Inhibitory influence of the dorsal nucleus of the lateral lemniscus on binaural responses in the rat's inferior colliculus.
The contribution of the dorsal nucleus of the lateral lemniscus (DNLL) to binaural processing was examined by recording single-unit activity in the rat's inferior colliculus before, during, and after a reversible block of the excitatory activity in DNLL by local injection of kynurenic acid. Recordings were made from the central nucleus of the inferior colliculus with glass micropipettes filled with 3 M sodium acetate. Kynurenic acid (2 mM in Locke's solution) was injected into the DNLL through one side of a double-barreled glass pipette. The other side of the pipette was filled with Locke's solution for making control injections and recording neural activity. Pressure injection of 0.7-2.0 microliter of kynurenic acid resulted in the complete cessation of tone-evoked responses in DNLL for periods of 45 min to 1 hr. Tone bursts were delivered separately to the two ears through headphones fitted to the external auditory meatus. Binaural responses in the inferior colliculus were determined by comparing the effects of monaural and binaural stimulation. Attention was focused on neurons that were excited by contralateral stimulation and inhibited by ipsilateral stimulation. Interaural intensity difference (IID) functions were generated by holding contralateral sound pressure constant at 10 dB above threshold while increasing ipsilateral sound pressure level. Prior to kynurenic acid injection, ipsilateral stimulation caused a pronounced suppression of contralaterally evoked single-unit activity. Unilateral injection of kynurenic acid into DNLL reduced the strength of binaural suppression in the contralateral inferior colliculus. In every cell tested, the IID curve in inferior colliculus was shifted following contralateral DNLL injection. The IID curve returned to normal after recovery of neural activity in DNLL. In contrast, no effect was seen in the inferior colliculus ipsilateral to the kynurenic acid injection. The injection of Locke's solution into DNLL had no effect on IID curves in the inferior colliculus. These data suggest that the DNLL plays a role in binaural processing through an inhibitory influence on responses in the contralateral inferior colliculus.


The information content of physiological and epileptic brain activity.
Cerebral cortex is a highly sophisticated computing machine, feeding on information provided by the senses, which is integrated with other, internally generated patterns of neural activity, to trigger behavioural outputs. Bit by bit, we are coming to understand how this may occur, but still, the nature of the 'cortical code' remains one of the greatest challenges in science. As with other great scientific challenges of the past, fresh insights have come from a coalescence of different experimental and theoretical approaches. These theoretical considerations are typically reserved for cortical function rather than cortical pathology. This approach, though, may also shed light on cortical dysfunction. The particular focus of this review is epilepsy; we will argue that the information capacity of different brain states provides a means of understanding, and even assessing, the impact and locality of the epileptic pathology. Epileptic discharges, on account of their all-consuming and stereotyped nature, represent instances where the information capacity of the network is massively compromised. These intense discharges also prevent normal processing in surrounding territories, but in a different way, through enhanced inhibition in these territories. Information processing is further compromised during the period of post-ictal suppression, during interictal bursts, and also at other times, through more subtle changes in synaptic function. We also comment on information processing in other more physiological brain states.


Profile of Somryst Prescription Digital Therapeutic for Chronic Insomnia: Overview of Safety and Efficacy.
Introduction: Prescription digital therapeutics (PDTs) represent a new class of software-based medical devices authorized by the Food and Drug Administration (FDA) to treat disease. Somryst™, the first PDT for treating chronic insomnia, delivers cognitive behavioral therapy for insomnia (CBT-I) via a mobile application. CBT-I is the guideline-recommended, first-line treatment for chronic insomnia, but availability of CBT-I therapists is limited. Somryst addresses this need by providing asynchronous access to CBT-I treatment. As a contactless therapeutic medium, Somryst is also an ideal option when face-to-face therapy is not available or recommended for safety reasons (e.g. because of possible exposure to the SARS-CoV-2 virus). Areas covered: This review summarizes the mechanisms of action and technical features of Somryst, and describes safety and effectiveness data from the randomized trials on which FDA clearance was based. Expert opinion: Somryst demonstrates robust clinical efficacy with a favorable benefit-to-risk profile for treating adults with chronic insomnia. FDA clearance was based on data from 2 clinical trials of the first-generation web-based CBT-I platform Sleep Healthy Using the Internet (SHUTi). Somryst, and PDTs in general, are promising devices to address the need for greater accessibility to effective therapies.


High-dose cyclophosphamide without stem cell rescue in 207 patients with aplastic anemia and other autoimmune diseases.
High-dose cyclophosphamide has long been used as an anticancer agent, a conditioning regimen for hematopoietic stem cell transplantation, and a potent immunosuppressive agent in autoimmune diseases including aplastic anemia. High-dose cyclophosphamide is highly toxic to lymphocytes but spares hematopoietic stem cells because of their abundant levels of aldehyde dehydrogenase, the major mechanism of cyclophosphamide inactivation. High-dose cyclophosphamide therapy induces durable remissions in most patients with acquired aplastic anemia. Moreover, high-dose cyclophosphamide without hematopoietic stem cell rescue has shown activity in a variety of other severe autoimmune diseases. Here we review the history of cyclophosphamide as it applies to aplastic anemia and other autoimmune diseases. We include historical data from early patients treated for aplastic anemia as well as data from 140 patients from an observational retrospective study in a single tertiary care hospital. This latter component was designed to assess the safety and efficacy of high-dose cyclophosphamide therapy without stem cell rescue in patients with refractory autoimmune diseases. We analyzed the 140 patients with severe, progressive autoimmune diseases treated. All patients discussed here received cyclophosphamide, 50 mg/kg per day for 4 consecutive days. Response, relapse, and overall survival were measured. Response was defined as a decrease in disease activity in conjunction with a decrease or elimination of immune-modulating drugs. Relapse was defined as worsening disease activity and/or a requirement for an increase in dose of, or administration of new, immunosuppressive medications. Hematologic recovery occurred in all patients. The overall response rate was 94%, and 44% of those patients remained progression free with a median follow-up of 36 months (range, 1-120 mo) for the 140 patients analyzed together. The overall actuarial and event-free survival across all diseases at 60 months was 90.7% and 20.6%, respectively. High-dose cyclophosphamide without stem cell rescue is well tolerated and induces a high rate of remission in severe autoimmune diseases.


Perceptions of skill development of participants in three national career development programs for women faculty in academic medicine.
The Association of American Medical Colleges (AAMC) and Drexel University College of Medicine have designed and implemented national career development programs (CDPs) to help women faculty acquire and strengthen skills needed for success in academic medicine. The authors hypothesized that skills women acquired in CDPs would vary by career stage and program attended. In 2011, the authors surveyed a national cohort of 2,779 women listed in the AAMC Faculty Roster who also attended one of three CDPs (Early- and Mid-Career Women in Medicine Seminars, and/or Executive Leadership in Academic Medicine) between 1988 and 2010 to examine their characteristics and CDP experiences. Participants indicated from a list of 16 skills whether each skill was newly acquired, improved, or not improved as a result of their program participation. Of 2,537 eligible CDP women, 942 clicked on the link in an invitation e-mail, and 879 (93%) completed the survey. Respondents were representative of women faculty in academic medicine. Participants rated the CDPs highly. Almost all reported gaining and/or improving skills from the CDP. Four skills predominated across all three programs: interpersonal skills, leadership, negotiation, and networking. The skills that attendees endorsed differed by respondents' career stages, more so than by program attended. Women participants perceived varying skills gained or improved from their attendance at the CDPs. Determining ways in which CDPs can support women's advancement in academic medicine requires a deeper understanding of what participants seek from CDPs and how they use program content to advance their careers.


Resuming Anticoagulation following Upper Gastrointestinal Bleeding among Patients with Nonvalvular Atrial Fibrillation-A Microsimulation Analysis.
Among patients with nonvalvular atrial fibrillation (NVAF) who have sustained an upper gastrointestinal bleed (UGIB), the benefits and harms of oral anticoagulation change over time. Early resumption of anticoagulation increases recurrent bleeding, while delayed resumption exposes patients to a higher risk of ischemic stroke. We therefore set out to estimate the expected benefit of resuming anticoagulation as a function of time after UGIB among patients with NVAF. We created a decision-analytic model estimating discounted quality-adjusted life-years when patients with NVAF resume anticoagulation on each day following UGIB. We simulated from a health system perspective over a lifelong time horizon. Peak utility for warfarin was achieved by resumption 41 days after hemostasis from the index UGIB. Resumption between days 32 and 51 produced greater than 99.9% of the peak utility. Peak utility for apixaban was achieved by resumption 32 days after the index UGIB. Resumption between days 21 and 47 produced greater than 99.9% of the peak utility. Of input parameters, results were most sensitive to underlying stroke risk. Specifically, across the range of CHA2DS2-Vasc scores, the optimal day of resumption varied by around 11 days for patients resuming warfarin and by around 15 days for patients resuming apixaban. Results were less sensitive to underlying risk of rebleeding. For patients with NVAF following UGIB, warfarin is optimally restarted approximately six weeks following hemostasis, and apixaban is optimally restarted approximately one month following hemostasis. Modest changes to this timing based on probability of thromboembolic stroke are reasonable.


Gene expression profiles from discordant monozygotic twins suggest that molecular pathways are shared among multiple systemic autoimmune diseases.
The objective of this study is to determine if multiple systemic autoimmune diseases (SAID) share gene expression pathways that could provide insights into pathogenic mechanisms common to these disorders. RNA microarray analyses (Agilent Human 1A(V2) 20K oligo arrays) were used to quantify gene expression in peripheral blood cells from 20 monozygotic (MZ) twin pairs discordant for SAID. Six affected probands with systemic lupus erythematosus (SLE), six with rheumatoid arthritis (RA), eight with idiopathic inflammatory myopathies (IIM), and their same-gendered unaffected twins, were enrolled. Comparisons were made between discordant twin pairs and these were also each compared to 40 unrelated control subjects (matched 2:1 to each twin by age, gender and ethnicity) using statistical and molecular pathway analyses. Relative quantitative PCR was used to verify independently measures of differential gene expression assessed by microarray analysis. Probands and unrelated, matched controls differed significantly in gene expression for 104 probes corresponding to 92 identifiable genes (multiple-comparison adjusted P values < 0.1). Differentially expressed genes involved several overlapping pathways including immune responses (16%), signaling pathways (24%), transcription/translation regulators (26%), and metabolic functions (15%). Interferon (IFN)-response genes (IFI27, OASF, PLSCR1, EIF2AK2, TNFAIP6, and TNFSF10) were up-regulated in probands compared to unrelated controls. Many of the abnormally expressed genes played regulatory roles in multiple cellular pathways. We did not detect any probes expressed differentially in comparisons among the three SAID phenotypes. Similarly, we found no significant differences in gene expression when comparing probands to unaffected twins or unaffected twins to unrelated controls. Gene expression levels for unaffected twins appeared intermediate between that of probands and unrelated controls for 6535 probes (32% of the total probes) as would be expected by chance. By contrast, in unaffected twins intermediate ordering was observed for 84 of the 104 probes (81%) whose expression differed significantly between probands and unrelated controls. Alterations in expression of a limited number of genes may influence the dysregulation of numerous, integrated immune response, cell signaling and regulatory pathways that are common to a number of SAID. Gene expression profiles in peripheral blood suggest that for genes in these critical pathways, unaffected twins may be in a transitional or intermediate state of immune dysregulation between twins with SAID and unrelated controls, perhaps predisposing them to the development of SAID given the necessary and sufficient environmental exposures.


Anatomic Evidence for Information Exchange between Primary Afferent Sensory Neurons Innervating the Anterior Eye Chamber and the Dura Mater in Rat.
Our previous studies suggested that mechanosensitive trigeminal ganglion (TG) nerve endings innervating the inner wall of the anterior eye chamber (IWAEC) might play a role in baroreception of the IOP. It has been reported that mechanosensitive TG nerve endings also innervate the dura mater. An acute IOP elevation evokes eye pain accompanied by an ipsilateral headache, suggesting that information exchange may occur between the primary afferent neurons (PANs) innervating the IWAEC and the dura mater. To verify the information exchange between PANs of the two locations, we investigated the anatomic connection between them. Non-trans-synaptic tracers, 1,1'-dilinoleyl-3,3,3',3'-tetramethylindo-carbocyanine, 4-chlorobenzenesulfonate (FAST Dil) and cholera toxin subunit-B with a 488-nm fluorescent tag (CTB-488), were applied to the dura of the anterior cranial fossa (DACF) and the anterior eye chamber (AEC) to label the PANs. A trans-synaptic tracer, GFP-expressing pseudorabies virus (PRV152), was injected into the AEC while FAST Dil was applied to the DACF to explore the connection between PANs. Fluorescent localization in the TG was studied with a confocal fluorescent microscope. Nine days after rats were treated with CTB-488 in the AEC and FAST Dil on the DACF, FAST Dil-labeled (red), and CTB-488-labeled (green) TG neurons were observed in the medial part of the TG, while double-labeled neurons were absent. If PRV152 was used to substitute CTB-488, then FAST Dil (red) and PRV152 (green) double-labeled TG neurons and axons were observed 3 days later. Our results indicate that synapses exist between PANs of the IWAEC and the DACF, providing anatomic evidence for information exchange between them.


RightReturn. Partnering to reduce the high rate of hospital readmission for dialysis-dependent patients.
The rate of rehospitalization is at a critical level. Twenty percent of all Medicare patients are rehospitalized within 30 days of discharge, and this rate is even higher (36%) for end-stage renal disease patients. Dialysis-dependent patients are commonly discharged from the hospital with a decline in various health measures (such as hemoglobin, albumin, and estimated dry weight) when compared to pre-hospital values, making the common response to resume previous orders" in the outpatient setting inadequate. Both quality of care and financial penalties by the Centers for Medicare & Medicaid Services have set the stage for partnerships between dialysis providers and hospitals to develop strategies to reduce readmissions for ESRD patients, and provide for the "RightReturn" to the outpatient setting with resumption of their daily lives at home in optimal health.


Implications for bio-psycho-social-spiritual concerns in cardiovascular nursing.
One of the most challenging areas of scientific investigation is to determine the connections of the human spirit, emotions, love, attitudes, meaning, and purpose with physiologic and pathophysiologic alterations. Fundamental changes must occur in the current health care system and in research models so that cardiovascular patients, their families, and health care providers are presented with new strategies for prevention, stabilization, or reversal of the devastating effects of cardiovascular disease. The current biologic, unidimensional, reductionistic, technologic approach to the treatment of heart disease must be expanded to include the psycho-social-spiritual dimension. This article explores the mind-body dilemma, the theory and research basis for the psychophysiology of bodymind healing, and implications for practice and research.


Respect for persons, informed consent and the assessment of infectious disease risks in xenotransplantation.
Given the increasing need for solid organ and tissue transplants and the decreasing supply of suitable allographic organs and tissue to meet this need, it is understandable that the hope for successful xenotransplantation has resurfaced in recent years. The biomedical obstacles to xenotransplantation encountered in previous attempts could be mitigated or overcome by developments in immunosuppression and especially by genetic manipulation of organ source animals. In this essay we consider the history of xenotransplantation, discuss the biomedical obstacles to success, explore recent developments in transgenic sourcing of organs and tissues, and analyze the problem of infectious disease resulting from xenotransplantation (xenosis). We then apply a model of risk analysis to these risks. The conclusions of this risk analysis are used in an ethical evaluation of informed consent in xenotransplantation, with an ethical foundation in Kantian autonomy and Levinasian heteronomic alterity. Our conclusion is that individual and collective informed consent to the infectious disease risks of xenotransplantation requires an open, participatory and dialogical public policy process not yet seen in the United States and Europe. Until that process is created, we propose caution in xenotransplantation in general and a postponement of solid organ xenotransplants in particular.


Activity patterns in seven captive lemur species: Evidence of cathemerality in Varecia and Lemur catta?
Cathemerality, or activity throughout the 24-hr cycle, is rare in primates yet relatively common among lemurs. However, the diverse ecological conditions under which cathemerality is expressed complicates attempts to identify species-typical behavior. For example, Lemur catta and Varecia have historically been described as diurnal, yet recent studies suggest that they might exhibit cathemeral behavior under some conditions. To investigate this variation, we monitored activity patterns among lemurs that are exposed to similar captive environments. Using MotionWatch 8 ® actigraphy data loggers, we studied 88 lemurs across seven species at the Duke Lemur Center (DLC). Six species were members of the family Lemuridae (Eulemur coronatus, E. flavifrons, E. mongoz, L. catta, V. rubra, V. variegata), while a seventh was strictly diurnal and included as an out-group (Propithecus coquereli). For each 24-hr cycle (N = 503), we generated two estimates of cathemerality: mean night (MN) activity and day/night (DN) activity ratio (day and night cutoffs were based on astronomical twilights). As expected, P. coquereli engaged in the least amount of nocturnal activity according to both measures; their activity was also outside the 95% confidence intervals of all three cathemeral Eulemur species, which exhibited the greatest evidence of cathemerality. By these estimates, Varecia activity was most similar to Eulemur and exhibited substantial deviations from P. coquereli (β (MN) = 0.22 ± SE 0.12; β (DN) = -0.21 ± SE 0.12). L. catta activity patterns also deviated from P. coquereli (β (MN) = 0.12 ± SE 0.11; β (DN) = -0.15 ± SE 0.12) but to a lesser degree than either Varecia or Eulemur. Overall, L. catta displayed an intermediate activity pattern between Eulemur and P. coquereli, which is somewhat consistent with wild studies. Regarding Varecia, although additional observations in more diverse wild habitats are needed, our findings support the existence of cathemeral behavior in this genus.


Australian midwives' attitudes towards care for women with emotional distress.
to assess Australian midwives' attitudes towards caring for women with emotional distress and their perceptions of the extent to which workplace policies and processes hindered such care. a postal survey. members of the Australian College of Midwives. 815 Australian midwives completed the survey. a modified version of the 17-item REASON questionnaire (McCall et al., 2002) that was originally developed for used by General Practitioners to measure their attitudes towards their role in the management of patients with mental health disorders. An exploratory factor analysis with Varimax rotation identified four factors that reflected midwives' (1) perceptions of systemic problems that hindered emotional care, (2) attitudes towards working with women experiencing emotional health problems, (3) perceived competence in using treatment techniques and (4) attitudes and perceived competence towards the referral of women with depression and anxiety to other health professionals. participating midwives indicated their willingness to offer assistance and acknowledged the importance of providing emotional care to women. In practice, emotional care by midwives is impeded by perceived lack of competency rather than a lack of interest. Midwives' competency in the assessment and care of women with conditions such as depression and anxiety may be enhanced through continuing professional education.


Assembly of "3D" plasmonic clusters by "2D" AFM nanomanipulation of highly uniform and smooth gold nanospheres.
Atomic force microscopy (AFM) nanomanipulation has been viewed as a deterministic method for the assembly of plasmonic metamolecules because it enables unprecedented engineering of clusters with exquisite control over particle number and geometry. Nevertheless, the dimensionality of plasmonic metamolecules via AFM nanomanipulation is limited to 2D, so as to restrict the design space of available artificial electromagnetisms. Here, we show that "2D" nanomanipulation of the AFM tip can be used to assemble "3D" plasmonic metamolecules in a versatile and deterministic way by dribbling highly spherical and smooth gold nanospheres (NSs) on a nanohole template rather than on a flat surface. Various 3D plasmonic clusters with controlled symmetry were successfully assembled with nanometer precision; the relevant 3D plasmonic modes (i.e., artificial magnetism and magnetic-based Fano resonance) were fully rationalized by both numerical calculation and dark-field spectroscopy. This templating strategy for advancing AFM nanomanipulation can be generalized to exploit the fundamental understanding of various electromagnetic 3D couplings and can serve as the basis for the design of metamolecules, metafluids, and metamaterials.


MYC overexpression induces prostatic intraepithelial neoplasia and loss of Nkx3.1 in mouse luminal epithelial cells.
Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina-features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These "Super-Lo-MYC" mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a "paradoxical" increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas.


The impact of global signal regression on resting state correlations: are anti-correlated networks introduced?
Low-frequency fluctuations in fMRI signal have been used to map several consistent resting state networks in the brain. Using the posterior cingulate cortex as a seed region, functional connectivity analyses have found not only positive correlations in the default mode network but negative correlations in another resting state network related to attentional processes. The interpretation is that the human brain is intrinsically organized into dynamic, anti-correlated functional networks. Global variations of the BOLD signal are often considered nuisance effects and are commonly removed using a general linear model (GLM) technique. This global signal regression method has been shown to introduce negative activation measures in standard fMRI analyses. The topic of this paper is whether such a correction technique could be the cause of anti-correlated resting state networks in functional connectivity analyses. Here we show that, after global signal regression, correlation values to a seed voxel must sum to a negative value. Simulations also show that small phase differences between regions can lead to spurious negative correlation values. A combination breath holding and visual task demonstrates that the relative phase of global and local signals can affect connectivity measures and that, experimentally, global signal regression leads to bell-shaped correlation value distributions, centred on zero. Finally, analyses of negatively correlated networks in resting state data show that global signal regression is most likely the cause of anti-correlations. These results call into question the interpretation of negatively correlated regions in the brain when using global signal regression as an initial processing step.


Iron Bioavailability Studies of the First Generation of Iron-Biofortified Beans Released in Rwanda.
This paper represents a series of in vitro iron (Fe) bioavailability experiments, Fe content analysis and polyphenolic profile of the first generation of Fe biofortified beans (Phaseolus vulgaris) selected for human trials in Rwanda and released to farmers of that region. The objective of the present study was to demonstrate how the Caco-2 cell bioassay for Fe bioavailability can be utilized to assess the nutritional quality of Fe in such varieties and how they may interact with diets and meal plans of experimental studies. Furthermore, experiments were also conducted to directly compare this in vitro approach with specific human absorption studies of these Fe biofortified beans. The results show that other foods consumed with beans, such as rice, can negatively affect Fe bioavailability whereas potato may enhance the Fe absorption when consumed with beans. The results also suggest that the extrinsic labelling approach to measuring human Fe absorption can be flawed and thus provide misleading information. Overall, the results provide evidence that the Caco-2 cell bioassay represents an effective approach to evaluate the nutritional quality of Fe-biofortified beans, both separate from and within a targeted diet or meal plan.


Expression of the "stem cell marker" CD133 in pancreas and pancreatic ductal adenocarcinomas.
It has been suggested that a small population of cells with unique self-renewal properties and malignant potential exists in solid tumors. Such "cancer stem cells" have been isolated by flow cytometry, followed by xenograft studies of their tumor-initiating properties. A frequently used sorting marker in these experiments is the cell surface protein CD133 (prominin-1). The aim of this work was to examine the distribution of CD133 in pancreatic exocrine cancer. Fifty-one cases of pancreatic ductal adenocarcinomas were clinically and histopathologically evaluated, and immunohistochemically investigated for expression of CD133, cytokeratin 19 and chromogranin A. The results were interpreted on the background of CD133 expression in normal pancreas and other normal and malignant human tissues. CD133 positivity could not be related to a specific embryonic layer of organ origin and was seen mainly at the apical/endoluminal surface of non-squamous, glandular epithelia and of malignant cells in ductal arrangement. Cytoplasmic CD133 staining was observed in some non-epithelial malignancies. In the pancreas, we found CD133 expressed on the apical membrane of ductal cells. In a small subset of ductal cells and in cells in centroacinar position, we also observed expression in the cytoplasm. Pancreatic ductal adenocarcinomas showed a varying degree of apical cell surface CD133 expression, and cytoplasmic staining in a few tumor cells was noted. There was no correlation between the level of CD133 expression and patient survival. Neither in the pancreas nor in the other investigated organs can CD133 membrane expression alone be a criterion for "stemness". However, there was an interesting difference in subcellular localization with a minor cell population in normal and malignant pancreatic tissue showing cytoplasmic expression. Moreover, since CD133 was expressed in shed ductal cells of pancreatic tumors and was found on the surface of tumor cells in vessels, this molecule may have a potential as clinical marker in patients suffering from pancreatic cancer.


Fatal outcome in Japanese encephalitis.
Forty-nine consecutive patients with laboratory-confirmed acute Japanese encephalitis were studied to identify risk factors present at hospital admission which were associated with a fatal outcome. Sixteen patients (33%) died. The following constellation of findings correlated with a fatal outcome: infectious virus in cerebrospinal fluid (CSF), low levels of Japanese encephalitis virus-specific IgG and IgM in both CSF and serum, and a severely depressed sensorium. Age, sex, days ill before admission, distance from home to the hospital, past medical history, CSF protein content, and CSF leukocyte count were not significant risk factors. Among patients hospitalized for acute Japanese encephalitis, a vigorous virus-specific immunoglobulin response, both systemically and locally within the central nervous system, is a good marker for survival, and may be an inherently important factor in recovery from illness.


A MEMS light modulator based on diffractive nanohole gratings.
We present the design, fabrication, and testing of a microelectromechanical systems (MEMS) light modulator based on pixels patterned with periodic nanohole arrays. Flexure-suspended silicon pixels are patterned with a two dimensional array of 150 nm diameter nanoholes using nanoimprint lithography. A top glass plate assembled above the pixel array is used to provide a counter electrode for electrostatic actuation. The nanohole pattern is designed so that normally-incident light is coupled into an in-plane grating resonance, resulting in an optical stop-band at a desired wavelength. When the pixel is switched into contact with the top plate, the pixel becomes highly reflective. A 3:1 contrast ratio at the resonant wavelength is demonstrated for gratings patterned on bulk Si substrates. The switching time is 0.08 ms and the switching voltage is less than 15V.


Self-recognition, color signals, and cycles of greenbeard mutualism and altruism.
Altruism presents a challenge to evolutionary theory because selection should favor selfish over caring strategies. Greenbeard altruism resolves this paradox by allowing cooperators to identify individuals carrying similar alleles producing a form of genic selection. In side-blotched lizards, genetically similar but unrelated blue male morphs settle on adjacent territories and cooperate. Here we show that payoffs of cooperation depend on asymmetric costs of orange neighbors. One blue male experiences low fitness and buffers his unrelated partner from aggressive orange males despite the potential benefits of defection. We show that recognition behavior is highly heritable in nature, and we map genetic factors underlying color and self-recognition behavior of genetic similarity in both sexes. Recognition and cooperation arise from genome-wide factors based on our mapping study of the location of genes responsible for self-recognition behavior, recognition of blue color, and the color locus. Our results provide an example of greenbeard interactions in a vertebrate that are typified by cycles of greenbeard mutualism interspersed with phases of transient true altruism. Such cycles provide a mechanism encouraging the origin and stability of true altruism.


Impact of pretransplantation conditioning regimens on outcomes of allogeneic transplantation for chemotherapy-unresponsive diffuse large B cell lymphoma and grade III follicular lymphoma.
Patients with chemorefractory non-Hodgkin lymphomas generally have a poor prognosis. We used the observational database of the Center for International Blood and Marrow Transplant Research to study the outcome of 533 patients with refractory diffuse large B cell lymphoma (DLBCL) or grade III follicular lymphoma (FL-III) who underwent allogeneic hematopoietic cell transplantation (allo-HCT) using either myeloablative (MA; n = 307) or reduced-intensity/nonmyeloablative conditioning (RIC/NST; n = 226) between 1998 and 2010. We analyzed nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Only 45% of the patients at transplantation had a Karnofsky performance score of ≥90%. Median follow-up of surviving patients after MA and RIC/NST allo-HCT is 35 months and 30 months, respectively. At 3 years, MA allo-HCT was associated with a higher NRM compared with RIC/NST (53% versus 42%; P = .03), similar PFS (19% versus 23%; P = .40), and lower OS (19% versus 28%; P = .02), respectively. On multivariate analysis, FL-III histology was associated with lower NRM (relative risk [RR], .52), reduced risk of relapse/progression (RR, .42), and superior PFS (RR, .51) and OS (RR, .53), whereas MA conditioning was associated with reduced risk of relapse/progression (RR, .66). Despite a refractory state, a small subset of DLBCL and FL-III patients can attain durable remissions after allo-HCT. Conditioning regimen intensity was not associated with PFS and OS despite a higher risk of relapse/progression with RIC/NST allo-HCT.


Nine-point plan to improve care of the injured patient: A case study from Kenya.
Injury rates in low- and middle-income countries are among the greatest in the world, with >90% of unintentional injury occurring in low- or middle-income countries. The risk of death from injuries is 6 times more in low- and middle-income countries than in high-income countries. This increased rate of injury is partly due to the lack of availability and access to timely and appropriate medical care for injured individuals. Kenya, like most low- and middle-income countries, has seen a 5-fold increase in injury fatalities throughout the past 4 decades, in large part related to the absence of a coordinated, integrated system of trauma care. We aimed to assess the trauma-care system in Kenya and to develop and implement a plan to improve it. A trauma system profile was performed to understand the landscape for the care of the injured patient in Kenya. This process helped identify key gaps in care ranging from prehospital to hospital-based care. In response to this observation, a 9-point plan to improve trauma care in Kenya was developed and implemented in close collaboration with local stakeholders. The 9-point plan was centered on engagement of the stakeholders, generation of key data to guide and improve services, capacity development for prehospital and hospital care, and strengthening policy and legislation. There is an urgent need for coordinated strategies to provide appropriate and timely medical care to injured individuals in low- or middle-income countries to decrease the burden of injuries and related fatalities. Our work in Kenya shows that such an integrated system of trauma care could be achieved through a step-by-step integrated and multifaceted approach that emphasizes engagement of local stakeholders and evidence-based approaches to ensure effectiveness, efficiency, and sustainability of system-wide improvements. This plan and lessons learned in its development and implementation could be adaptable to other similar settings to improve the care of the injured patient in low- or middle-income countries.


Glycyrrhizin inhibits human parainfluenza virus type 2 replication by the inhibition of genome RNA, mRNA and protein syntheses.
The effect of glycyrrhizin on the replication of human parainfluenza virus type 2 (hPIV-2) was examined. Cell fusion induced by hPIV-2 was inhibited by glycyrrhizin, and glycyrrhizin reduced the number of viruses released from the cells. Glycyrrhizin did not change cell morphology at 1 day of culture, but caused some damage at 4 days, as determined by the effect on actin microfilaments. However, it affected the cell viability at 1 day: about 20% of the cells were not alive by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay at 1 day of culture. Real-time polymerase chain reaction (PCR) and PCR showed that virus genome synthesis was largely inhibited. mRNA synthesis was also inhibited by glycyrrhizin. Viral protein synthesis was largely inhibited as observed by an indirect immunofluorescence study. Multinucleated giant cell formation was studied using a recombinant green fluorescence protein (GFP)-expressing hPIV-2 without matrix protein (rhPIV-2ΔMGFP). A few single cells with fluorescence were observed, but the formation of giant cells was completely blocked. Taken together, it was shown that viral genome, mRNA and protein syntheses, including F and HN proteins, were inhibited by glycyrrhizin, and consequently multinucleated giant cell formation was not observed and the infectious virus was not detected in the culture medium.


The Swedish two county trial of mammographic screening for breast cancer: recent results and calculation of benefit.
The Swedish two county trial of breast cancer screening is now in its tenth year. This paper presents detailed results on mortality from breast cancer and from all other causes, and on the population denominators at risk for each of the first 8 years of follow up, for each county separately. These data represent a two year update on the last major report. Results show an increasingly significant deficit in deaths from breast cancer among the 77,092 women invited to screening relative to the 56,000 not invited (RR = 0.68, p = 0.002), with no significant difference between the effects of screening in the two counties (p = 0.5). These results remain the same when adjusted for age. Analysis of all cause deaths shows no significant effect of screening (p = 0.5), nor was there any significant effect of screening on deaths from all causes other than breast cancer (p = 0.9). The rates of deaths from intercurrent illness in breast cancer cases were almost identical in the group invited to screening and the group not invited (p = 0.7). This result remained the same when adjusted for age. We calculate that in the age group 50-69 at entry, one breast cancer death was prevented per 4000 woman/years, per 1460 mammographic examinations, per 13.5 biopsies, and per 7.4 breast cancers detected.


Identification of medicinal mushroom species based on nuclear large subunit rDNA sequences.
The purpose of this study was to develop molecular identification method for medical mushrooms and their preparations based on the nucleotide sequences of nuclear large subunit (LSU) rDNA. Four specimens were collected of each of the three representative medicinal mushrooms used in Korea: Ganoderma lucidum, Coriolus versicolor, and Fomes fomentarius. Fungal material used in these experiments included two different mycelial cultures and two different fruiting bodies from wild or cultivated mushrooms. The genomic DNA of mushrooms were extracted and 3 nuclear LSU rDNA fragments were amplified: set 1 for the 1.1-kb DNA fragment in the upstream region, set 2 for the 1.2-kb fragment in the middle, and set 3 for the 1.3-kb fragment downstream. The amplified gene products of nuclear large subunit rDNA from 3 different mushrooms were cloned into E. coli vector and subjected to nucleotide sequence determination. The sequence thus determined revealed that the gene sequences of the same medicinal mushroom species were more than 99.48% homologous, and the consensus sequences of 3 different medicinal mushrooms were more than 97.80% homologous. Restriction analysis revealed no useful restriction sites for 6-bp recognition enzymes for distinguishing the 3 sequences from one another, but some distinctive restriction patterns were recognized by the 4-bp recognition enzymes AccII and HhaI. This analysis was also confirmed by PCR-RFLP experiments on medicinal mushrooms.


Teaching young nonverbal children with autism useful speech: a pilot study of the Denver Model and PROMPT interventions.
This single subject design study examined two models of intervention: Denver Model (which merges behavioral, developmental, and relationship-oriented intervention), and PROMPT (a neuro-developmental approach for speech production disorders). Ten young, nonverbal children with autism were matched in pairs and randomized to treatment. They received 12 1-h weekly sessions of therapy and daily 1-h home intervention delivered by parents. Fidelity criteria were maintained throughout. Eight of the ten children used five or more novel, functional words spontaneously and spoke multiple times per hour by the conclusion of treatment. There were no differences in acquired language skills by intervention group. Initial characteristics of the best responders were mild to moderate symptoms of autism, better motor imitation skills, and emerging joint attention skills.


Characterisation of inositol 1,4,5-trisphosphate binding sites in rabbit aortic smooth muscle.
The present study investigated the characteristics of D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) binding sites in crude membrane preparations of rabbit aortic smooth muscle. A particular aim was to demonstrate if increases in cytoplasmic cyclic guanosine 3':5' monophosphate (cGMP), which mediates the effect of nitrovasodilators, may cause smooth muscle relaxation in part by the displacement of Ins(1,4,5)P3 binding. Negligible Ins(1,4,5)P3 binding was observed at pH < 7, while maximum binding occurred over the pH range 8-9. Saturation analysis of isotopic dilution binding data revealed an apparently homogenous population of Ins(1,4,5)P3 binding sites with a KD of 4.02 +/- 0.53 nM and a Bmax of 27.7 +/- 4.6 fmol/mg protein. Heparin, an Ins(1,4,5)P3 receptor antagonist, inhibited binding with an IC50 of 11.43 +/- 2.81 micrograms/ml. The ability of other polyphosphate compounds to inhibit Ins(1,4,5)P3 binding in this preparation was also examined. D-myo-Inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), adenosine 5'-triphosphate (ATP) and guanosine 5'-triphosphate (GTP) inhibited Ins(1,4,5)P3 binding, although each was significantly less potent that Ins(1,4,5)P3. In contrast, cyclic guanosine 3':5' monophosphate (cGMP) did not significantly alter Ins(1,4,5)P3 binding in rabbit aortic smooth muscle. This observation suggests that competitive inhibition of Ins(1,4,5)P3 receptor binding is not an important consideration in cGMP-mediated vascular smooth muscle cell relaxation.


Idiopathic pulmonary fibrosis in infants: good prognosis with conservative management.
Pulmonary interstitial fibrosis in children is a disease of unknown aetiology, usually associated with a poor prognosis. In this case series we describe 11 children presenting over a 10 year period, managed conservatively and associated with a good prognosis. In six, symptoms were present from birth and 10 had symptoms at or before 3 months. Diagnosis was made using chest computed tomography and percutaneous lung biopsy. All patients were treated with oral prednisolone. In five no steroid response was noted. One patient responded to hydroxychloroquine. Home oxygen was required in five patients. At follow up all patients are alive at a median age of 6 years (range 1 to 12 years). The two recently diagnosed children have significant symptoms, seven have dyspnoea on exercise, and two are symptom free. The good prognosis seen in these patients is different to previous case reports, indicating a greater than 50% mortality.


Association of excessive mobile phone use during pregnancy with birth weight: an adjunct study in Kumamoto of Japan Environment and Children's Study.
Low birth weight has been shown to be closely associated with neonatal mortality and morbidity, inhibited growth, poor cognitive development, and chronic diseases later in life. Some studies have also shown that excessive mobile phone use in the postnatal period may lead to behavioral complications in the children during their growing years; however, the relationship between mobile phone use during pregnancy and neonatal birth weight is not clear. The aim of the present study was to determine the associations of excessive mobile phone use with neonatal birth weight and infant health status. A sample of 461 mother and child pairs participated in a survey on maternal characteristics, infant characteristics, and maternal mobile phone usage information during pregnancy. Our results showed that pregnant women tend to excessively use mobile phones in Japan. The mean infant birth weight was lower in the excessive use group than in the ordinary use group, and the frequency of infant emergency transport was significantly higher in the excessive use group than in the ordinary use group. Excessive mobile phone use during pregnancy may be a risk factor for lower birth weight and a high rate of infant emergency transport.


Amputation, phantom pain and subjective well-being: a qualitative study.
The purpose of this qualitative study was to explore the impact of an amputation and of phantom pain on the subjective well-being of amputees. Sixteen lower-limb amputees were interviewed. A semi-structured interview and two Visual Analogue Scales were used. To interpret the results, a new socio-medical model joining two models, 'The Disablement Process model' and the 'Social Production Function theory', was used. Questions were asked concerning the factors influencing patients' subjective well-being prior to, at the time of and after an amputation. These factors were patients' medical history, their phantom sensations and phantom pain, their daily activities, the social support they received, and the influence of an amputation and phantom pain on long-term behaviour and on their subjective well-being. All factors were found to have an influence on the individual's subjective well-being. All these factors, however, seemed to reinforce each other. Therefore, the greatest influence of factors on subjective well-being occurred when more than one factor was involved. Substituting certain activities by others then becomes less and less effective in inducing a sense of subjective well-being.


Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor.
The activating transcription factor-4 (ATF-4) is translationally induced under anoxic conditions, mediates part of the unfolded protein response following endoplasmic reticulum (ER) stress, and is a critical regulator of cell fate. Here, we identified the zipper II domain of ATF-4 to interact with the oxygen sensor prolyl-4-hydroxylase domain 3 (PHD3). The PHD inhibitors dimethyloxalylglycine (DMOG) and hypoxia, or proteasomal inhibition, all induced ATF-4 protein levels. Hypoxic induction of ATF-4 was due to increased protein stability, but was independent of the ubiquitin ligase von Hippel-Lindau protein (pVHL). A novel oxygen-dependent degradation (ODD) domain was identified adjacent to the zipper II domain. Mutations of 5 prolyl residues within this ODD domain or siRNA-mediated down-regulation of PHD3, but not of PHD2, was sufficient to stabilize ATF-4 under normoxic conditions. These data demonstrate that PHD-dependent oxygen-sensing recruits both the hypoxia-inducible factor (HIF) and ATF-4 systems, and hence not only confers adaptive responses but also cell fate decisions.


The association of erythroblasts with macrophages promotes erythroid proliferation and maturation: a 30-kD heparin-binding protein is involved in this contact.
Although the association of erythroblasts with macrophages has been well documented in the human bone marrow, the function and identification of the intimate contacts occurring between the membranes of these two cell types in the physiology of erythropoiesis is not known. Using in vitro cultures of human peripheral blood derived erythroid progenitors, we have shown the presence of erythroblastic islands consisting of a central macrophage surrounded by a ring of erythroblasts that undergo terminal maturation leading to enucleation. However, when cultures were carried in the absence of intact macrophages, erythroid cells matured to the late erythroblast stage but failed to enucleate. Furthermore, the number of erythroid cells was markedly reduced in macrophage-depleted cultures, suggesting that the erythroblast-macrophage contact promotes proliferation and terminal maturation of erythroid cells leading to their enucleation. To examine the molecule(s) involved in the interaction between erythroblasts and macrophages, we have used a cell attachment assay involving incubation of solubilized surface-labeled erythroblasts with macrophage membrane proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to a nitrocellulose membrane. Erythroblast surface proteins specifically attached to a 30-kD protein from macrophage membranes, whereas no adhesion was seen to the protein standards. An apparently similar protein of 30 kD was also detected on erythroblasts and was shown to mediate erythroblast-erythroblast contact in addition to the erythroblast-macrophage contact. The extraction of plasma membranes with Triton X-100 showed that the 30-kD protein is linked to the membrane skeleton via an integral membrane protein both in erythroblasts and macrophages. Furthermore, our results show that the cell:cell interactions mediated by the 30-kD protein are calcium-independent and could be specifically inhibited by heparin. We conclude that the association of erythroblasts with macrophages promotes erythroid proliferation and maturation leading to erythroblast enucleation and that a 30-kD heparin-binding protein present on the surface of macrophages and erythroblasts is involved in this contact. This protein is capable of binding homotypic and heterotypic cells.


Analytical approaches for monitoring exposure to organophosphorus and carbamate agents through analysis of protein adducts.
Appropriate treatment of a poisoned patient requires knowing the identity of the poison. This review summarizes the methods for identifying poisoning by organophosphorus and carbamate poisons. Mass spectrometry methods identify the poison from the adducts they form with proteins in blood. The most sensitive method uses potassium fluoride to release the organophosphorus agent from its covalent binding to serine 198 of human butyrylcholinesterase. The released poison is identified by gas chromatography-mass spectrometry. The drawback of this method is that it does not detect exposure to agents such as soman, because butyrylcholinesterase adducts with these agents age to a non-reactivatable form. A method that detects both aged and non-aged organophosphylated adducts as well as carbamate adducts is one that digests butyrylcholinesterase with a protease and analyzes the modified peptide by mass spectrometry. This method does not distinguish between poisons that have the same mass after reaction with butyrylcholinesterase--for example, between exposure to chlorpyrifos oxon and paraoxon. Albumin forms a stable, covalent bond with organophosphates on tyrosine 411. The rate of reaction with albumin is much slower than with butyrylcholinesterase, but albumin adducts persist for a longer time in the circulation; they do not age; and they do not release the organophosphate when a patient is treated with an oxime.


Laparoscopic adjustable gastric banding for the treatment of morbid (grade 3) obesity and its metabolic complications: a three-year study.
Weight loss ameliorates arterial hypertension and glucose metabolism in obese patients, but the dietary approach is unsatisfactory because obesity relapses. Durable reduction of body weight, obtained through major nonreversible surgical procedures, such as jejunal and gastric bypass, allows improvement of glucose metabolism and arterial blood pressure in morbid (grade 3) obesity. Laparoscopic adjustable gastric banding (LAGB) is a minimally invasive and reversible surgical procedure that yields a significant reduction of gastric volume and hunger sensation. In this study, 143 patients with grade 3 obesity [27 men and 116 women; age, 42.9 +/- 0.83 yr; body mass index (BMI), 44.9 +/- 0.53 kg/m(2); normal glucose tolerance (NGT; n = 77); impaired glucose tolerance (IGT; n = 47); type 2 diabetes mellitus (T2DM; n = 19)] underwent LAGB and a 3-yr follow-up for clinical (BMI, waist circumference, waist to hip ratio, and arterial blood pressure) and metabolic variables (glycosylated hemoglobin, fasting insulin and glucose, insulin and glucose response to oral glucose tolerance test, homeostasis model assessment index, total and high-density lipoprotein cholesterol, triglycerides, uric acid, and transaminases). At baseline and 1 yr after LAGB, patients underwent computerized tomography and ultrasound evaluation of visceral and sc adipose tissue. One-year metabolic results were compared with 120 obese patients (51 men and 69 women; age, 42.9 +/- 1.11 yr; BMI, 43.6 +/- 0.46 kg/m(2); NGT, n = 66; IGT, n = 8; T2DM, n = 46) receiving standard dietary treatment. LAGB induced a significant and persistent weight loss and decrease of blood pressure. Greater metabolic effects were observed in T2DM patients than in NGT and IGT patients, so that at 3 yr glycosylated hemoglobin was no longer different in NGT and T2DM subjects. Clinical and metabolic improvements were proportional to the amount of weight loss. LAGB induced a greater reduction of visceral fat than sc fat. At 1-yr evaluation, weight loss and metabolic improvements were greater in LAGB-treated than diet-treated patients. We conclude that LAGB is an effective treatment of grade 3 obesity in inducing long-lasting reduction of body weight and arterial blood pressure, modifying body fat distribution, and improving glucose and lipid metabolism, especially in T2DM.


Astaxanthin Inhibits Mitochondrial Dysfunction and Interleukin-8 Expression in Helicobacter pylori-Infected Gastric Epithelial Cells.
Helicobacter pylori (H. pylori) infection leads to gastric inflammation, peptic ulcer and gastric carcinoma. H. pylori activates NADPH oxidase and increases reactive oxygen species (ROS), which induce NF-κB activation and IL-8 expression in gastric epithelial cells. Dysfunctional mitochondria trigger inflammatory cytokine production. Peroxisome proliferator-activated receptors-γ (PPAR-γ) regulate inflammatory response. Astaxanthin is a powerful antioxidant that protects cells against oxidative stress. The present study was aimed at determining whether astaxanthin inhibits H. pylori-induced mitochondrial dysfunction, NF-κB activation, and IL-8 expression via PPAR-γ activation in gastric epithelial cells. Gastric epithelial AGS cells were treated with astaxanthin, NADPH oxidase inhibitor apocynin and PPAR-γ antagonist GW9662, and infected with H. pylori. As a result, H. pylori caused an increase in intracellular and mitochondrial ROS, NF-κB activation and IL-8 expression, but decreased mitochondrial membrane potential and ATP level. Astaxanthin inhibited H. pylori-induced alterations (increased ROS, mitochondrial dysfunction, NF-κB activation, and IL-8 expression). Astaxanthin activated PPAR-γ and its target gene catalase in H. pylori-infected cells. Apocynin reduced ROS and inhibited IL-8 expression while astaxanthin did not affect NADPH oxidase activity. Inhibitory effects of astaxanthin on ROS levels and IL-8 expression were suppressed by addition of GW9662. In conclusion, astaxanthin inhibits H. pylori-induced mitochondrial dysfunction and ROS-mediated IL-8 expression by activating PPAR-γ and catalase in gastric epithelial cells. Astaxanthin may be beneficial for preventing oxidative stress-mediated gastric inflammation-associated H. pylori infection.


Effects of Tart Cherry Juice on Biomarkers of Inflammation and Oxidative Stress in Older Adults.
Inflammation and oxidative stress are important factors in the development of cardiovascular disease and atherosclerosis. The findings of our previous study suggest that 12 weeks consumption of tart cherry juice lowers the levels of systolic blood pressure (BP) and low-density lipoprotein (LDL) cholesterol in older adults. The present study investigated the effects of tart cherry juice on blood biomarkers of inflammation and oxidative stress. In this randomized-controlled clinical trial, a total of 37 men and women between the ages of 65⁻80 were randomly assigned to consume 480 mL of tart cherry juice or control drink daily for 12 weeks. Several blood biomarkers of inflammation and oxidative stress were assessed at baseline and after 12 weeks intervention. After the 12 weeks intervention, tart cherry juice significantly increased the plasma levels of DNA repair activity of 8-oxoguanine glycosylase (p < 0.0001) and lowered (p = 0.03) the mean c-reactive protein (CRP) level compared to the control group. There was a significant group effect observed for plasma CRP (p = 0.03) and malondialdehyde (MDA) (p = 0.03), and a borderline significant group effect observed for plasma oxidized low-density lipoprotein (OxLDL) (p = 0.07). Within group analysis showed that the plasma levels of CRP, MDA, and OxLDL decreased numerically by 25%, 3%, and 11%, respectively after 12 weeks of tart cherry juice consumption compared with corresponding baseline values. The present study suggests that the ability of tart cherry juice to reduce systolic BP and LDL cholesterol, in part, may be due to its anti-oxidative and anti-inflammatory properties. Larger and longer follow-up studies are needed to confirm these findings.


Patient preferences and quality of life associated with colorectal cancer screening.
The goal of this study was to describe the attitudes of patients toward colorectal cancer screening, colon cancer, and colostomy. Using the time trade-off technique, we interviewed four groups of patients at a veterans' hospital: 1) 46 patients with colorectal cancer, 2) 24 patients undergoing screening sigmoidoscopy, 3) 114 subjects participating in a screening colonoscopy study, and 4) 62 patients who have never undergone endoscopic screening for colorectal cancer. Using this technique, we measured quality of life for six scenarios pertaining to screening for colorectal cancer, the patient's current health, colorectal cancer, and colostomy. Unscreened patients were willing to give up significantly more time to avoid screening sigmoidoscopy and colonoscopy (median 91 days and 183 days, respectively) than were patients undergoing screening sigmoidoscopy (median 0 days and 7 days, respectively), screening colonoscopy (median 0 days and 0 days, respectively), or patients with colorectal cancer (median 0 days and 0 days, respectively). Cancer patients rated their current health state lower than volunteers for screening. Colon cancer and colostomy were rated similarly by all four groups. Substantial variation in patient attitudes was present in all groups. Patients are generally very accepting of endoscopic screening for colorectal cancer. However, decisions regarding recommendations for colorectal cancer screening must take into account the variability in patient preferences. Effective alternative strategies should be available for those whose preferences do not comply with standard recommendations. The effect of patient education and physician recommendations on subjects' attitudes toward screening warrants further investigation.


Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins.
Inside-out signaling regulation of the beta2-integrin leukocyte function-associated antigen-1 (LFA-1) by different cytoplasmic proteins, including 14-3-3 proteins, is essential for adhesion and migration of immune cells. Here, we identify a new pathway for the regulation of LFA-1 activity by Cbl-b, an adapter molecule and ubiquitin ligase that modulates several signaling pathways. Cbl-b-/- mice displayed increased macrophage recruitment in thioglycollate-induced peritonitis, which was attributed to Cbl-b deficiency in macrophages, as assessed by bone marrow chimera experiments. In vitro, Cbl-b-/- bone marrow-derived mononuclear phagocytes (BMDMs) displayed increased adhesion to endothelial cells. Activation of LFA-1 in Cbl-b-deficient cells was responsible for their increased endothelial adhesion in vitro and peritoneal recruitment in vivo, as the phenotype of Cbl-b deficiency was reversed in Cbl-b-/-LFA-1-/- mice. Consistently, LFA-1-mediated adhesion of BMDM to ICAM-1 but not VLA-4-mediated adhesion to VCAM-1 was enhanced by Cbl-b deficiency. Cbl-b deficiency resulted in increased phosphorylation of T758 in the beta2-chain of LFA-1 and thereby in enhanced association of 14-3-3beta protein with the beta2-chain, leading to activation of LFA-1. Consistently, disruption of the 14-3-3/beta2-integrin interaction abrogated the enhanced ICAM-1 adhesion of Cbl-b-/- BMDMs. In conclusion, Cbl-b deficiency activates LFA-1 and LFA-1-mediated inflammatory cell recruitment by stimulating the interaction between the LFA-1 beta-chain and 14-3-3 proteins.


High-pressure glass formation of a series of 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide homologues.
We investigated the stability of the liquid phase of a series of 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([Cnmim][TFSI]) homologues with different alkyl chain lengths for 3 ≤ n ≤ 10 at room temperature. We found that all [Cnmim][TFSI] samples (n = 3-10) formed a glassy state when pressure was applied. Intriguingly, the glass transition pressure (pg) slightly increases up to n = 5, reaches a plateau at n ≧ 8, and increases again at n = 10. This is completely different from the high-pressure glass formation of [Cnmim][BF4], where the pg decreases as n increases. We discussed the local structural changes occurring in [Cnmim][TFSI] in view of the conformational changes of the cation and anion, and small-angle X-ray scattering data. It seems that [Cnmim][TFSI] is resistant to external pressure and retains its local liquid structure by conformational adjustments of the cation and anion.


Women's self-reported experiences using misoprostol obtained from drug sellers: a prospective cohort study in Lagos State, Nigeria.
This study aimed to assess the safety and effectiveness of self-managed misoprostol abortions obtained outside of the formal health system in Lagos State, Nigeria. This was a prospective cohort study among women using misoprostol-containing medications purchased from drug sellers. Three telephone-administered surveys were conducted over 1 month. Data were collected in 2018 in six local government areas in Lagos State. Drug sellers attempted to recruit all women who purchased misoprostol-containing medication. To remain in the study, participants had to be female and aged 18-49, and had to have purchased the medication for the purpose of abortion. Of 501 women initially recruited, 446 were eligible for the full study, and 394 completed all three surveys. Using self-reported measures, we assessed the quality of information provided by drug sellers; the prevalence of potential complications; and the proportion with completed abortions. Although drug sellers provided inadequate information about the pills, 94% of the sample reported a complete abortion without surgical intervention about 1 month after taking the medication. Assuming a conservative scenario where all individuals lost to follow-up had failed terminations, the completion rate dropped to 87%. While 86 women reported physical symptoms suggestive of complications, only six of them reported wanting or needing health facility care and four subsequently obtained care. Drug sellers are an important source of medical abortion in this setting. Despite the limitations of self-report, many women appear to have effectively self-administered misoprostol. Additional research is needed to expand the evidence on the safety and effectiveness of self-use of misoprostol for abortion in restrictive settings, and to inform approaches that support the health and well-being of people who use this method of abortion.


Control and reversal of the electrophoretic force on DNA in a charged nanopore.
Electric field driven transport of DNA through solid-state nanopores is the key process in nanopore-based DNA sequencing that promises dramatic reduction of genome sequencing costs. A major hurdle in the development of this sequencing method is that DNA transport through the nanopores occurs too quickly for the DNA sequence to be detected. By means of all-atom molecular dynamics simulations, we demonstrate that the velocity of DNA transport through a nanopore can be controlled by the charge state of the nanopore surface. In particular, we show that the charge density of the nanopore surface controls the magnitude and/or direction of the electro-osmotic flow through the nanopore and thereby can significantly reduce or even reverse the effective electrophoretic force on DNA. Our work suggests a physical mechanism to control DNA transport in a nanopore by chemical, electrical or electrochemical modification of the nanopore surface.


Rapid detection of diagnostic targets using isothermal amplification and HyBeacon probes--a homogenous system for sequence-specific detection.
Isothermal amplification is a rapid, simple alternative to PCR, with amplification commonly detected using fluorescently labelled oligonucleotide probes, intercalating dyes or increased turbidity as a result of magnesium pyrophosphate generation. SNP identification is possible but requires either allele-specific primers or multiple dye-labelled probes, but further downstream processing is often required for allelic identification. Here we demonstrate that modification of common isothermal amplification methods by the addition of HyBeacon probes permits homogeneous sequence detection and discrimination by melting or annealing curve analysis. Furthermore, we demonstrate that isothermal amplification and sequence discrimination is possible directly from a crude sample such as an expressed buccal swab.


Evaluation of all Types of Metabolic Bariatric Surgery and its Consequences: a Systematic Review and Meta-Analysis.
Considering conflicting results on the consequences of all types of obesity surgery, we were to summarize them via a systematic review. Electronic literature search was done via scientific search engines. After the removal of duplicates and selection of articles of interest, 771 studies were included. Insulin resistance indicators were significantly improved after bariatric surgery. Leptin was also significantly decreased while adiponectin was significantly increased. Although the level of metabolic hormones changed after bariatric surgery, they were not statistically significant. Inflammation indicators were significantly decreased. Significant reduction was also detected in PAI-1 and sICAM-1. Bariatric surgery is beneficial in morbidly obese patients. Although treating obesity in a surgical way may cause some complications, the weight loss is generally safe and effective.


Thyroid function in a hibernator, Spermophilus tridecemlineatus.
Thyroid hormone secretion (assessed as thyroid 125I release rate) was monitored in Spermophilus tridecemlineatus from summer to winter (July-December) in 1973. The average release rate in July was 2.3% per day, but in August this rate decreased significantly and remained at an average 0.52% per day until December. This low rate (being similar to that of hypophysectomized rats), and the absence of any change in oxygen consumption following thyroidectomy, suggested hormone secretion was "turned off" during this period. During the period August-December, four S. tridecemlineatus showed normal thermoregulatory responses to anterior hypothalamic cooling but no thyroidal response whether restrained, unrestrained, or anesthetized. Thyroid 125I uptake (and presumably hormone manufacture) continued during the period August-December and 24-h uptake averaged 27.0% in December. Possible reasons for "turning off" thyroid hormone secretion are discussed, and it is concluded this is to allow the membrane fatty acids to revert to a less-saturated condition in preparation for low body temperatures during hibernation.


Rickettsia rickettsii (Rickettsiales: Rickettsiaceae) Infecting Amblyomma sculptum (Acari: Ixodidae) Ticks and Capybaras in a Brazilian Spotted Fever-Endemic Area of Brazil.
The bacterium Rickettsia rickettsii is the agent of Brazilian spotted fever (BSF), a highly fatal disease that is transmitted in Brazil mainly by the tick Amblyomma sculptum Berlese, which uses capybaras (Hydrochoerus hydrochaeris Linnaeus) as major hosts. In 2015, we captured nine capybaras in a BSF-endemic area of southeastern Brazil. From each capybara, we collected blood sera that were tested through the immunofluorescence assay using Rickettsia spp. antigens, and A. sculptum ticks, processed for isolation of R. rickettsii through guinea pig inoculation. All capybaras (100%) were seroreactive to Rickettsia spp., with highest titers to R. rickettsii. A total of 166 A. sculptum ticks were macerated and inoculated into nine guinea pigs, from which only one presented high fever and seroconverted to R. rickettsii. Blood from this febrile animal was inoculated into additional guinea pigs (guinea pig passages), which also became febrile and seroconverted, or when euthanized during the fever period, their internal organs (spleen, lung) were shown to contain R. rickettsii DNA. The present rickettsial isolate has been maintained cryopreserved as infected guinea pig organs. There was at least one R. rickettsii-infected tick among the 166 macerated ticks, giving a minimal infection rate of 0.6% (1/166). This infection rate is within the range of previous studies, which reported that only 0.05% to at most 1.28% A. sculptum ticks were infected by R. rickettsii in other BSF-endemic areas. These low infection rates support the low incidence of BSF, despite of A. sculptum being the most frequent human-biting tick in southeastern Brazil.


Characterization of bony anatomic regions in pediatric and adult healthy volunteers using diffuse optical spectroscopic imaging.
Diffuse optical spectroscopic imaging (DOSI) measures quantitative functional and molecular information in thick tissue in a noninvasive manner using near-infrared light. DOSI may be useful for diagnosis and prognosis of bone pathologies including osteosarcoma and Ewing's sarcoma, but little is currently known about DOSI-derived parameters in bony anatomic locations where this disease occurs. Our goal is to quantify the optical characteristics and chromophore content of bony anatomic locations of healthy volunteers and assess differences due to anatomic region, age, sex, ethnicity, race, and body fat. Fifty-five healthy volunteers aged 4 to 72 were enrolled in the study. The optical properties and quantitative tissue concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipids were assessed at the distal humerus, distal femur, and proximal tibia. Body fat was assessed using skinfold calipers. One volunteer underwent a more comprehensive body scan from neck to foot to explore chromophore distributions within an individual. Regression analysis was used to identify the most important sources of variation in the measured data set. Statistical differences between bony locations were found for scattering, water, and lipids, but not for hemoglobin. All chromophores had statistical differences with sex, but there were no significant age-related correlations. Regression analysis revealed that body fat measured with skinfold calipers was the most important predictor of oxy-, deoxy-, total hemoglobin, and lipids. Hemoglobin and lipid levels were highly correlated (ρ ≥ 0.7) over the subject population and within the single-subject body scan. DOSI can successfully measure bony anatomic sites where osteosarcomas and Ewing's sarcomas commonly occur. Future studies of bone pathology using DOSI should account for the variation caused by anatomic region, sex, race and ethnicity, and body fat as these cause substantial variations in DOSI-derived metrics.


Salt removal during Off-Gel electrophoresis of protein samples.
The Off-Gel technology was recently described for protein fractionation in a solution placed on top of an immobilized pH gradient gel. In addition, this process was found to remove salts from the biological samples to analyze. This desalting effect is studied experimentally in a conductometric prototype cell. A simplified analytical model is developed to understand this process and a good agreement is found with the conductivity measurements. To illustrate the desalting of a biological sample, a 1 mg.mL(-1) solution of beta-lactoglobulin A in 0.1 M NaCl is subjected to electrophoresis in a single compartment Off-Gel cell. The analysis of the resulting sample by ESI-MS demonstrates the effective removal of salt. A finite element diffusion-migration model is also used to illustrate how the nonuniformity of the electric field in the cell, associated with the salt migration, can slow down the desalting process.


Risk prediction and treatment assessment in glioma patients using SEER database: a prospective observational study.
To use a nomogram to predict the risk of mortality and estimate the impact of current treatment on the prognosis of glioma patients. A total of 3798 cases were obtained from the Surveillance Epidemiology and End Results database according to the selection criteria. A nomogram was built on the independent clinical factors screened by the variance inflation factor, univariate analyses and a multivariate Cox regression model. Then, categorising the overall population into high-risk, medium-risk and low-risk groups using nomogram-derived risk scores, to study the impact of treatment on different subgroups' survival outcomes. Furthermore, based on the postmatch cohorts, the influences of treatment on survival outcomes were assessed by the log-rank test. Age, race, stage of disease, histological type, histological grade, surgery, radiotherapy and chemotherapy were identified as the independent prognostic factors. A nomogram with good discrimination and consistency was built. Generally, the patients who underwent surgery, radiotherapy and chemotherapy were more likely to achieve better prognosis than those who did not, except for those who received radiotherapy in the low-risk cohort and those who underwent surgery in the high-risk cohort. Furthermore, the isocitrate dehydrogenase 1/2 (IDH1/2) wild-type patients with surgery, radiotherapy or chemotherapy tended to have higher survival probabilities, while some inconsistent results were observed in the IDH mutant-type cohort. Surgery, radiotherapy and chemotherapy improved the prognosis, while appropriate selection of topical treatment for the low-risk or high-risk patients deserves further consideration. IDH status gene might be a reliable indicator of therapeutic effectiveness.


Peritoneal Dialysis in Pediatric Postoperative Cardiac Surgical Patients.
We determined the prevalence of acute kidney injury requiring peritoneal dialysis (PD), the factors associated with early PD initiation, prolonged PD and mortality among pediatric postoperative cardiac surgical patients. The hospital records of 23 children, aged 12 years or younger, who had undergone cardiac surgery and required PD subsequently, during a 1-year period were reviewed. Demographic data, intraoperative variables, and postoperative complications were compared between survivors and nonsurvivors of PD, between the short and long duration PD groups, and between the early and late PD initiation groups. Six hundred and eight pediatric patients who underwent open heart surgery were enrolled in this study. 23 (3.78%) of them required PD. When compared with survivors (n = 11), non survivors (n =12) were more likely to have a higher serum procalcitonin (p = 0.01), higher serum potassium on day 2 (p = 0.001), day 3 (p = 0.04), day of termination of PD (p = 0.001) and a lower urine output on day 3 of PD (p = 0.03). Prolonged PD was associated with time of PD initiation (p = 0.01), a higher postoperative serum creatinine on day 3 (p = 0.01) of PD initiation as well on the day of PD termination (p = 0.01) and the final outcome in terms of survival (p = 0.02). Factors significantly associated with an early PD initiation were CPB time (p = 0.04), sepsis (p = 0.02) and shorter PD duration (p = 0.003). PD is very useful mode of renal replacement therapy among pediatric postoperative cardiac surgical patients. The intraoperative and postoperative variables have important association with the time of PD initiation, PD duration and patient survival. Sahu MK, Bipin C, Arora Y, Singh SP, Devagouru V, Rajshekar P, et al. Peritoneal Dialysis in Pediatric Postoperative Cardiac Surgical Patients. Indian J Crit Care Med 2019;23(8):371-375.


A clinical, aetiological, and public health perspective on central nervous system infections in Bolivia, 2017-2018.
Central nervous system (CNS) infections are important causes of morbidity and mortality worldwide. In Bolivia, aetiologies, case fatality, and determinants of outcome are poorly characterised. We attempted to investigate such parameters to guide diagnosis, treatment, prevention, and health policy. From Nov-2017 to Oct-2018, we prospectively enrolled 257 inpatients (20.2% HIV-positive patients) of all ages from healthcare centers of Cochabamba and Santa Cruz, Bolivia with a suspected CNS infection and a lumbar puncture performed. Biological diagnosis included classical microbiology, molecular, serological and immunohistochemical tests. An infectious aetiology was confirmed in 128/257 (49.8%) inpatients, including, notably among confirmed single and co-infections, Cryptococcus spp. (41.7%) and Mycobacterium tuberculosis (27.8%) in HIV-positive patients, and Mycobacterium tuberculosis (26.1%) and Streptococcus pneumoniae (18.5%) in HIV-negative patients. The total mortality rate was high (94/223, 42.1%), including six rabies cases. In multivariate logistic regression analysis, mortality was associated with thrombocytopenia (Odds ratio (OR) 5.40, 95%-CI 2.40-11.83) and hydrocephalus (OR 4.07, 95%-CI 1.35-12.23). The proportion of untreated HIV patients, late presentations of neurotuberculosis, the rate of pneumococcal cases, and rabies patients who did not benefit from a post-exposure prophylaxis, suggest that decreasing the burden of CNS infections requires reinforcing health policy regarding tuberculosis, rabies, S. pneumoniae vaccination, and HIV-infections.


Endovascular approaches to complex thoracic aortic disease.
Diseases of the thoracic aorta remain among the most lethal and difficult to treat conditions. In 2005, the US Food and Drug Administration approved the first endoprosthesis for the treatment of aneurysms of the descending thoracic aorta; at present, there are 3 thoracic devices approved by the US Food and Drug Administration. Although approved only for the treatment of descending aneurysms, thoracic endografting has other potential off-label applications, including acute and chronic aortic dissection and traumatic aortic transection. Endovascular repair of thoracic aortic pathology is emerging as the preferred treatment strategy in certain patients, as increasing data suggest that endovascular repair may be performed with lower peri-operative morbidity and mortality rates and similar midterm survival, when compared with standard open repair. However, because of anatomic constraints related to required endograft seal zones, a significant number of patients are excluded from standard endovascular repair. Hybrid techniques, including open aortic arch and thoracoabdominal debranching procedures, have been described to allow creation of proximal and/or distal landing zones for the stent graft seal. This review describes the surgical and anesthetic considerations relevant to thoracic endografting, with an emphasis on hybrid procedures used to treat more complex thoracic aortic pathology. Hybrid techniques may be performed with lower rates of morbidity and mortality than conventional open repair, and they appear to be a safe alternative to open repair for thoracoabdominal and aortic arch aneurysms in properly selected patients with significant comorbidity or prior open aortic surgery.


Importance and prevention of malaria in pregnancy.
Malaria in pregnancy is one of the most important preventable causes of low birthweight deliveries worldwide. It is also a major cause of severe maternal anaemia contributing to maternal mortality. It is estimated that 40% of the world's pregnant women are exposed to malaria infection during pregnancy. The clinical features of Plasmodium falciparum malaria in pregnancy depend to a large extent on the immune status of the woman, which in turn is determined by her previous exposure to malaria. In pregnant women with little or no pre-existing immunity, such as women from non-endemic areas or travellers to malarious areas, infection is associated with high risks of severe disease with maternal and perinatal mortality. Women are at particular risk of cerebral malaria, hypoglycaemia, pulmonary oedema and severe haemolytic anaemia. Fetal and perinatal loss has been documented to be as high as 60-70% in non-immune women with malaria. Adults who are long-term residents of areas of moderate or high malaria transmission, including large parts of sub-Saharan Africa, usually have a high level of immunity to malaria. Infection is frequently asymptomatic and severe disease is uncommon. During pregnancy this immunity to malaria is altered. Infection is still frequently asymptomatic, so may go unsuspected and undetected, but is associated with placental parasitization. Malaria in pregnancy is a common cause of severe maternal anaemia and low birthweight babies, these complications being more common in primigravidae than multigravidae. Preventative strategies include regular chemoprophylaxis, intermittent preventative treatment with antimalarials and insecticide-treated bednets.


Ultra-sparse Connectivity within the Lateral Hypothalamus.
The lateral hypothalamic area (LH) is a vital controller of arousal, feeding, and metabolism [1, 2], which integrates external and internal sensory information. Whereas sensory and whole-body output properties of LH cell populations have received much interest, their intrinsic synaptic organization has remained largely unstudied. Local inhibitory and excitatory connections could help integrate and filter sensory information and mutually inhibitory connections [3] could allow coordinating activity between LH cell types, some of which have mutually exclusive behavioral effects, such as LH VGLUT2 and VGAT neurons [4-7] and orexin- (ORX) and melanin-concentrating hormone (MCH) neurons [8-10]. However, classical Golgi staining studies did not find interneurons with locally ramifying axons in the LH [11, 12], and nearby subthalamic and thalamic areas lack local synaptic connectivity [13, 14]. Studies with optogenetic circuit mapping within the LH have demonstrated only a minority of connections when a large pool of presynaptic neurons was activated [15-19]. Because multiple patch clamp has not been used to study LH connectivity, aside from a limited dataset of MCH neurons where no connections were discovered [15], we used quadruple whole-cell recordings to screen connectivity within the LH with standard methodology we previously used in the neocortex [20-22]. Finding a lack of local connectivity, we used optogenetic circuit mapping to study the strength of LH optogenetic responses and network oscillations, which were consistent with ultra-sparse intrinsic connectivity within the LH. These results suggest that input from other brain structures is decisive for selecting active populations in the LH.


Self-assembly of single amino acid/pyrene conjugates with unique structure-morphology relationship.
This article describes the self-assembly of π-conjugated building blocks composed of single amino acid and pyrene (Py) moieties. In aqueous conditions, the Py-capped amino acids undergo self-assembly through various non-covalent interactions such as hydrogen-bonding, π-π stacking as well as electrostatic interactions to form supramolecular nanostructures in acidic and basic conditions. Interestingly, we found that the blend of different Py-gelators with oppositely charged amino acids (Py-Glu and Py-Lys) displays unique nano-structural morphologies and gelation properties of the resulting hydrogels at physiological pH when compared with single Py conjugates, which was attributed to additional electrostatic interactions. Overall, this report illustrates the importance of two-component supramolecular co-assembled hydrogels and their structure-morphology relationship, improved mechanical properties, and biocompatibility and thus provides a new insight into the design of self-assembled nanomaterials.


Unexpected effects of expressive writing on post-disaster distress in the Hurricane Harvey Study: a randomized controlled trial in perinatal women.
Expressive writing requires journaling stressor-related thoughts and feelings over four daily sessions of 15 min. Thirty years of research have popularized expressive writing as a brief intervention for fostering trauma-related resilience; however, its ability to surpass placebo remains unclear. This study aimed to determine the efficacy of expressive writing for improving post-traumatic stress symptoms in perinatal women who were living in the Houston area during major flooding caused by Hurricane Harvey. A total of 1090 women were randomly allocated (1:1:1) to expressive writing, neutral writing or no writing. Interventions were internet-based. Online questionnaires were completed before randomization and at 2 months post-intervention. The primary outcome was post-traumatic stress symptoms, measured with the Impact of Event Scale-Revised; secondary outcomes were affective symptoms, measured with the 40-item Inventory of Depression and Anxiety Scales. Feelings throughout the intervention were reported daily using tailored questionnaires. In intention-to-treat analyses, no post-treatment between-group differences were found on the primary and secondary outcomes. Per-protocol analyses yielded similar results. A number of putative moderators were tested, but none interacted with expressive writing. Expressive writing produced greater feelings of anxiety and sadness during the intervention compared to neutral writing; further, overall experiences from the intervention mediated associations between expressive writing and greater post-traumatic stress at 2 months post-intervention. Among disaster-stricken perinatal women, expressive writing was ineffective in reducing levels of post-traumatic stress, and may have exacerbated these symptoms in some.


NFBD1/MDC1 regulates Cav1 and Cav2 independently of DNA damage and p53.
NFBD1/MDC1 is involved in DNA damage checkpoint signaling and DNA repair. NFBD1 binds to the chromatin component γH2AX at sites of DNA damage, causing amplification of ataxia telangiectasia-mutated gene (ATM) pathway signaling and recruitment of DNA repair factors. Residues 508-995 of NFBD1 possess transactivation activity, suggesting a possible role of NFBD1 in transcription. Furthermore, NFBD1 influences p53-mediated transcription in response to adriamycin. We sought to determine the role of NFBD1 in ionizing radiation (IR)-responsive transcription and if NFBD1 influences transcription independently of p53. Using microarray analysis, we identified genes altered upon NFBD1 knockdown. Surprisingly, most NFBD1 regulated genes are regulated in both the absence and presence of IR, thus pointing toward a novel function for NFBD1 outside of the DNA damage response. Furthermore, NFBD1 knockdown regulated genes mostly independent of p53 knockdown. These genes are involved in pathways including focal adhesion signaling, carbohydrate metabolism, and insulin signaling. We found that CAV1 and CAV2 mRNA and protein levels are reduced by both NFBD1 knockdown and knockout independently of IR and p53. NFBD1-depleted cells exhibit some similar phenotypes to Cav1-depleted cells. Furthermore, like Cav1-depletion, NFBD1 shRNA increases Erk phosphorylation. Thus, Cav1 could act as a mediator of the DNA-damage independent effects of NFBD1 in mitogenic signaling.


Perspectives on the divorce process: parental perceptions of the legal system and its impact on family relations.
Through semistructured interviews, divorcing parents provide a consumer perspective of the legal process of divorce discussed in law and mental health literature. The parents offer a heightened awareness of families' basic needs within the legal system that may otherwise be overlooked by professionals. This article focuses on narrative accounts provided by 41 divorcing parents to describe both their positive and negative experiences with the legal system and court-related professionals. Although many parents entered the divorce process with hopes for a fair and reasonable experience and outcome, only 12 percent of the parents ended the process with positive expectations. Parents conveyed feelings of a lack of power and control over divorce outcomes. The responses from parents provide valuable insight into how reforms of the legal system can be structured best to increase the quality of the process and ameliorate potentially destructive effects of divorce on the family.


Effect of polymorphs of cellulose nanocrystal on the thermal properties of poly(lactic acid)/cellulose nanocrystal composites.
Cellulose nanocrystals (CNCs) with different polymorphs CNC I and II were fabricated from native and mercerized microcrystalline cellulose (MCC) by sulfuric acid hydrolysis. CNC I and II were successfully acetylated by a "green" method, which was performed in an ionic liquid of 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF4). X-ray diffraction (XRD) proved that the crystal structure of CNC I and II was maintained after acetylation. Transmission electron microscopy (TEM) showed the rod-like structure for acetylated CNC I and spherical crystal morphologies for acetylated CNC II. Thermogravimetric analysis (TGA) revealed that the thermal stability of CNC I and II was enhanced after acetylation. The effect of CNC polymorphs on the crystallization behavior and thermal stability of poly(lactic acid)/acetylated CNC (PLA/ACN) composites was investigated by differential scanning calorimetry (DSC) and TGA, respectively. It was found that compared to ACN I, ACN II was better able to promote the cold crystallization of PLA-based composites, and PLA/ ACN II possessed higher thermal stability.


Intrinsic, Transitional, and Extrinsic Morphological Factors Associated With Rupture of Intracranial Aneurysms.
As diagnosis and treatment of unruptured intracranial aneurysms continues to increase, management principles remain largely based on size. This is despite mounting evidence that aneurysm location and other morphologic variables could play a role in predicting overall risk of rupture. Morphological parameters can be divided into 3 main groups, those that are intrinsic to the aneurysm, those that are extrinsic to the aneurysm, and those that involve both the aneurysm and surrounding vasculature (transitional). We present an evaluation of intrinsic, transitional, and extrinsic factors and their association with ruptured aneurysms. Using preoperative computed tomographic angiography, we generated 3-dimensional models of aneurysms and their surrounding vasculature with Slicer software. Using univariate and multivariate analyses, we examined the association of intrinsic, transitional, and extrinsic aspects of aneurysm morphology with rupture. Between 2005 and 2013, 227 cerebral aneurysms in 4 locations were evaluated/treated at a single institution, and computed tomographic angiographies of 218 patients (97 unruptured and 130 ruptured) were analyzed. Ruptured aneurysms analyzed were associated with clinical factors of absence of multiple aneurysms and history of no prior rupture, and morphologic factors of greater aspect ratio. On multivariate analysis, aneurysm rupture remained associated with history of no prior rupture, greater flow angle, greater daughter-daughter vessel angle, and smaller parent-daughter vessel angle. By studying the morphology of aneurysms and their surrounding vasculature, we identified several parameters associated with ruptured aneurysms that include intrinsic, transitional, and extrinsic factors of cerebral aneurysms and their surrounding vasculature.


Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation.
Diamond-Blackfan anaemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterised by erythroid hypoplasia. It is associated with congenital anomalies and a high risk of developing specific cancers. DBA is caused predominantly by autosomal dominant pathogenic variants in at least 15 genes affecting ribosomal biogenesis and function. Two X-linked recessive genes have been identified. We aim to identify the genetic aetiology of DBA. Of 87 families with DBA enrolled in an institutional review board-approved cohort study (ClinicalTrials.gov Identifier:NCT00027274), 61 had genetic testing information available. Thirty-five families did not have a known genetic cause and thus underwent comprehensive genomic evaluation with whole exome sequencing, deletion and CNV analyses to identify their disease-associated pathogenic variant. Controls for functional studies were healthy mutation-negative individuals enrolled in the same study. Our analyses uncovered heterozygous pathogenic variants in two previously undescribed genes in two families. One family had a non-synonymous variant (p.K77N) in RPL35; the second family had a non-synonymous variant (p. L51S) in RPL18. Both of these variants result in pre-rRNA processing defects. We identified heterozygous pathogenic variants in previously known DBA genes in 16 of 35 families. Seventeen families who underwent genetic analyses are yet to have a genetic cause of disease identified. Overall, heterozygous pathogenic variants in ribosomal genes were identified in 44 of the 61 families (72%). De novo pathogenic variants were observed in 57% of patients with DBA. Ongoing studies of DBA genomics will be important to understand this complex disorder.