention programming.


Longitudinal heritability of childhood aggression.
The genetic and environmental contributions to the variation and longitudinal stability in childhood aggressive behavior were assessed in two large twin cohorts, the Netherlands Twin Register (NTR), and the Twins Early Development Study (TEDS; United Kingdom). In NTR, maternal ratings on aggression from the Child Behavior Checklist (CBCL) were available for 10,765 twin pairs at age 7, for 8,557 twin pairs at age 9/10, and for 7,176 twin pairs at age 12. In TEDS, parental ratings of conduct disorder from the Strength and Difficulty Questionnaire (SDQ) were available for 6,897 twin pairs at age 7, for 3,028 twin pairs at age 9 and for 5,716 twin pairs at age 12. In both studies, stability and heritability of aggressive behavioral problems was high. Heritability was on average somewhat, but significantly, lower in TEDS (around 60%) than in NTR (between 50% and 80%) and sex differences were slightly larger in the NTR sample. In both studies, the influence of shared environment was similar: in boys shared environment explained around 20% of the variation in aggression across all ages while in girls its influence was absent around age 7 and only came into play at later ages. Longitudinal genetic correlations were the main reason for stability of aggressive behavior. Individual differences in CBCL-Aggressive Behavior and SDQ-Conduct disorder throughout childhood are driven by a comparable but significantly different genetic architecture. © 2016 Wiley Periodicals, Inc.


Arthroscopic suture bridge fixation of tibial intercondylar eminence fractures.
Tibial intercondylar eminence fractures that are displaced and non-reducible require open or arthroscopically assisted repair. Ideally, fracture reduction and fixation would be performed with a technique that has low morbidity, allows easy visualization and reduction, provides firm fixation, does not violate the proximal tibial physis, avoids metal hardware, and does not require a second procedure for implant removal. The suture bridge technique, used in the shoulder for rotator cuff tears and greater tuberosity fracture repair, has the ability to produce high contact pressures with rigid fixation. We describe an all-inside and all-epiphyseal arthroscopic suture bridge technique for tibial intercondylar eminence fracture repair performed with PushLock anchors (Arthrex, Naples, FL). One or 2 anchors preloaded with No. 2 FiberWire (Arthrex) are placed in the posterior fracture bed, followed by fracture reduction. The suture limbs are shuttled through and around the anterior cruciate ligament and over the fracture fragment in crossing fashion and are secured by use of additional anchors placed at the anteromedial and anterolateral fracture margin. The anchors are placed obliquely to avoid the proximal tibial physis in the pediatric population. Anatomic reduction and secure fixation allow more aggressive rehabilitation and faster restoration of joint function.


A continent-wide assessment of the form and intensity of large mammal herbivory in Africa.
Megafaunal extinctions and a lack of suitable remote sensing technology impede our understanding of both the ecological legacy and current impacts of large mammal herbivores in the Earth system. To address this, we reconstructed the form and intensity of herbivory pressure across sub-Saharan Africa ~1000 years ago. Specifically, we modeled and mapped species-level biomass for 92 large mammal herbivores using census data, species distributions, and environmental covariates. Trait-based classifications of these species into herbivore functional types, and analyses of their biomass surfaces, reveal four ecologically distinct continental-scale herbivory regimes, characterized by internally similar forms and intensities of herbivory pressure. Associations between herbivory regimes, fire prevalence, soil nutrient status, and rainfall provide important insights into African ecology and pave the way for integrating herbivores into global-scale studies.


Treatment Outcomes for Mandibular Mini-Implant-Retained Overdentures: A Systematic Review.
This systematic review evaluated treatment outcomes for mandibular mini-implant-retained overdentures (MMIOs) in terms of (1) implant survival rate, (2) peri-implant marginal bone loss, (3) prosthodontic maintenance and complication occurrence, and (4) patient satisfaction. Pertinent literature published in English before October 12, 2015 was identified using a MEDLINE and EMBASE search strategy and hand searching of relevant journals. Inclusion and exclusion criteria were applied to the titles and abstracts and subsequently to the full text of included studies. A total of 16 articles were included, from which qualitative and quantitative data were extracted for analysis. Of the 16 evaluated articles, 5 were randomized controlled trials, 8 were prospective studies, and 3 were retrospective studies. The follow-up time range from implant placement was 1 to 6 years, and only four studies included more than 3 years of follow-up. The mini-implant survival rate ranged from 86.9% to 100%. Mean marginal bone resorption was 0.28 to 1.2 mm after 1 year of loading. Of the 16 studies, 5 reported prosthodontic maintenance and complications, and all included studies showed significant improvement in patient satisfaction. Despite the limitations of this systematic review, particularly the short follow-up periods, the results suggest that MMIOs showed predictable results regarding implant survival rates, marginal bone resorption, and patient satisfaction.


A support group for fathers whose partners died from cancer.
Men who are raising dependent children after their spouses or partners have died from cancer face unique challenges adjusting to single parenthood while managing their grief and the grief of their children. Unfortunately, the needs of those widowers have been overlooked in the clinical literature and no published interventions are designed specifically for that population. The current article details the creation and implementation of a peer support group for fathers recently widowed because of their wives' deaths from cancer. Initial observations and emergent themes from the group are described. Group members suggested that they benefited from participation in the support group and that this form of psychosocial support is a promising intervention for fathers in similar circumstances.


Isolation and characterization of pirital virus, a newly discovered South American arenavirus.
Specific rodent species are principal hosts for each of the well-characterized members of the virus family Arenaviridae. Guanarito virus (Arenaviridae) is the etiologic agent of Venezuelan hemorrhagic fever. A previous study on the epidemiology of Venezuelan hemorrhagic fever revealed extensive arenavirus infection (presumed to be caused by Guanarito virus) in two rodent species. Sigmodon alstoni and Zygodontomys brevicauda, collected from the region of Venezuela in which the disease is endemic. In the present study, four arenavirus isolates recovered from the Municipality of Guanarito (two isolates each from S. alstoni and Z. brevicauda) were characterized to learn more about the natural rodent host relationships of Guanarito virus. Serologic tests and analyses of nucleocapsid protein gene sequence data indicated that the two isolates from Z. brevicauda are strains of Guanarito virus and that the two isolates from S. alstoni are representatives of a novel New World arenavirus (proposed name Pirital) that is antigenically and phylogenetically distinct from all known New World arenaviruses. The results of the present study provide further evidence that the cane mouse Z. brevicauda is a natural host of Guanarito virus and suggest that the cotton rat S. alstoni is the natural reservoir host of Pirital but not Guanarito virus.


Degradation of B-Myb by ubiquitin-mediated proteolysis: involvement of the Cdc34-SCF(p45Skp2) pathway.
B-Myb, a highly conserved member of the Myb oncoprotein family, is a 110 kDa sequence-specific DNA binding protein expressed in virtually all proliferating cells. B-myb expression reaches its maximum at the G1/S phase boundary and during the S phase of the cell cycle. We have previously shown that B-Myb activity is cell cycle regulated and it is controlled by the antagonistic effects of cyclin D1 and A. Here we show that ectopic expression of cyclin A causes a pronounced reduction of B-Myb protein level. We provide evidence that in addition to triggering B-Myb activity an important effect of cyclin A is to facilitate multiple ubiquitination of B-Myb. The C-terminal domain of B-Myb is of key importance in mediating this effect of cyclin A. Contrary to full-length B-Myb, a C-terminal deletion mutant displays activity irrespective of cyclin A expression, does not undergo ubiquitination, and its half-life is not affected by cyclin A. Ectopic expression of either Cdc34 or the F-box protein p45Skp2, respectively the E2 and E3 components of a ubiquitination pathway that regulates the G1/S transition, accelerates degradation of B-Myb. We show that B-Myb physically and functionally interacts with components of the Cdc34-SCFp45Skp2 ubiquitin pathway and propose that B-Myb degradation may be required for controlling the correct alternation of events during progression through the cell division cycle. Oncogene (2000).


Second-Order Perturbation Theory with Fractional Charges and Fractional Spins.
In this work the behavior of MP2 for fractional occupations is investigated. The consideration of fractional charge behavior gives a simple derivation of an expression for the chemical potential (or the derivative of energy with respect to the number of electrons) of MP2. A generalized optimized effective potential formalism (OEP) has been developed in which the OEP is a nonlocal potential, which can be applied to explicit functionals of the orbitals and eigenvalues and also facilitates the evaluation of the chemical potential. The MP2 derivative improves upon the corresponding Koopmans' theorem in Hartree-Fock theory for the ionization energy and also gives a good estimate of the electron affinity. In strongly correlated systems with degeneracies and fractional spins, MP2 diverges, and another corrected second-order perturbative method ameliorates this failure for the energy but still does not recapture the correct behavior for the energy derivatives that yield the gap. Overall we present a view of wave function based methods and their behavior for fractional charges and spins that offers insight into the application of these methods to challenging chemical problems.


Resonant Raman detection of macular pigment levels in the living human retina.
We have used resonant Raman scattering as a novel, noninvasive in vivo optical technique to measure the concentration of macular carotenoid pigments in the living human retina. Using a backscattering geometry and resonant molecular excitation in the visible, we measure the Raman peaks that originate from the single- and double-bond stretch vibrations of the p -conjugated molecule's carbon backbone. The Raman signals scale linearly with carotenoid content, whereas the required laser excitation is well under safety limits for macular exposure. The Raman technique is objective and quantitative and may lead to a new method for rapid screening of carotenoid pigment levels in large human populations that are at risk for vision loss from age-related macular degeneration, the leading cause of blindness of the elderly in the United States.


Functional connectivity separates switching operations in the posterior lateral frontal cortex.
Task representations consist of different aspects such as the representations of the relevant stimuli, the abstract rules to be applied, and the actions to be performed. To be flexible in our daily lives, we frequently need to switch between some or all aspects of a task. In the present study, we examined whether switching between abstract task rules and switching between response hands is associated with overlapping regions in the posterior lateral frontal cortex and whether switching between these two aspects of a task representation is neurally implemented by distinct functional brain networks. Subjects performed a cue-based task-switching paradigm where the location of the task cue additionally specified the response hand to be used. Overlapping activity for switching between abstract rules versus response hands was present in the inferior frontal junction area of the posterolateral frontal cortex. This region, however, showed very distinct patterns of functional connectivity depending on the content of the switch: Increased functional connectivity with anterior prefrontal, superior frontal, and hippocampal regions was present for abstract rule switching, whereas response hand switching led to increased coupling with motor regions surrounding the central sulcus. These results reveal that a rather general involvement of the posterior lateral frontal cortex in different switching contexts can be further characterized by highly specific functional interactions with other task-relevant regions, depending on the content of the switch.


Deception of children in research.
The aim of this article is to draw attention to an under-recognised but ethically important phenomenon involving the deception of children in research. The type of deception we are referring to is not planned deception that is part of the research design. Instead it is deception that occurs in individual cases where parents ask researchers not to reveal something about the research to their child. Our focus is children who do not have ultimate decisional authority--children around the ages of 7-14 years old who may have the cognitive capacity to understand but not to consent for themselves; children whose agreement is required but not sufficient to authorise research. We provide three illustrative scenarios for analysis. Then, we identify circumstances in which non-disclosure might be justified and set out reasons why providing information to non-competent children is ethically required. On this basis, we argue that non-planned deception requested by parents is very unlikely to be ethically acceptable. Finally, we recommend that guidelines should (a) require researchers to consider what to do if parents do not want to disclose information to a child and (b) clarify that the most ethical response is to simply not include that child in the research.


The effects of reducing worry in patients with persecutory delusions: study protocol for a randomized controlled trial.
Our approach to advancing the treatment of psychosis is to focus on key single symptoms and develop interventions that target the mechanisms that maintain them. In our theoretical research we have found worry to be an important factor in the development and maintenance of persecutory delusions. Worry brings implausible ideas to mind, keeps them there, and makes the experience distressing. Therefore the aim of the trial is to test the clinical efficacy of a cognitive-behavioral intervention for worry for patients with persecutory delusions and determine how the worry treatment might reduce delusions. An explanatory randomized controlled trial--called the Worry Intervention Trial (WIT)--with 150 patients with persecutory delusions will be carried out. Patients will be randomized to the worry intervention in addition to standard care or to standard care. Randomization will be carried out independently, assessments carried out single-blind, and therapy competence and adherence monitored. The study population will be individuals with persecutory delusions and worry in the context of a schizophrenia spectrum diagnosis. They will not have responded adequately to previous treatment. The intervention is a six-session cognitive-behavioral treatment provided over eight weeks. The control condition will be treatment as usual, which is typically antipsychotic medication and regular appointments. The principal hypotheses are that a worry intervention will reduce levels of worry and that it will also reduce the persecutory delusions. Assessments will be carried out at 0 weeks (baseline), 8 weeks (post treatment) and 24 weeks (follow-up). The statistical analysis strategy will follow the intention-to-treat principle and involve the use of linear mixed models to evaluate and estimate the relevant between- and within-subjects effects (allowing for the possibility of missing data). Both traditional regression and newer instrumental variables analyses will examine mediation. The trial is funded by the UK Medical Research Council (MRC)/NHS National Institute of Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) Programme. This will be the first large randomized controlled trial specifically focused upon persecutory delusions. The project will produce a brief, easily administered intervention that can be readily used in mental health services. Current Controlled Trials ISRCTN23197625.


Efficacy of the In2Care® auto-dissemination device for reducing dengue transmission: study protocol for a parallel, two-armed cluster randomised trial in the Philippines.
Mosquito-borne viruses are imposing an ever increasing health burden worldwide. In addition to the recent Zika and chikungunya virus epidemics, dengue viruses have become the fastest growing problem with a 40-fold increase in the number of reported cases over the past five decades. Current mosquito control techniques involving larval source reduction, larviciding, and space spray of adulticides are costly, laborious, and of debatable efficacy. There remains an urgent need for the development of intervention methods that can be reasonably implemented in the context of modern day urbanisation. Auto-dissemination (AD) of insecticide by adult mosquitoes offers a potentially practical and useful tool in an integrated vector control programme. Recently, an immediately employable AD device, the In2Care® mosquito trap, has been commercialised and shows promise as an effective tool. However, there remains a lack of demonstration of epidemiological efficacy. This trial aims to assess the extent to which implementation of In2Care® mosquito traps can reduce vector Aedes (Stegomyia) spp. adult mosquito densities and dengue virus transmission as measured by sequential sero-conversion rates in children 6-16 years of age in a dengue endemic location: Lipa City, Philippines. To achieve this, we will carry out a parallel, two-armed cluster randomised trial evaluating AD efficacy for reducing the incidence of dengue over a 2-year period with 4 consecutive months of vector control during peak dengue transmission each year. For decades, it has been commonly accepted that an integrated approach to mosquito control is required. The World Health Organization (WHO) Global Strategic Framework for Integrated Vector Management recommends a range of interventions, in combination, to increase control impact to reduce transmission. This efficacy trial of the first commercial product using the AD approach will be informative in assessing the general utility of AD in reducing not only adult vector densities but, more importantly, reducing the incidence of dengue. The AD technique may complement source reduction and larviciding campaigns by more efficiently targeting the most productive containers and those beyond human reach. If successful, this mosquito control strategy could prove an invaluable tool in the fight against urban mosquito vectors and a reduction in the burden of associated disease. ISRCTN44272773 . Registered on 31 January 2019.


Substance use disorders and risk of suicide in a general US population: a case control study.
Prior research suggests that substance use disorders (SUDs) are associated with risk of suicide mortality, but most previous work has been conducted among Veterans Health Administration patients. Few studies have examined the relationship between SUDs and suicide mortality in general populations. Our study estimates the association of SUDs with suicide mortality in a general US population of men and women who receive care across eight integrated health systems. We conducted a case-control study using electronic health records and claims data from eight integrated health systems of the Mental Health Research Network. Participants were 2674 men and women who died by suicide between 2000-2013 and 267,400 matched controls. The main outcome was suicide mortality, assessed using data from the health systems and confirmed by state death data systems. Demographic and diagnostic data on substance use disorders and other health conditions were obtained from each health system. First, we compared descriptive statistics for cases and controls, including age, gender, income, and education. Next, we compared the rate of each substance use disorder category for cases and controls. Finally, we used conditional logistic regression models to estimate unadjusted and adjusted odds of suicide associated with each substance use disorder category. All categories of substance use disorders were associated with increased risk of suicide mortality. Adjusted odds ratios ranged from 2.0 (CI 1.7, 2.3) for patients with tobacco use disorder only to 11.2 (CI 8.0, 15.6) for patients with multiple alcohol, drug, and tobacco use disorders. Substance use disorders were associated with increased relative risk of suicide for both women and men across all categories, but the relative risk was more pronounced in women. Substance use disorders are associated with significant risk of suicide mortality, especially for women, even after controlling for other important risk factors. Experiencing multiple substance use disorders is particularly risky. These findings suggest increased suicide risk screening and prevention efforts for individuals with substance use disorders are needed.


Exposure of endothelial cells to free heme potentiates damage mediated by granulocytes and toxic oxygen species.
Endothelial damage may follow exposure to toxic oxygen species generated by closely apposed ("marginated") granulocytes. Because iron markedly catalyzes oxidant damage in diverse systems, we wondered whether intercalculated heme, and/or its constituent iron, might potentiate oxidant damage of endothelium. Cultured monolayers of porcine aortic endothelial cells were exposed for brief periods to purified hemin. Uptake of heme was rapid, dose dependent, and not reversible by buffer or serum washes. Despite high levels of cell-associated heme, no direct heme-mediated cytotoxicity occurred, but heme-loaded endothelium became highly sensitive to oxidant challenge by (a) reagent H2O2, (b) enzymatically generated oxidants (xanthine/xanthine oxidase), or (c) phorbol-activated polymorphonuclear leukocytes. An increase in endothelial cell lipid peroxidation accompanied heme-augmented oxidant cytolysis, and both parameters were reduced in parallel by micromolar amounts of the hydrophobic oxygen radical scavenger/iron chelator U74500A. Endothelial uptake of heme was inhibited by a specific heme-binding protein, hemopexin. Concomitantly, hemopexin completely blocked augmented H2O2- and polymorphonuclear leukocyte-mediated cytotoxicity but only if added simultaneously and stoichiometrically with hemin. Significant loss of protection occurred if hemopexin addition was delayed 15 minutes, and protection was completely lost after a 60-minute interval. The iron moiety of heme was critical to oxidant sensitization because neither iron-free protoporphyrin IX nor tin-protoporphyrin was able to sensitize endothelial cells to H2O2 or activated polymorphonuclear leukocytes. These results may provide mechanistic insights into atherogenesis, reperfusion injury, and the organ injury accompanying hemoglobinemia or myoglobinemia.


Cajal-Retzius cells instruct neuronal migration by coincidence signaling between secreted and contact-dependent guidance cues.
Cajal-Retzius (CR) cells are a transient cell population of the CNS that is critical for brain development. In the neocortex, CR cells secrete reelin to instruct the radial migration of projection neurons. It has remained unexplored, however, whether CR cells provide additional molecular cues important for brain development. Here, we show that CR cells express the immunoglobulin-like adhesion molecule nectin1, whereas neocortical projection neurons express its preferred binding partner, nectin3. We demonstrate that nectin1- and nectin3-mediated interactions between CR cells and migrating neurons are critical for radial migration. Furthermore, reelin signaling to Rap1 promotes neuronal Cdh2 function via nectin3 and afadin, thus directing the broadly expressed homophilic cell adhesion molecule Cdh2 toward mediating heterotypic cell-cell interactions between neurons and CR cells. Our findings identify nectins and afadin as components of the reelin signaling pathway and demonstrate that coincidence signaling between CR cell-derived secreted and short-range guidance cues direct neuronal migration.


Interaction of intraleukocytic bacteria and antibiotics.
Bacteria that survive inside polymorphonuclear neutrophils (PMN) following phagocytosis are protected from the bactericidal action of most antibiotics. Two possible explanations are altered metabolism by intraleukocytic bacteria or failure of antibiotics to enter the phagosome. The oxygen consumption of intraleukocytic and extraleukocytic bacteria was measured as an index of bacterial metabolism. PMN respiration and bactericidal activity were suppressed with large doses of hydrocortisone and extraleukocytic bacterial oxygen consumption was abolished by the addition of lysostaphin. Intraleukocytic bacterial continued to consume oxygen suggesting that surviving ingested micro-organisms are metabolically active. Neither penicillin (which cannot kill intraleukocytic bacteria) nor rifampin (which can kill intraleukocytic bacteria) was bactericidal for staphylococci at 5 degrees C. Thus, rifampin is not uniquely able to kill "resting" bacteria.Intraleukocytic or extraleukocytic Staphylococcus aurens were incubated with [benzyl-(14)C]penicillin for 2 h at 37 degrees C. Live intraleukocytic bacteria bound only 13% as much penicillin as live bacteria incubated with killed PMN. To measure the penetration of antibiotics into PMN, [(14)C]rifampin and [(14)C]penicillin were measured in leukocyte pellets and in the supernatant fluid. The total water space in the pellets was quantitated using tritium water and the extracellular water space was measured using Na(235)SO(4). All penicillin associated with the cell pellet could be accounted for in extracellular water. Thus penicillin was completely excluded from the leukocytes. Rifampin was concentrated in the cell pellet 2.2 times when compared with the supernatant concentration. These studies suggest that a likely explanation for the survival of phagocytized bacteria in the presence of high concentrations of most antibiotics is the inability of the antibiotic to enter the phagocyte. Rifampin, which is highly lipid soluble, can enter leukocytes and kill intracellular bacteria.


The association between disease activity and duration in systemic sclerosis.
The absence of a standardized disease activity index has been an important barrier in systemic sclerosis (SSc) research. We applied the newly derived Valentini Scleroderma Disease Activity Index (SDAI) among our cohort of patients with SSc to document changes in disease activity over time and to assess possible differences in activity between limited and diffuse disease. Cross-sectional study of a national cohort of patients enrolled in the Canadian Scleroderma Research Group Registry. Disease activity was measured using the SDAI. Depression scores were measured using the Centre for Epidemiologic Studies Depression Scale (CES-D). A total of 326 out of 639 patients had complete datasets at the time of this analysis; 87% were female, of mean age 55.6 years, with mean disease duration 14.1 years. SDAI declined steeply in the first 5 years after disease onset and patients with diffuse disease had 42% higher SDAI scores than patients with limited disease with the same disease duration and depression scores (standardized relative risk 1.42, 95% CI 1.21, 1.65). Patients with higher CES-D scores had higher SDAI scores relative to patients with the same disease duration and disease subset (standardized RR 1.22, 95% CI 1.14, 1.31). Among the 10 components that make up the SDAI, only skin score (standardized OR 0.59, 95% CI 0.43, 0.82) and patient-reported change in skin (standardized OR 0.64, 95% CI 0.45, 0.92) decreased with increasing disease duration. High skin scores (standardized OR 32.2, 95% CI 15.8, 72.0) were more likely and scleredema (standardized OR 0.58, 95% CI 0.37, 0.92) was less likely to be present in patients with diffuse disease. High depression scores were associated with positive responses for patient-reported changes in skin and cardiopulmonary function. Disease activity declined with time and patients with diffuse disease had consistently higher SDAI scores. Depression was found to be associated with higher patient activity scores and strongly associated with patient self-response questions. The role of depression should be carefully considered in future applications of the SDAI, particularly as several components of the score rely upon patient recall.


A typological approach to testing the evolutionary functions of human female orgasm.
Building on previous work that identified different types of orgasm in women (King, Belsky, Mah, & Binik, 2011), the goal of the present study was to extend such typological work and determine whether female orgasmic variability tracked potentially evolutionarily salient sexual partner characteristics (e.g., those displaying possible immune-system compatibility). A total of 265 females completed an Internet survey about their orgasmic experience-achieved either with partners or alone. For partnered orgasms, they also provided details of partner characteristics and sexual behaviors. Latent class analysis revealed two orgasm types which were meaningfully distinguishable in terms of sensations and location-either centered on the surface of genitalia or deep inside. Deep orgasms were associated with internal sensations consistent with proposed functions of female orgasm in terms of differential sperm insuck. Such orgasms were associated with partners who were perceived as considerate, dominant, with a noticeably attractive smell, and as providing firm penetration. However, some hypothesized reproductively significant partner characteristics were not differentially associated with deep orgasms (i.e., muscularity, aggression, masculinity). Results were discussed and future research directions outlined. In particular, it is suggested that sexual passion between partners is a non-accidental component of sexual functioning and that this has too frequently been missing in sex research involving humans. Direct physiological measures of the results of female orgasm need to be undertaken. Additionally, the intriguing phenomenon of female ejaculation deserves scientific attention.