The "tamponade test" in the management of massive postpartum hemorrhage.
Massive postpartum hemorrhage is a major cause of pregnancy-related death in the United States. To date there is no diagnostic test to identify those women with intractable hemorrhage who will need surgery. Delay in making this decision can be catastrophic. The successful use of the inflated stomach balloon of a Sengstaken-Blakemore tube as a therapy for obstetric hemorrhage has been reported previously. Using the insertion of the Sengstaken-Blakemore tube as a diagnostic test has not been reported. An inflated Sengstaken-Blakemore balloon catheter creates tamponade and identifies those who will or will not need surgery. This is the basis for the "tamponade test." We evaluated the tamponade test in the management of women with massive postpartum hemorrhage. In this prospective study, 16 cases of intractable postpartum hemorrhage were managed by the tamponade test. All 16 women had persistent bleeding despite the maximal and optimal application of conservative measures. Their condition deteriorated, such that surgical intervention was considered mandatory. It was at this predefined end point that the tamponade test was applied. Fourteen (87.5%) had a positive tamponade test result and therefore did not require surgery. Two (12.5%) had a negative test result and underwent laparotomy. This diagnostic test rapidly identifies those patients with postpartum hemorrhage who will require a laparotomy. Even when results are positive, life-threatening hemorrhage is arrested and time is also allowed to correct any consumptive coagulopathy.


[Effects of thyroxine and methimazolum on thermosensitive neurons in preoptic/anterior hypothalamic area in rats].
The effects of thyroxine (subcutaneous injection) and methimazolum (intubation feeding) on thermosensitive neurons (TSN) in the preoptic/anterior hypothalamic (PO/AH) area in rats were observed. The ratio of warm-sensitive neurons (WSN) to cold-sensitive neurons (CSN) was 1.86:1 and thermo-insensitive neurons (TIN) to thermosensitive neurons (TSN) 1:1.43 in the control group. The ratio of WSN to CSN decreased to 1.20:1 and the ratio of TIN to 1:2.36 in the thyroxine group, while the former increased to 2.40:1 and the latter decreased to 1:1.29 in the methimazolum group. There was significant difference among three groups, (X2 = 9.64, P less than 0.05). Thirty-two percent of neurons (11/34) showed higher firing rates (greater than 15Hz) in the control group, only 8% (3/37) in the thyroxine group and 9% (3/32) in the methimazolum group. In addition, the tolerance of TSN to warming stimulation was obviously lower in both pathological groups, as compared with the control group. The results suggest that a rise or fall of body temperature in rats with subcutaneous injecting thyroxine and intubation feeding methimazolum may be related to the changes of proportion and excitability of PO/AH neurons, and that the disturbance of thyroxine synthesis, release and metabolism may interfere temperature regulation at the level of hypothalamus.


The complex interactions between nutrition, immunity and infection in insects.
Insects are the most diverse animal group on the planet. Their success is reflected by the diversity of habitats in which they live. However, these habitats have undergone great changes in recent decades; understanding how these changes affect insect health and fitness is an important challenge for insect conservation. In this Review, we focus on the research that links the nutritional environment with infection and immune status in insects. We first discuss the research from the field of nutritional immunology, and we then investigate how factors such as intracellular and extracellular symbionts, sociality and transgenerational effects may interact with the connection between nutrition and immunity. We show that the interactions between nutrition and resistance can be highly specific to insect species and/or infection type - this is almost certainly due to the diversity of insect social interactions and life cycles, and the varied environments in which insects live. Hence, these connections cannot be easily generalised across insects. We finally suggest that other environmental aspects - such as the use of agrochemicals and climatic factors - might also influence the interaction between nutrition and resistance, and highlight how research on these is essential.


Comparative usefulness of deamidated gliadin antibodies in the diagnosis of celiac disease.
Serologic tests are used frequently in celiac disease diagnosis. Gliadin antibodies generally lack the accuracy required for proper diagnosis. We evaluated the value of deamidated gliadin antibody measurements in the diagnosis and follow-up evaluation of celiac disease and compared their potential usefulness with that of gliadin and tissue-transglutaminase antibodies. We tested deamidated gliadin, gliadin, and tissue-transglutaminase-immunoglobulin (Ig)A and -IgG in 216 biopsy-selected subjects including 92 biopsy-proven untreated celiac patients (46% with total villous atrophy and 54% with partial villous atrophy) and 124 biopsy-proven nonceliac controls. Fifty-nine celiac patients also were tested after treatment with a gluten-free diet. Antibodies were measured by commercial enzyme-linked immunosorbent assays. Deamidated gliadin-IgA+G was detected using a conjugate reactive to both isotypes, which gives a positive if either isotype is present. The sensitivity, specificity, and accuracy of deamidated gliadin-IgA (74%, 95%, and 86%), deamidated gliadin-IgG (65%, 98%, and 84%), and deamidated gliadin-IgA+G (75%, 94%, and 86%) were superior to gliadin-IgA (63%, 90%, and 79%) (P < .05) and gliadin-IgG (42%, 90%, and 69%) (P < .01), and were similar to tissue-transglutaminase-IgA (78%, 98%, and 90%) before treatment. The sensitivity of IgA isotype for all tests was significantly greater in celiac patients with total villous atrophy compared with those with partial villous atrophy (P < .05). The proportion of positive test results for all tests decreased significantly after treatment (P < .0001). Deamidated gliadin antibody is a better diagnostic test for celiac disease than the conventional gliadin antibody testing; although histopathology remains the gold standard test for diagnosis of celiac patients.


Lower mean platelet volume predicts poor prognosis in renal cell carcinoma.
Altered mean platelet volume (MPV) is found in several malignancies. Remarkably, there is little consensus on using the value of MPV in the prognostic evaluations of renal cell carcinoma (RCC). The aim of this study is to examine the feasibility of MPV value as a prognostic indicator of RCC. The retrospective study recruited 306 consecutive RCC patients between January 2009 and December 2009. The relationships between MPV and clinicopathological characteristics were analyzed. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of MPV. Of the 306 RCC patients, low MPV levels were detected in 61 (19.9%) patients. Reduced MPV was associated with histology types, T classification, UCLA Integrated Scoring System (UISS) category, and Mayo clinic stage, size, grade, and necrosis score (SSIGN) category (P < 0.05). Patients with decreased MPV had significantly shorter survival time than patients with normal MPV (P < 0.001). Cox regression analysis revealed that reduced MPV was an independent prognostic factor for overall survival (hazard ratio, 1.758; 95% confidence interval [CI], 1.083-2.855, P = 0.023). Moreover, the prognostic accuracy of TNM stage, UISS, and SSIGN prognostic models were improved when MPV was added. In conclusion, reduced MPV is identified as an independent predictor of adverse clinical outcome in RCC.


Transformation and Closure for Anatomical Donor Families that Meet Medical Students.
The University of Oklahoma College of Medicine has conducted an annual Anatomical Donor Luncheon where families of the anatomical donors met anatomy dissection groups of medical students. The luncheon presented an opportunity for donor family members to share the life story of their loved one with the medical students prior to the start of the anatomy course. This study was designed to understand the impact of the Anatomical Donor Luncheon on families of the donors. Seven families in two different focus groups were included to explore the reactions and attitudes of the donor families to meeting the medical students. Conversations were digitally recorded and transcribed. Qualitative analysis of textual data were coded by three investigators using the Constant Comparative Method. To provide evidence of validity, a form of member checking was utilized. For further triangulation, an analyst not involved in conducting the focus groups or analyzing the data, re-coded all data. This analyst used categories and themes identified by the original analysts, ensuring validity of the themes and any negative cases (data not supporting or contradictory of the established categories and themes). One meta-theme and three sub-themes were identified. The meta-theme was Donor Family Participants Experience Transformation and Closure, and sub-themes were Motivators for Participation, Optimal Venue Factors, and Optimal Medical Student-Anatomical Donor Family Interactions. Study findings indicated the Anatomical Donor Luncheon facilitated closure on the death of their loved one, and transformed their apprehension about the luncheon and body donation into an attitude of gratitude and appreciation.


Parasporins from a Caribbean Island: evidence for a globally dispersed Bacillus thuringiensis strain.
Parasporins represent a new functional class of Cry (crystal protein) toxins produced by the bacterium Bacillus thuringiensis (Bt). Unlike Cry toxins that demonstrate activity mainly against some insect cells, parasporins are characterized as being non-hemolytic, yet capable of preferentially killing some human cancer cells. Globally, six different parasporin types, PS1-PS6, based on protein sequence homology, have been identified in only four countries (Japan, Vietnam, India, and Canada). Herein we report the results of a screening study of 160 Bt isolates collected from the Caribbean island of Trinidad. One isolate (strain 64-1-94) was shown to kill human cancer cells and to contain one ps6 and two ps1 parasporin genes. The two ps1 genes were located approximately 6 kb apart from each other, sharing a similar spatial arrangement, and high sequence homology, with two plasmid-located ps1 genes, ps1Aa6 and ps1Ad1, recently isolated from a Japanese strain. Evidence is also presented that a parasporin gene reported previously for a Canadian strain, ps1Aa2, is most likely derived from a recombination event between these same two genes found in the Trinidadian and Japanese strains. Notably, all three strains share a ps6 parasporin gene, presumably located on a separate plasmid. These data suggest that the global population of ps1 genes may be have originated from a single pair of parasporin genes. Given the large geographical distance between the collection sites, which are located on both continental land masses and islands at sea, ps1 genes are able to retain a remarkable level of homology not easily explained.


A critical evaluation of the prothrombin time for monitoring oral anticoagulant therapy.
The Quick prothrombin time is the most common clotting test performed, principally for monitoring oral anticoagulant therapy. The International Normalized Ratio (INR) for comparing patient results from prothrombin time measurements and the International Standardized Index (ISI) for achieving greater consistency of results using different thromboplastins have made it possible to compare the results of vitamin K antagonist drug therapy that was impossible before the introduction of the INR and ISI. However, INR values obtained from the same patient plasma sample using different thromboplastins are significantly different. This is so even when the thromboplastins have nearly the same ISI values. We suggest that investigation of patient-specific differences can provide a means by which the INR discrepancies can be identified and understood and thus lead to better methods for monitoring oral anticoagulant therapy.


Organizations' Ways of Employing Early Retirees: The Role of Age-Based HR Policies.
We examine whether from an organizational perspective it is possible to distinguish different ways of employing early retirees and explore how the employment of early retirees is related to the application of 4 age-based human resource (HR) policies, namely demotion, offering training opportunities to older workers, offering early retirement, and allowing flexible working hours. We perform a latent class analysis on a sample of 998 Dutch organizations in order to categorize them based on 3 dimensions of their employment of early retirees. We then run a multinomial logistic regression to relate the employment of early retirees to the 4 age-based HR policies. We distinguish 4 types of organizations based on their way of employing early retirees: nonusers (52.6%), users for mainly standard work (20.8%), users for mainly nonstandard work (9.8%), and users for standard and nonstandard work (16.7%). We find that organizations that apply demotion, offer early retirement, and allow flexible working hours are more likely to be users for mainly standard work. Also, organizations that do not offer early retirement are less likely to employ early retirees. Age-based HR policies, especially demotion, offering early retirement, and allowing flexible working hours, are conducive to the employment of early retirees for mainly standard work. Broader implementation of these policies may provide opportunities for older workers to make a more gradual transition from work to retirement.


Corrective surgery for kyphosis in a case of Gaucher's disease without history of vertebral compression fractures.
Gaucher's disease is a congenital metabolic disorder characterized by the accumulation of glucocerebroside in the reticuloendothelial system. Its clinical manifestations include splenomegaly, osteopenia, and pathological fractures. Cases of patients with kyphotic deformities caused by pathological vertebral compression fractures associated with Gaucher's disease are well reported. However, there has been no report regarding surgical treatment of kyphotic deformity caused by Gaucher's disease without compression fractures. In the present report, we describe surgical treatment for kyphotic deformity caused by Gaucher's disease without a past history of vertebral compression fractures. The patient was diagnosed with Gaucher's disease at the age of 15 months. The patient was a 10-year-old girl with progressive kyphosis (84° between T6 and L3, with T12 as the apical vertebra) without compression fractures. Although the patient had been treated using a brace since the age of 3 years, the kyphosis progressed to the point where corrective surgery was required. We initially performed T3-L3 posterior spinal fusion, followed by anterior fusion 3 months later, which corrected the kyphosis to 35°. Postoperatively, the patient suffered fractures of the upper and lower extremities but did not have spinal fractures. Two-stage anterior/posterior combined correction and fusion was performed in a patient with kyphotic deformity caused by Gaucher's disease without compression fractures. Because of bone fragility in Gaucher's disease, careful selection of the fusion range and postoperative therapy was necessary.


A common sense approach to the retina.
Retinal surgery can be simple if the binocular indirect ophthalmoscope is mastered and certain surgical principles followed. Mastering the binocular indirect ophthalmoscope is described in step by step detail. Thereafter which eyes develop which sort of retinal detachment are discussed with special reference to the type and position of retinal breaks. Treatment emphasises that there is no such thing as a single retinal operation but rather a series of legitimate manoeuvres which may be used alone or in combination as the eye demands. To seek the simplest intervention that seals the retinal break(s) is the aim; to do so without closing off the central retinal artery is the art.


Artemisinin Ameliorates Osteoarthritis by Inhibiting the Wnt/β-Catenin Signaling Pathway.
Current drug therapies for osteoarthritis (OA) are not practical because of the cytotoxicity and severe side-effects associated with most of them. Artemisinin (ART), an antimalarial agent, is well known for its safety and selectivity to kill injured cells. Based on its anti-inflammatory activity and role in the inhibition of OA-associated Wnt/β-catenin signaling pathway, which is crucial in the pathogenesis of OA, we hypothesized that ART might have an effect on OA. The chondro-protective and antiarthritic effects of ART on interleukin-1-beta (IL-1β)-induced and OA patient-derived chondrocytes were investigated in vitro using cell viability assay, glycosaminoglycan secretion, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blotting. We also used OA model rats constructed by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) in the joints to investigate the effects of ART on OA by gross observation, morphological staining, immunohistochemistry, and enzyme-linked immunosorbent assay. ART exhibited potent anti-inflammatory effects by inhibiting the expression of proinflammatory chemokines and cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha, and matrix metallopeptidase-13. It also showed favorable chondro-protective effect as evidenced by enhanced cell proliferation and viability, increased glycosaminoglycan deposition, prevention of chondrocyte apoptosis, and degeneration of cartilage. Further, ART inhibited OA progression and cartilage degradation via the Wnt/β-catenin signaling pathway, suggesting that it might serve as a Wnt/β-catenin antagonist to reduce inflammation and prevent cartilage degradation. In conclusion, ART alleviates IL-1β-mediated inflammatory response and OA progression by regulating the Wnt/β-catenin signaling pathway. Thereby, it might be developed as a potential therapeutic agent for OA.


Multi-staged development and pilot testing of a self-assessment tool for organizational health literacy.
Until now a comprehensive, consensus-based tool that can be used by a variety of health care organizations for assessing their organizational health literacy (OHL) is not available. Therefore, we aimed to develop and test a literature- and consensus-based self-assessment tool. The study is based on a scoping review that was previously published by the authors. For the development of the self-assessment tool, the criteria identified in the literature were synthesized with criteria gained through group discussions with representatives of different types of health care organizations (N = 27) all based in Hamburg (Germany). Consensus on the criteria was reached by conducting a Delphi process (N = 22). A review by the project's patient advisory council was included in the process. The self-assessment tool was converted into an online tool and refined by a pretest. Finally, the online survey was piloted (N = 53) and the reliability and item loadings for each scale were analyzed. In total, 77 criteria (items) characterizing a health literate health care organization were developed and grouped into five main categories (scales): (1) "easy access and navigation", (2) "integration, prioritization, and dissemination of OHL", (3) "qualification, quality management, evaluation, and needs assessment", (4) "communication with target groups", and (5) "involvement and support of target groups". The results of the online survey showed that the tool is suitable for assessing an organization's status quo on OHL. The psychometric analysis showed good to excellent internal consistency. Item analyses of the developed self-assessment tool was satisfactory. We were able to define a set of 77 items to characterize OHL, which were integrated into a new, comprehensive, and consensus-based self-assessment tool to identify areas for improvement. We found evidence that the self-assessment tool, based on the identified criteria, consists of the assumed five scales. Further research should analyze the validity of the self-assessment tool on a higher detail level.


Initial characterization of Wnt-Tcf functions during Ciona heart development.
In vertebrate embryos, the cardiopharyngeal mesoderm gives rise to both cardiac and branchiomeric head muscles. The canonical Wnt signaling pathway regulates many aspects of cardiomyocyte specification, and modulates a balance between skeletal and cardiac myogenesis during vertebrate head muscle development. However, the role of Wnt signaling during ascidian cardiopharyngeal development remains elusive. Here, we documented the expression of Wnt pathway components during cardiopharyngeal development in Ciona, and generated tools to investigate potential roles for Wnt signaling, and its transcriptional effector Tcf, on heart vs. pharyngeal muscle fate specification. Neither focused functional analyses nor lineage-specific transcriptome profiling uncovered a significant role for Tcf during early cardiac vs. pharyngeal muscle fate choice. By contrast, Wnt gene expression patterns of Frizzled4 and Lrp4/8 and CRISPR/Cas9-mediated Tcf knock-down suggested a later requirement for Wnt signaling during heart morphogenesis and/or cardiomyocyte differentiation. This study provides a provisional set of reagents to study Wnt signaling function in Ciona, and promising insights for future analyses of Wnt functions during heart organogenesis.


The causes of sea-level rise since 1900.
The rate of global-mean sea-level rise since 1900 has varied over time, but the contributing factors are still poorly understood1. Previous assessments found that the summed contributions of ice-mass loss, terrestrial water storage and thermal expansion of the ocean could not be reconciled with observed changes in global-mean sea level, implying that changes in sea level or some contributions to those changes were poorly constrained2,3. Recent improvements to observational data, our understanding of the main contributing processes to sea-level change and methods for estimating the individual contributions, mean another attempt at reconciliation is warranted. Here we present a probabilistic framework to reconstruct sea level since 1900 using independent observations and their inherent uncertainties. The sum of the contributions to sea-level change from thermal expansion of the ocean, ice-mass loss and changes in terrestrial water storage is consistent with the trends and multidecadal variability in observed sea level on both global and basin scales, which we reconstruct from tide-gauge records. Ice-mass loss-predominantly from glaciers-has caused twice as much sea-level rise since 1900 as has thermal expansion. Mass loss from glaciers and the Greenland Ice Sheet explains the high rates of global sea-level rise during the 1940s, while a sharp increase in water impoundment by artificial reservoirs is the main cause of the lower-than-average rates during the 1970s. The acceleration in sea-level rise since the 1970s is caused by the combination of thermal expansion of the ocean and increased ice-mass loss from Greenland. Our results reconcile the magnitude of observed global-mean sea-level rise since 1900 with estimates based on the underlying processes, implying that no additional processes are required to explain the observed changes in sea level since 1900.


Cancer studies based on secondary data analysis of the Taiwan's National Health Insurance Research Database: A computational text analysis and visualization study.
There has been a surge in the academic publication output based on secondary analyses of the data from the Taiwan's National Health Insurance claim records. It has become a challenge to comprehend such a rapid expansion of the literature. Therefore, this study aimed to explore the conceptual content of National Health Insurance Research Database-based cancer research, using the abstract of articles extracted from PubMed between 2002 and 2015. Search terms including "National Health Insurance Research Database (NHIRD) AND Taiwan," "Taiwan AND population-based," and "Taiwan AND nationwide" were used to search in PubMed with the publication date limited to between 1997 and 2015. The retrieved articles were manually screened to retain only those that were cancer-related and were based on secondary data analysis of the NHIRD. A total 589 articles were selected for subsequent text mining using the R software. Among the 589 articles, the top 5 most studied cancer types were breast (16.3%), lung (11.4%), colorectal (10.4%), liver (8.3%), and prostate (7.5%). The articles that received the highest number of citations by PubMed Central articles were cited 92 times. The top 3 most frequently occurred keywords in the abstracts of the 589 articles were cancer, patient, and risk, with 3670, 2535, and 1652 times, respectively. Analysis of key conception indicated that the most common conceptions were diabetes, survival, breast cancer, lung cancer, and colorectal cancer. In conclusion, in this study of 589 published articles on secondary data analysis of the NHIRD, indexed by PubMed between 2002 and 2015, we found that while the risk factors of cancer, treatment of cancer, and survival of cancer patients were popular research topics, end-of-life cancer care issues were less studied. Further studies should explore these areas since they are as important as treatment of the disease itself for many patients.


Pediatric emergency intravenous access. Evaluation of a protocol.
Effectiveness of a protocol for intravenous (IV) access during pediatric resuscitation was prospectively evaluated to determine whether utilization of a specified sequence of measures would reduce IV access time compared with resuscitations deviating from the protocol. The protocol involved rapid sequential attempts at percutaneous femoral vein catheterization, saphenous vein cutdown, and intraosseous infusions if initial percutaneous peripheral IV insertion failed. While no single technique provided completely reliable and rapid IV access, utilization of all techniques per protocol significantly improved IV access time. When initial percutaneous peripheral IV attempts failed, resuscitations in compliance with the protocol achieved IV access more rapidly (median, 4.5 minutes) than those deviating from the protocol (median, 10.0 minutes). Even with incomplete compliance, 66% of resuscitations achieved IV access within the first five minutes. Our experience indicates that IV access during pediatric resuscitation should rarely be delayed beyond the fifth minute if all available IV techniques are used.


The significance of caloric restriction mimetics as anti-aging drugs.
Aging is an intricate process characterized by the gradual deterioration of the physiological integrity of a living organism. This unfortunate phenomenon inevitably leads to a decline in functionality and a heightened susceptibility to the ultimate fate of mortality. Therefore, it is of utmost importance to implement interventions that possess the capability to reverse or preempt age-related pathology. Caloric restriction mimetics (CRMs) refer to a class of molecules that have been observed to elicit advantageous outcomes on both health and longevity in various model organisms and human subjects. Notably, these compounds offer a promising alternative to the arduous task of adhering to a caloric restriction diet and mitigate the progression of the aging process and extend the duration of life in laboratory animals and human population. A plethora of molecular signals have been linked to the practice of caloric restriction, encompassing Insulin-like Growth Factor 1 (IGF1), Mammalian Target of Rapamycin (mTOR), the Adenosine Monophosphate-Activated Protein Kinase (AMPK) pathway, and Sirtuins, with particular emphasis on SIRT1. Therefore, this review will center its focus on several compounds that act as CRMs, highlighting their molecular targets, chemical structures, and mechanisms of action. Moreover, this review serves to underscore the significant relationship between post COVID-19 syndrome, antiaging, and importance of utilizing CRMs. This particular endeavor will serve as a comprehensive guide for medicinal chemists and other esteemed researchers, enabling them to meticulously conceive and cultivate novel molecular entities with the potential to function as efficacious antiaging pharmaceutical agents.


A Short-Term High-Fat Diet Alters Glutathione Levels and IL-6 Gene Expression in Oxidative Skeletal Muscles of Young Rats.
Obesity and ensuing disorders are increasingly prevalent worldwide. High-fat diets (HFD) and diet-induced obesity have been shown to induce oxidative stress and inflammation while altering metabolic homeostasis in many organs, including the skeletal muscle. We previously observed that 14 days of HFD impairs contractile functions of the soleus (SOL) oxidative skeletal muscle. However, the mechanisms underlying these effects are not clarified. In order to determine the effects of a short-term HFD on skeletal muscle glutathione metabolism, young male Wistar rats (100-125 g) were fed HFD or a regular chow diet (RCD) for 14 days. Reduced (GSH) and disulfide (GSSG) glutathione levels were measured in the SOL. The expression of genes involved in the regulation of glutathione metabolism, oxidative stress, antioxidant defense and inflammation were measured by RNA-Seq. We observed a significant 25% decrease of GSH levels in the SOL muscle. Levels of GSSG and the GSH:GSSG ratio were similar in both groups. Further, we observed a 4.5 fold increase in the expression of pro-inflammatory cytokine interleukin 6 (IL-6) but not of other cytokines or markers of inflammation and oxidative stress. We hereby demonstrate that a short-term HFD significantly lowers SOL muscle GSH levels. This effect could be mediated through the increased expression of IL-6. Further, the skeletal muscle antioxidant defense could be impaired under cellular stress. We surmise that these early alterations could contribute to HFD-induced insulin resistance observed in longer protocols.


Workers' compensation cost-shifting: a unique concern of providers and purchasers of prepaid health care.
Contract health care plans exclude workers' compensation from among the prepaid medical benefits. Under present contract relationships, compensable injury and illness can be billed to the employer as fee-for-service care. The provision of health care, normally an expense for the prepaid health care provider, generates income when it is given under a compensation rubric. Per capita workers' compensation costs at eight federal shipyards range from less than $500 in yards with no health maintenance organization (HMO) coverage to more than $1,000 in yards with more than two-thirds of employees enrolled in prepaid health care plans. A statistically significant relationship between prepaid health care plan enrollment and per capita workers' compensation costs at these yards suggests the likelihood of systematic cost-shifting by overdiagnosis of compensable injury and illness. Changes in prepaid contract incentives may improve the ethical and economic health care climate for workers' compensation.


The geometry of the forisome-sieve element-sieve plate complex in the phloem of Vicia faba L. leaflets.
Forisomes are contractile protein bodies that appear to control flux rates in the phloem of faboid legumes by reversibly plugging the sieve tubes. Plugging is triggered by Ca(2+) which induces an anisotropic deformation of forisomes, consisting of a longitudinal contraction and a radial expansion. By conventional light microscopy and confocal laser-scanning microscopy, the three-dimensional geometry of the forisome-sieve element-sieve plate complex in intact sieve tubes of leaflets of Vicia faba L. was reconstructed. Forisomes were mostly located close to sieve plates, and occasionally were observed drifting unrestrainedly along the sieve element, suggesting that they might be utilized as internal markers of flow direction. The diameter of forisomes in the resting state correlated with the diameter of their sieve elements, supporting the idea that radial expansion of forisomes is the geometric basis of reversible sieve tube plugging. Comparison of the present results regarding forisome geometry in situ with previously published data on forisome reactivity in vitro makes it questionable, however, whether forisomes are capable of completely sealing sieve tubes in V. faba leaves.


Know Thyself: RIG-I-Like Receptor Sensing of DNA Virus Infection.
The RIG-I-like receptors (RLRs) are double-stranded RNA-binding proteins that play a role in initiating and modulating cell intrinsic immunity through the recognition of RNA features typically absent from the host transcriptome. While they are initially characterized in the context of RNA virus infection, evidence has now accumulated establishing the role of RLRs in DNA virus infection. Here, we review recent advances in the RLR-mediated restriction of DNA virus infection with an emphasis on the RLR ligands sensed.


The resident as a teacher: a neglected role.
Residents are frequently requested to take on teaching responsibilities, especially with medical students, but they receive little formal preparation for this role. This paper reviews some of the problems residents may face when teaching and describes a training workshop designed to enhance the teaching skills of residents. The workshop is based around a simulated teaching event that focuses on the organizational and practical, as well as didactic tasks involved in supervision of a clinical clerk. Such a workshop helps the resident to identify and prepare for some of the problems they may encounter and provides them with an opportunity to develop new skills that will improve the quality of their teaching.


Coherent multiscale image processing using dual-tree quaternion wavelets.
The dual-tree quaternion wavelet transform (QWT) is a new multiscale analysis tool for geometric image features. The QWT is a near shift-invariant tight frame representation whose coefficients sport a magnitude and three phases: two phases encode local image shifts while the third contains image texture information. The QWT is based on an alternative theory for the 2-D Hilbert transform and can be computed using a dual-tree filter bank with linear computational complexity. To demonstrate the properties of the QWT's coherent magnitude/phase representation, we develop an efficient and accurate procedure for estimating the local geometrical structure of an image. We also develop a new multiscale algorithm for estimating the disparity between a pair of images that is promising for image registration and flow estimation applications. The algorithm features multiscale phase unwrapping, linear complexity, and sub-pixel estimation accuracy.


Managing the placebo effect: enhancing the signal-to-noise ratio.
Confirming the absence of the placebo response has been the bane of researchers throughout the ages. Thus, the gold standard of research methodology is the evidence for a treatment modality provided by a prospective randomized controlled trial. The "control" arm of a trial is the arm in which the placebo has been administered. Increasing evidence from basic science and clinical research is pointing to the fact that the placebo response may have some biological basis that can translate into enduring therapeutic benefit. Have our placebo-controlled trials simply compared one treatment effect to the treatment effect of the "placebo"? Thus, the "δ" is relative treatment effect; perhaps this may provide some insight as to why some treatment response is low compared to a relatively strong placebo response. How can we use this knowledge to create more robust clinical designs that help establish true treatment effect? This article aims to provide an overview of the contemporary insight into the placebo response.


Elucidation of consistent enantioselectivity for a homologous series of chiral compounds in homochiral metal-organic frameworks.
The members of a homologous series of chiral compounds often show inconsistent enantioselectivities when separated on the same chiral stationary phase. The reasons behind this are subject to debate due to the lack of an efficient way to probe the molecular level separation mechanisms on conventional chiral stationary phases. Homochiral metal-organic frameworks (HMOFs) are a family of new porous, crystalline materials that can be used as chiral stationary phases. The regular structures of HMOFs make possible the detailed interrogation of chiral separation mechanisms through molecular modeling. In this report, molecular modeling techniques were used to study the enantioselectivities of a homologous series of chiral compounds in two different HMOFs. We demonstrate that a shift in the adsorption site is one reason for the lack of a correlation between the enantioselectivities of a homologous series of chiral compounds. In addition, we demonstrate that a smooth HMOF pore can help preserve the adsorption site and the separation mechanism, and hence achieve consistent enantioselectivity for a homologous series of chiral compounds.


Glycobiology simplified: diverse roles of glycan recognition in inflammation.
Glycans and complementary glycan-binding proteins are essential components in the language of cell-cell interactions in immunity. The study of glycan function is the purview of glycobiology, which has often been presented as an unusually complex discipline. In fact, the human glycome, composed of all of its glycans, is built primarily from only 9 building blocks that are combined by enzymes (writers) with specific and limited biosynthetic capabilities into a tractable and increasingly accessible number of potential glycan patterns that are functionally read by several dozen human glycan-binding proteins (readers). Nowhere is the importance of glycan recognition better understood than in infection and immunity, and knowledge in this area has already led to glycan mimetic anti-infective and anti-inflammatory drugs. This review includes a brief tutorial on human glycobiology and a limited number of specific examples of glycan-binding protein-glycan interactions that initiate and regulate inflammation. Examples include representatives from different glycan-binding protein families, including the C-type lectins (E-selectin, P-selectin, dectin-1, and dectin-2), sialic acid-binding immunoglobulin-like lectins (sialic acid-binding immunoglobulin-like lectins 8 and 9), galectins (galectin-1, galectin-3, and galectin-9), as well as hyaluronic acid-binding proteins. As glycoscience technologies advance, opportunities for enhanced understanding of glycans and their roles in leukocyte cell biology provide increasing opportunities for discovery and therapeutic intervention.


Role of glutathione in the antiulcer effect of hot water extract of black tea (Camellia sinensis).
The role of a hot water extract of black tea (Camellia sinensis (L). O. Kuntze Theaceae) in the gastric cytoprotective mechanisms was studied using gastric mucosal lesions produced by various ulcerogens in rats as an experimental model. Prior oral administration of black tea extract (BTE) at 20 ml/kg, i.g. once a day for 7 days significantly reduced the incidence of gastric erosions and severity induced by ethanol, diethyldithiocarbamate (DDC) and diethylmaleate (DEM). This treatment also favorably altered the changes in acid and peptic activity of gastric juice in these ulcerogen-treated animals. Singular administration of succimer (60 mg/kg, i.g.), the standard sulfhydryl containing antiulcer drug used as a reference drug, was also effective. The levels of glutathione and glutathione peroxidase were significantly decreased after treatment with ethanol, DDC and DEM, and this decrease was prevented by BTE pretreatment in the aforesaid manner. Other major features of BTE-induced reversal of ulcerogenic agents include a significant decrease in the protein content and a marked increase in hexosamine and sialic acid content. These results suggest a major role for glutathione, an endogenous antioxidant, in the cytoprotection against ulceration afforded by BTE.


Epstein-Barr virus SM protein functions as an alternative splicing factor.
Alternative splicing of RNA increases the coding potential of the genome and allows for additional regulatory control over gene expression. The full extent of alternative splicing remains to be defined but is likely to significantly expand the size of the human transcriptome. There are several examples of mammalian viruses regulating viral splicing or inhibiting cellular splicing in order to facilitate viral replication. Here, we describe a viral protein that induces alternative splicing of a cellular RNA transcript. Epstein-Barr virus (EBV) SM protein is a viral protein essential for replication that enhances EBV gene expression by enhancing RNA stability and export. SM also increases cellular STAT1 expression, a central mediator of interferon signal transduction, but disproportionately increases the abundance of the STAT1beta splicing isoform, which can act as a dominant-negative suppressor of STAT1alpha. SM induces splicing of STAT1 at a novel 5' splice site, resulting in a STAT1 mRNA incapable of producing STAT1alpha. SM-induced alternative splicing is dependent on the presence of an RNA sequence to which SM binds directly and which can confer SM-dependent splicing on heterologous RNA. The cellular splicing factor ASF/SF2 also binds to this region and inhibits SM-RNA binding and SM-induced alternative splicing. These results suggest that viruses may regulate cellular gene expression at the level of alternative mRNA splicing in order to facilitate virus replication or persistence in vivo.


Relevance of foreign alerts and newsletters for the medication errors reporting programme in the Netherlands: an explorative retrospective study.
National reporting programmes usually collect and analyse medication error reports from healthcare providers in their own country and only disseminate guidance to healthcare providers within the borders of their country. It is unclear how much different national programmes could learn from each other. The aim of this study was therefore to explore to what extent alerts and newsletters about medication errors issued in other countries could also be relevant for the Netherlands. Ninety disseminated information items that had been issued by three national programmes (Canada, the US and the UK) in the period from June 2009 until June 2012 were collected. These items were compared with the national reporting programme Central Medication Incidents Registration (CMR-NL) in The Netherlands. Each selected item was subsequently assessed independently with six assessment criteria: is the medicine available in the Netherlands? If so, could a similar error occur in the Netherlands? Did the CMR-NL reporting programme receive any reports about a comparable (or even identical) error? If so, did these reports include any errors with serious temporary or permanent harm? Did the CMR-NL disseminate output about it?; If so, what was the dissemination date of CMR-NL? From the 90 items, 87.8 % (n = 79) were relevant for Dutch healthcare. For 43 of the 90 items (47.8 %), the CMR-NL had received comparable (or even identical) errors but had not disseminated any alert or newsletter about these errors. The CMR-NL had disseminated an alert or newsletter for 14 of the 90 items (15.6 %). This study showed for a broad range of errors that the Dutch national reporting programme could learn from the three reporting programmes in Canada, the US and the UK. National reporting programmes can benefit from sharing alerts and newsletters that enhance the learning between countries.


Circadian rhythm of nucleoli in rat superior cervical ganglion neurons: the two types of fibrillar centres and their quantitative relationship with the nucleolar organizing regions.
A quantitative stereological analysis was undertaken in nucleoli of rat superior cervical ganglion neurons. In this model, two types of fibrillar centres were observed: (1) small-type fibrillar centres were observed during the light span; and (2) a single large-type fibrillar centre occurred during the dark span near the smaller ones. The present data showed that the drastic increase in the mean volume of fibrillar centres during the dark span involved the occurrence and the progressive enlargement of one single large-type fibrillar centre and a marked rise in the number of small-type centres from 18 +/- 2 to 74 +/- 5 at 1500 h and 0100 h corresponding to light and dark spans, respectively. The total number of these small-type fibrillar centres per nucleolus increased with the total volume whereas their unit volume remained unchanged. This enabled us to establish some relationship with nucleolar organizing regions (NORs).


Limited Sampling Strategies for Estimating Busulfan Area Under the Concentration-Time Curve: Based on Peak and Trough Concentrations in Saliva.
Therapeutic drug monitoring for busulfan is currently performed by multiple plasma sampling. Saliva is considered a noninvasive therapeutic drug monitoring matrix. This study aimed to investigate intravenous busulfan pharmacokinetics (PK) in plasma and saliva, and establish a limited sampling strategy (LSS) for predicting the area under the concentration-time curve from time zero to infinity in plasma (AUC0-∞,p) by using saliva samples. Therefore, the PK of busulfan was studied in 37 Chinese patients. Pearson correlation analysis was used to evaluate the correlation between the AUC of busulfan in plasma and saliva. LSS models were established by the multiple linear regression analysis. The prediction error, the mean prediction error, and the root mean square error were used to evaluate the predictive accuracy. The agreement between the predicted and observed AUC0-∞ in saliva was investigated by the intraclass correlation coefficient and Bland-Altman analysis. The accuracy and robustness of the models were evaluated by using the bootstrap procedure. The result of PK analysis 62.2% of patients (23/37) was within the target range of AUC0-∞,p . A good correlation between saliva and plasma busulfan AUC0-∞ was observed (r = 0.63, p < .01). The bias and precision of the models 7 and 13 were less than 15%. The intraclass correlation coefficient exceeded 0.9, and the limits of agreement were within ±15%. The 2-point LSS model in saliva is a convenient and desirable approach to predict the AUC0-∞ of 4 times daily intravenous busulfan in plasma, which can be used to design personalized dosing for busulfan.


Hydrogen-deuterium (H/D) exchange mapping of Abeta 1-40 amyloid fibril secondary structure using nuclear magnetic resonance spectroscopy.
We describe here details of the hydrogen-deuterium (H/D) exchange behavior of the Alzheimer's peptide Abeta(1)(-)(40), while it is a resident in the amyloid fibril, as determined by high-resolution solution NMR. Kinetics of H/D exchange in Abeta(1)(-)(40) fibrils show that about half the backbone amide protons exchange during the first 25 h, while the other half remain unexchanged because of solvent inaccessibility and/or hydrogen-bonded structure. After such a treatment for 25 h with D(2)O, fibrils of (15)N-enriched Abeta were dissolved in a mixture of 95% dimethyl sulfoxide (DMSO) and 5% dichloroacetic acid (DCA) and successive heteronuclear (1)H-(15)N HSQC spectra were collected to identify the backbone amides that did not exchange in the fibril. These studies showed that the N and C termini of the peptide are accessible to the solvent in the fibril state and the backbone amides of these residues are readily exchanged with bulk deuterium. In contrast, the residues in the middle of the peptide (residues 16-36) are mostly protected, suggesting that that many of the residues in this segment of the peptide are involved in a beta structure in the fibril. Two residues, G25 and S26, exhibit readily exchangeable backbone amide protons and therefore may be located on a turn or a flexible part of the peptide. Overall, the data substantially supports current models for how the Abeta peptide folds when it engages in the amyloid fibril structure, while also addressing some discrepancies between models.


Biomimetic total syntheses of cassiarins A and B.
Total syntheses of cassiarins A and B have been efficiently accomplished using a common strategy with biomimetic considerations. Key reactions involved in this synthesis include a Negishi-type coupling, a Ag(I)-promoted formation of the tricyclic 8H-pyrano[2,3,4-de]chromen-8-one core, and a sequential amine-condensation and cyclization. Three new analogues of cassiarin A bearing different substituents at the C-11 position were synthesized in parallel from the same intermediate. In addition, two other transformations to the key tricyclic cores and cassiarins A and B were achieved from corresponding chemically equivalent precursors.


Improved image quality and computation reduction in 4-D reconstruction of cardiac-gated SPECT images.
Spatiotemporal reconstruction of cardiac-gated SPECT images permits us to obtain valuable information related to cardiac function. However, the task of reconstructing this four-dimensional (4-D) data set is computation intensive. Typically, these studies are reconstructed frame-by-frame: a nonoptimal approach because temporal correlations in the signal are not accounted for. In this work, we show that the compression and signal decorrelation properties of the Karhunen-Loève (KL) transform may be used to greatly simplify the spatiotemporal reconstruction problem. The gated projections are first KL transformed in the temporal direction. This results in a sequence of KL-transformed projection images for which the signal components are uncorrelated along the time axis. As a result, the 4-D reconstruction task is simplified to a series of three-dimensional (3-D) reconstructions in the KL domain. The reconstructed KL components are subsequently inverse KL transformed to obtain the entire spatiotemporal reconstruction set. Our simulation and clinical results indicate that KL processing provides image sequences that are less noisy than are conventional frame-by-frame reconstructions. Additionally, by discarding high-order KL components that are dominated by noise, we can achieve savings in computation time because fewer reconstructions are needed in comparison to conventional frame-by-frame reconstructions.


The estimated glomerular filtration rate is associated with subclinical atherosclerosis, independently of albuminuria, in patients with type 2 diabetes.
The aim of this paper was to study the relationship between the intima-media thickness (IMT) of the carotid artery and the estimated glomerular filtration rate (eGFR) and albuminuria in the Chinese patients with type 2 diabetes mellitus. As a cross-sectional study, common carotid artery (CCA) IMT as a surrogate marker of cardiovascular disease is adopted. Data were obtained from a study undertaken to evaluate the prevalence of diabetic complications. Body mass measurements, fasting blood measures, urinary albuminuria creatinine ratio and carotid atherosclerotic measurements were investigated. Association of the carotid IMT with albuminuria stage and eGFR was determined by stepwise multivariate regression analysis adjusting for the possible confounders. 1) The mean age of all 721 patients was 65.33±11.32 years and the duration of diabetes was 7.72±6.93 years. 2) The percentage of impaired eGFR (<60 mL/min/1.73 m2) and albuminuria was 4.9% and 41.3% respectively, 37.0% with microalbuminuria and 4.3% with macroalbuminuria. 3) Compared to subjects with normoalbuminuria (28.8%), the percentage of CCA-IMT thickening in subjects with macroalbuminuria (41.9%) and microalbuminuria (43.1%) was higher (P<0.01). Moreover, compared to patients with eGFR ≥90 mL/min/1.73 m2 (28.8%), patients with eGFR ranged from 60 to 89 mL/min/1.73 m2 (43.2%) and eGFR< 60 mL/min/1.73 m2 (51.4%) tended to have greater percentage of CCA-IMT thickening (P<0.01). 4) In a stepwise regression model, age, fasting blood glucose, total cholesterol, reduced HDL-cholesterol and eGFR were independent predictors of CCA-IMT, after adjusting for potential confounders including gender, current smoker, duration of diabetes, waist circumference, hypertension, systolic blood pressure, diastolic blood pressure, triglyceride, LDL-cholesterol, postprandial glucose, HbA1c and albuminuria stage. Reduced eGFR associated with IMT thickening independently of albuminuria is found in the patients with type 2 diabetes mellitus, and further studies investigating the clinical outcomes are needed because this study is based on a cross-sectional design.


Antibiotic prophylaxis in organophosphorus poisoning: A study of health and economic outcomes.
Objective: Organophosphorus poisoning (OPP) is a major concern for developing countries. There are no guidelines for the prophylactic use of antibiotics in the management of OPP which in such critical cases might add to the economic burden of the patients as well as antibiotic resistance. We compared the health and economic outcomes in patients prescribed with prophylactic antibiotics with respect to the patients not prescribed with any antibiotics. Methods: A retrospective observational study was carried out for two years for patients admitted to ICU with OPP. Patients were graded for severity of OPP, and divided into two groups based on prophylactic prescription and no prescription of antibiotics. The length of stay (LOS), hospitalization cost and outcomes were measured and compared between the two groups using statistical tests. Results: Out of the 254 patients observed, 108 were prescribed with prophylactic antibiotics and 94 were not prescribed with any antibiotic. There was a significant difference between LOS, cost of treatment and outcomes in the two groups (p < 0.001). When antibiotics were not prescribed, the odds of improvement was 1.854 times higher compared to those who received prophylactic antibiotics although after adjusting for severity of poisoning, significance was lost. On an average, 2-3 antibiotics were prescribed to every patient in the first group. Conclusion: OPP is an important health concern where issues of antibiotic misuse and overuse are practiced. Our study suggested that systemic antibiotic prophylaxis did not offer any advantage over non-use of any antibiotics in patients with OPP.


A conformation-equilibrium model captures ligand-ligand interactions and ligand-biased signalling by G-protein coupled receptors.
G-protein coupled receptors (GPCRs) are a versatile, important class of cell-surface receptors. GPCRs occur in different conformations that exist in a dynamic ligand-sensitive equilibrium. These conformations vary in their affinities for intracellular signalling proteins and initiate signalling via different intracellular routes. The binding of extracellular ligands and allosteric ligand-ligand interactions shift conformation equilibria to cause biased signalling. Here, we present a mathematical model that describes the effects of ligands on the conformation equilibria of GPCRs. Our extended Monod-Wyman-Changeux model describes the receptor as shifting between active and inactive receptor conformations under the influence of extracellular ligands. For each receptor conformation, the intracellular domain of the receptor can attain alternative domain conformations that differ in their affinity for intracellular signalling proteins. At the extracellular domain, the model can accommodate different mechanisms for allosteric ligand-ligand interactions that induce shifts in receptor and domain conformation equilibria. We use the model to study ligand-biased signalling and how ligand affinity, ligand sensitivity and maximal signalling output depend on allosteric ligand-ligand interactions.


Kinetics of enzymatic high-solid hydrolysis of lignocellulosic biomass studied by calorimetry.
Enzymatic hydrolysis of high-solid biomass (>10% w/w dry mass) has become increasingly important as a key step in the production of second-generation bioethanol. To this end, development of quantitative real-time assays is desirable both for empirical optimization and for detailed kinetic analysis. In the current work, we have investigated the application of isothermal calorimetry to study the kinetics of enzymatic hydrolysis of two substrates (pretreated corn stover and Avicel) at high-solid contents (up to 29% w/w). It was found that the calorimetric heat flow provided a true measure of the hydrolysis rate with a detection limit of about 500 pmol glucose s(-1). Hence, calorimetry is shown to be a highly sensitive real-time method, applicable for high solids, and independent on the complexity of the substrate. Dose-response experiments with a typical cellulase cocktail enabled a multidimensional analysis of the interrelationships of enzyme load and the rate, time, and extent of the reaction. The results suggest that the hydrolysis rate of pretreated corn stover is limited initially by available attack points on the substrate surface (<10% conversion) but becomes proportional to enzyme dosage (excess of attack points) at later stages (>10% conversion). This kinetic profile is interpreted as an increase in polymer end concentration (substrate for CBH) as the hydrolysis progresses, probably due to EG activity in the enzyme cocktail. Finally, irreversible enzyme inactivation did not appear to be the source of reduced hydrolysis rate over time.


Tau protein binds to microtubules through a flexible array of distributed weak sites.
Tau protein plays a role in the extension and maintenance of neuronal processes through a direct association with microtubules. To characterize the nature of this association, we have synthesized a collection of tau protein fragments and studied their binding properties. The relatively weak affinity of tau protein for microtubules (approximately 10(-7) M) is concentrated in a large region containing three or four 18 amino acid repeated binding elements. These are separated by apparently flexible but less conserved linker sequences of 13-14 amino acids that do not bind. Within the repeats, the binding energy for microtubules is delocalized and derives from a series of weak interactions contributed by small groups of amino acids. These unusual characteristics suggest tau protein can assume multiple conformations and can pivot and perhaps migrate on the surface of the microtubule. The flexible structure of the tau protein binding interaction may allow it to be easily displaced from the microtubule lattice and may have important consequences for its function.


From the Revolution to Embodiment: 25 Years of Cognitive Psychology.
In 1988, the cognitive revolution had become institutionalized: Cognition was the manipulation of abstract symbols by rules. But, much like institutionalized political parties, some of the ideas were becoming stale. Where was action? Where was the self? How could cognition be smoothly integrated with emotions, with social psychology, with development, with clinical analyses? Around that time, thinkers in linguistics, philosophy, artificial intelligence, biology, and psychology were formulating the idea that just as overt behavior depends on the specifics of the body in action, so might cognition depend on the body. Here we characterize (some would say caricature) the strengths and weaknesses of cognitive psychology of that era, and then we describe what has come to be called embodied cognition: how cognition arises through the dynamic interplay of brain controlling bodily action controlling perception, which changes the brain. We focus on the importance of action and how action shapes perception, the self, and language. Having the body in action as a central consideration for theories of cognition promises, we believe, to help unify psychology.


Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer.
Resistance to endocrine therapy (ET) is common in patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Consequently, new targeted treatment options are needed in the post-ET setting, with validated biomarkers to inform treatment decisions. Hyperactivation of the phosphoinositide 3-kinase (PI3K) signaling pathway is common in ABC and is implicated in resistance to ET. The most frequent mechanism of PI3K pathway activation is activating mutations or amplification of PIK3CA, which encodes the α-isoform of the catalytic subunit of PI3K. Combining buparlisib, a pan-PI3K-targeted agent, with ET demonstrated modest clinical benefits in patients with aromatase inhibitor-resistant, HR+, human epidermal growth receptor 2 negative (HER2-) ABC in two phase III trials. Importantly, greater efficacy gains were observed in individuals with PIK3CA-mutated disease versus PIK3CA-wild-type tumors. Although the challenging safety profile did not support widespread use of this treatment combination, isoform-selective PI3K inhibitors may improve tolerability. In early clinical trials, promising disease control benefits were demonstrated with the PI3K isoform-selective inhibitors alpelisib and taselisib in patients with PIK3CA-mutated HR+, HER2- ABC. Ongoing biomarker-guided phase II/III studies may provide further opportunities to identify patients most likely to benefit from treatment with PI3K inhibitors and provide insight into optimizing the therapeutic index of PI3K inhibitors. Challenges facing the implementation of routine PIK3CA mutation testing must be addressed promptly so robust and reproducible genotyping can be obtained with liquid and tumor biopsies in a timely and cost-effective manner. IMPLICATIONS FOR PRACTICE: The development of phosphoinositide 3-kinase (PI3K) inhibitors, especially those that selectively target isoforms, may be an effective strategy for overcoming endocrine therapy resistance in hormone receptor positive, human epidermal growth receptor 2 negative advanced breast cancer. Early-phase studies have confirmed that patients with PIK3CA mutations respond best to PI3Kα-isoform inhibition. Ongoing phase III trials will provide further data regarding the efficacy and safety of PI3K inhibitors in patients with different biomarker profiles.


[The adaptation potential of student youth].
The research data concerning the social psychological adaptation of student youth to the general social conditions and the immediate vitality environment is discussed. The University entrance is characterized by changing of activities and hence intensifying of the adaptation processes. The students experience higher psychological physiological stress factually of all body systems. It results in the development of chronic non-infectious diseases among future specialists. On the basis on the analysis of positive-negative assessment by the students of major aspects of their life and the level of being satisfied with occurring social changes it was established that only 28,1% of students managed to fit into the new social environment and to adapt to the conditions of modern life.


Validating a clinical measure of levator hiatus size.
We evaluate the interrater reliability of levator hiatus (LH) size and correlate size to other measures of muscle function. Participants were examined independently by 2 examiners. During maximal contraction of the levator ani, the muscle was assessed by using Brink's scale. The LH was measured in the transverse and sagittal dimensions by digital palpation. The paired t test was used to compare continuous variables and Spearman's coefficient was used for correlations. The mean LH transverse was 4.5 cm and the mean LH sagittal was 3 cm. The inter-rater correlation for the LH transverse measurement was 0.6 (P < .01) and 0.8 (P < .01) for the LH sagittal measurement. The correlations between the LH size and Brink's scale were moderate (correlation coefficient -0.4 to -0.5, P < .01). Eighty-three percent of measurements were within 1 cm. This technique for clinical measurement of levator hiatus size shows good interrater reliability.


Prevention of vocal fold scarring by topical injection of hepatocyte growth factor in a rabbit model.
Vocal fold scarring disrupts the layer structure of the vocal fold lamina propria that is essential for optimal mucosal vibration. Prevention of vocal fold scarring remains challenging. Hepatocyte growth factor (HGF) has strong antifibrotic activity. The authors' previous studies have found that HGF stimulates hyaluronic acid production and suppresses collagen production from vocal fold fibroblasts, suggesting that HGF has therapeutic potential in prevention of vocal fold scarring. The present study aimed to demonstrate the effects of HGF on vocal fold scarring in an in vivo rabbit model. Animal experiment. The vocal fold mucosa was stripped unilaterally in 20 rabbits, then HGF or saline (sham-treated group) was immediately injected into the injured site. At 6 months after the procedure, histological, rheological, and physiological examinations of vibratory behavior were completed. Histological examination revealed excessive collagen deposition and disorganized elastin in the sham-treated group, whereas the HGF-treated group presented with better wound healing exhibiting less collagen deposition. Contraction of the injured vocal folds observed in the sham-treated group did not occur in the HGF-treated group. Rheological data indicated that the HGF-treated vocal folds were less stiff and viscous compared with the sham-treated group. Mucosal vibration of HGF-treated vocal folds appeared much better than the sham-treated group in terms of phonation threshold pressure, vocal efficiency, mucosal wave amplitude, and glottal closure. Hepatocyte growth factor proved to be useful in preventing vocal fold scarring and maintaining viscoelastic shear properties of the vocal fold.


A role for phosphatidylinositol 3-kinase in platelet aggregation in response to low, but not high, concentrations of PAF or thrombin.
In this study we show that platelet activating factor (PAF) activates PI 3-kinase over a rapid time course that correlates closely with the aggregation response. Tyrosine kinases are involved in this response, since there is increased PI 3-kinase activity associated with tyrosine-phosphorylated proteins. PI 3-kinase inhibitors were used to probe the dependence of PAF-induced aggregation on PI 3-kinase. Both wortmannin and LY-294002 inhibited PAF-induced aggregation that correlated with PI 3-kinase inhibition only when using lower concentrations of PAF giving reversible aggregation (primary phase). Similar results were obtained with human platelets using thrombin or thrombin receptor activating peptide. The same pattern of response was observed when activation of GPIIbIIIa was assessed by flow cytometry, i.e., PI 3-kinase inhibitors blocked integrin activation only when lower concentrations of agonist were used. We suggest that PI 3-kinase is important for reversible (primary) aggregation of platelets in response to PAF or thrombin, perhaps by contributing to the 'inside-out' activation of the platelet integrin GPIIbIIIa, only when submaximal concentrations of agonists are used. The lack of effect of PI 3-kinase inhibitors, when high concentrations of agonist are used, suggests that PI 3-kinase-independent pathways contribute to aggregation under these conditions.


Magnetoencephalography reveals a unique neurophysiological profile of focal-onset epileptic spasms.
Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to experience epileptic seizures and the neurobiological, cognitive, psychological, and social difficulties relating to the condition. An epileptic spasm (ES) is a type of seizure characterized by clusters of short contractions involving axial muscles and proximal segments. However, the precise mechanism of ESs remains unknown. Despite the potential of magnetoencephalography (MEG) as a tool for investigating the neurophysiological mechanism of ESs, it has been difficult to use this methodology due to magnetic artifacts attributable to patient movement. We report on an 8-year-old girl suffering from intractable epileptic spasms from the age of 7 months. She was diagnosed with possible Aicardi syndrome [corrected] (AGS), characterized by the triad of callosal agenesis, infantile spasms, and chorioretinal lacunae. She is now intellectually delayed and suffers from intractable ES. We used both MEG and electroencephalography to investigate her epilepsy. The recording captured two series of spasm clusters. Spikes were clearly identified with MEG in about four-fifths of all spasms but were identified poorly or not at all in the remainder. MEG findings support previous studies that used intracranial electrodes to analyze patients with ESs and that showed variability in ES-associated spikes in terms of manner of cortical involvement and magnitude. Given the limitations of intracranial electrodes, such as sampling restrictions and invasiveness, MEG may be a helpful tool for non-invasively investigating the unique pathophysiological profile of focal-onset ESs.


Correlation of morphology with viability of Mycobacterium leprae.
A concept has been developed in the recent years that the evenly stained 'solid' bacilli are living and the 'non-solid' forms are degenerate and dead. This communication presents the findings in experimental mice inoculated with material containing 1 to 10% solid evenly stained M. leprae and also with material containing 0% solid organisms. There was multiplication of the bacilli in both the groups. Quantitatively, the yield also was not significantly different. These fundings do not support the belief that the non-solid bacilli are necessarily dead. The non-solid bacilli were further classified on the basis of their morphology to the following forms:-- (a) short but evenly stained (b) indented (c) beaded (d) dumb-bell shaped (e) coccoid and (f) fragmented. Material without solid bacilli, but containing different proportions of the above types of bacilli also gave similar results, making it diffcult to say which types of morphological forms are non-living. It appears, therefore, that the recognition of the living status of M. leprae by its morphology is highly equivocal and subject to error.


Wrist denervation in isolation: a prospective outcome study with patient selection by wrist blockade.
Surgical wrist denervation involves division of the anterior and posterior interosseous nerves and articular branches of the superficial radial nerve. In this outcome study, 37 patients were individually assessed and deemed suitable for denervation surgery due to appreciable symptom resolution following a local anesthetic wrist block. At a mean of 18 months following denervation surgery, median activity pain scores had decreased by 60% (p < 0.001) from initial assessment levels, and more than three quarters (30/37) of patients reported continued improvement in their activity pain (p < 0.001). More than two thirds of patients had a satisfaction VAS of greater than 50, with less postoperative resting pain and a greater reduction in postoperative activity pain as the important predictors of patient satisfaction. Thirty-one out of the 37 patients had not represented to our department for revision wrist surgery by a mean of 10.3 years follow-up. We have found this procedure useful in ameliorating symptoms for some patients who would conventionally have required partial or total wrist fusions with greater residual functional limitation.


The association of postcardiac surgery acute kidney injury with intraoperative systolic blood pressure hypotension.
Background. Postoperative acute kidney injury (AKI) is associated with high mortality and substantial cost after aortocoronary bypass graft (CABG) surgery. We tested the hypothesis that intraoperative systolic blood pressure variation is associated with postoperative AKI. Methods. We gathered demographic, procedural, blood pressure, and renal outcome data for 7,247 CABG surgeries at a single institution between 1996 and 2005. A development/validation cohort methodology was randomly divided (66% and 33%, resp.). Peak postoperative serum creatinine rise relative to baseline (%ΔCr) was the primary AKI outcome variable. Markers reflective of intraoperative systolic blood pressure variation were derived for each patient including (1) peak and nadir values (absolute and relative to baseline) and (2) excursion episodes beyond selected thresholds (by duration, frequency, and duration × degree). Each marker of systolic blood pressure variation was then separately evaluated for association with AKI using linear regression models with adjustment for several known risk factors (age, aprotinin use, congestive heart failure, previous myocardial infarction, baseline creatinine, bypass time, diabetes, weight, concomitant valve surgery, gender, and preoperative pulse pressure). Results. An association was identified between systolic blood pressure relative to baseline and postoperative AKI (P < 0.006). Conclusions. In CABG surgery patients, intraoperative systolic blood pressure decrease relative to baseline systolic blood pressure is independently associated with postoperative AKI.


[Left ventricular-arterial coupling in the resuscitation of refractory septic shock].
To explore the role of left ventricular-arterial coupling in the resuscitation of refractory septic shock. A total of 58 patients with refractory septic shock admitted from January 2010 to July 2011 were retrospectively studied. Hemodynamic data, arterial lactate concentration and APACHEII (acute physiology & chronic health evaluation II) score at the beginning of and 24 hours after cardiac output monitoring, as well as the outcome of Day 28 post-diagnosis were recorded. Stroke volume index (SVI), cardiac index (CI) and global end diastolic volume index (GEDVI) were obtained through transpulmonary thermodilution technique by a pulse induced continuous cardiac output (PiCCO) system. Left ventricular end systolic volume index (LVESVI) was approximated to (GEDVI/4-SVI) while effective arterial elastance index/ventricular end systolic elastance index (EaI/EesI) was approximated to LVESVI/SVI. (1) APACHEII score at the 24th hour, 24 hs lactate clearance rate and 24 hs Ea/Ees variation (ΔEa/Ees) were higher in non-survivors than those in survivors; (2) binary Logistic regression analysis showed that ΔEa/Ees and APACHEII score at the 24th hour were the independent risk factors of mortality for refractory septic shock. And the OR value of ΔEa/Ees was higher than that of APACHEII score (2.04 vs 1.63). Their areas of ROC curve were 0.705 (95%CI 0.569 - 0.841, P = 0.007) and 0.939 (95%CI 0.878 - 1.000, P = 0.000) respectively; (3) all hemodynamic parameters at the beginning had no difference between ΔEa/Ees > 0 and ΔEa/Ees ≤ 0 groups. CI, SVI, EGDT (early goal-directed therapy) compliance rate at the 24th hour in the ΔEa/Ees > 0 group were lower than those in the ΔEa/Ees ≤ 0 group. The effective arterial elastance index (EaI) at the 24th hour and the mortality rate of Day 28 in the ΔEa/Ees > 0 group were higher than those in the ΔEa/Ees ≤ 0 group; (4) during the 24 hs treatment, ΔEa/Ees was correlated negatively with the variations of CI, SVI, EesI and lactate clearance rate and positively with the variations of heart rate, GEDVI, systolic vascular resistance index and EaI. ΔEa/Ees may be used as an excellent marker of predicting the outcome of refractory septic shock. Lowing Ea/Ees in resuscitation has beneficial effects on EGDT compliance, lactate clearance and outcome.


Ral GTPases contribute to regulation of cyclin D1 through activation of NF-kappaB.
Ral GTPases have been implicated as mediators of Ras-induced signal transduction from observations that Ral-specific guanine nucleotide exchange factors associate with Ras and are activated by Ras. The cellular role of Ral family proteins is unclear, as is the contribution that Ral may make to Ras-dependent signaling. Here we show that expression of activated Ral in quiescent rodent fibroblasts is sufficient to induce activation of NF-kappaB-dependent gene expression and cyclin D1 transcription, two key convergence points for mitogenic and survival signaling. The regulation of cyclin D1 transcription by Ral is dependent on NF-kappaB activation and is mediated through an NF-kappaB binding site in the cyclin D1 promoter. Ral activation of these responses is likely through an as yet uncharacterized effector pathway, as we find activation of NF-kappaB and the cyclin D1 promoter by Ral is independent of association of Ral with active phospholipase D1 or Ral-binding protein 1, two proteins proposed to mediate Ral function in cells.


Near-optimal combination of disparity across a log-polar scaled visual field.
The human visual system is foveated: we can see fine spatial details in central vision, whereas resolution is poor in our peripheral visual field, and this loss of resolution follows an approximately logarithmic decrease. Additionally, our brain organizes visual input in polar coordinates. Therefore, the image projection occurring between retina and primary visual cortex can be mathematically described by the log-polar transform. Here, we test and model how this space-variant visual processing affects how we process binocular disparity, a key component of human depth perception. We observe that the fovea preferentially processes disparities at fine spatial scales, whereas the visual periphery is tuned for coarse spatial scales, in line with the naturally occurring distributions of depths and disparities in the real-world. We further show that the visual system integrates disparity information across the visual field, in a near-optimal fashion. We develop a foveated, log-polar model that mimics the processing of depth information in primary visual cortex and that can process disparity directly in the cortical domain representation. This model takes real images as input and recreates the observed topography of human disparity sensitivity. Our findings support the notion that our foveated, binocular visual system has been moulded by the statistics of our visual environment.


An agent-based model of the female rivalry hypothesis for concealed ovulation in humans.
After half a century of debate and few empirical tests, there remains no consensus concerning why ovulation in human females is considered concealed. The predominant male investment hypothesis states that females were better able to obtain material investment from male partners across those females' ovulatory cycles by concealing ovulation. We build on recent work on female competition to propose and investigate an alternative-the female rivalry hypothesis-that concealed ovulation benefited females by allowing them to avoid aggression from other females. Using an agent-based model of mating behaviour and paternal investment in a human ancestral environment, we did not find strong support for the male investment hypothesis, but found support for the female rivalry hypothesis. Our results suggest that concealed ovulation may have benefitted females in navigating their intrasexual social relationships. More generally, this work implies that explicitly considering female-female interactions may inspire additional insights into female behaviour and physiology.


Impact of yoga on blood pressure and quality of life in patients with hypertension - a controlled trial in primary care, matched for systolic blood pressure.
Medical treatment of hypertension is not always sufficient to achieve blood pressure control. Despite this, previous studies on supplementary therapies, such as yoga, are relatively few. We investigated the effects of two yoga interventions on blood pressure and quality of life in patients in primary health care diagnosed with hypertension. Adult patients (age 20-80 years) with diagnosed hypertension were identified by an electronic chart search at a primary health care center in southern Sweden. In total, 83 subjects with blood pressure values of 120-179/≤109 mmHg at baseline were enrolled. At baseline, the patients underwent standardized blood pressure measurement at the health care center and they completed a questionnaire on self-rated quality of life (WHOQOL-BREF). There were three groups: 1) yoga class with yoga instructor (n = 28); 2) yoga at home (n = 28); and 3) a control group (n = 27). The participants were matched at the group level for systolic blood pressure. After 12 weeks of intervention, the assessments were performed again. At baseline a majority of the patients (92%) were on antihypertensive medication, and the patients were requested not to change their medication during the study. The yoga class group showed no improvement in blood pressure or self-rated quality of life, while in the yoga at home group there was a decline in diastolic blood pressure of 4.4 mmHg (p < 0.05) compared to the control group. Moreover, the yoga at home group showed significant improvement in self-rated quality of life compared to the control group (p < 0.05). A short yoga program for the patient to practice at home seems to have an antihypertensive effect, as well as a positive effect on self-rated quality of life compared to controls. This implies that simple yoga exercises may be useful as a supplementary blood pressure therapy in addition to medical treatment when prescribed by primary care physicians.


Association between Continuity of Care and Health-Related Quality of Life.
Patient-reported outcomes (PROs) are considered potential quality metrics for patients with multiple chronic medical conditions (MCC). Although continuity of care (COC) is an essential MCC care process, the association between common PROs and COC is unknown. We assessed baseline and two-year follow-up self-reported health status, physical, and emotional well-being, and COC in seniors with MCC. Using mixed effects models with repeated measures adjusting for age, gender, and morbidity, we assessed each outcome as a function of COC. Of 2,078 seniors, 961 completed the initial survey and 806 completed follow-up. On a 0-100 scale, mean (sd) baseline self-reported health status, physical well-being, and emotional well-being were 48.7 (22.0), 36.4 (11.4), and 54.8 (9.0). On a 0 to 1 scale, mean baseline and 2-year COC were 0.24 (sd 0.22) and 0.22 (0.18). Follow-up self-reported health status, physical well-being, and emotional well-being were 48.8 (23.1), 36.5 (11.5), and 55.3 (8.8). In adjusted primary and secondary analyses using all available data, there were no associations between any outcomes and COC. Given the measurement burden of quality assessment, negative associations between potential quality metrics and care processes are informative. Systematic assessment of PROs can inform patient-centered MCC care. However, PRO scores should be used with caution as quality measures.


Ethics seminars: vulnerable populations in emergency medicine research.
Regulatory bodies and institutional review boards are increasingly considering human subjects who are vulnerable to research not because of their intrinsic characteristics, but because of the particular situations or circumstances that they bring with them as potential research participants. Several subsets of emergency department patients may be considered vulnerable in the research setting. This may include patients who are vulnerable because of a medical condition, a baseline limitation of intellectual function, a social setting, psychosocial stressors, or other factors. These issues should be carefully considered when including such patients in research protocols. Special efforts should be made to ensure voluntary participation and understanding of the purposes and risks of participation.


[Certain technical aspects of performing carotid endarterectomy].
The study was aimed at improving the results of carotid endarterectomy (CEA) by means of improving technical methods of performing reconstruction of the carotid bifurcation. From January 2012 to December 2014 at the Department of Vascular Surgery we performed a total of 703 CEA operations, including 183 (26%) according to the classical technique and 520 (74%) according to the eversion technique. The average age of patients amounted to 61.8±9.5 years. Operations were performed in patients with more than 70% stenoses of the internal carotid artery (ICA). 673 reconstructions were performed under general anaesthesia and 30 under the regional one. The preoperative examination included ultrasound duplex scanning (USDS), transcranial dopplerography, transcranial duplex scanning, magnetic resonance tomography (angiography). The technical result of the operation was assessed by means of intraoperative USDS. 62 (9%) patients underwent eversion CEA with prolongation of the cut on the ICA and external carotid artery (ECA) with the formation of an "extended" anastomosis between them. 28 (4%) patients were subjected to the classical CEA with the use of the technique of formation of a new bifurcation of the carotid artery by means of Y-shaped arteriotomy of the common carotid artery, ICA and ECA. In order to prevent flotation of the proximal portion of the atherosclerotic plaque cut in the common carotid artery it was fixed by II-shaped sutures. The remote results of eversion CEA with the creation of the "extended" anastomosis were followed up in 42 (68%) patients within the terms of 21±8 months. There were neither lethal outcomes nor strokes. Significant stenosis (more than 70% of the ICA lumen) was revealed in one patient. After CEA with the formation of a new bifurcation in the immediate postoperative period there were no cerebral circulation impairments. 18 (64%) patients were examined in the remote terms (21±9 months). There were neither lethal outcomes nor strokes. The check USDS revealed no significant restenoses of carotid arteries. Conclusion were drawn that preliminary marking of the carotid bifurcation with the help of USDS made it possible to optimize the length of the approach during CEA. The routine application of intraoperative USDS gives a possibility to reveal floating portions of the intima, thrombotic masses and to timely take measures aimed at removing these defects. The method of forming a new bifurcation of the carotid artery may be used in prolonged stenotic lesions of carotid arteries. This makes it possible to avoid the use of a synthetic patch with possible unfavourable aftermaths, thus considerably shortening the duration of the main stage of reconstruction.


D-Chiro-inositol and its significance in polycystic ovary syndrome: a systematic review.
The pathogenesis of polycystic ovary syndrome (PCOS) has been linked to the development of insulin resistance and hyperinsulinemia. The objective of this study is to investigate the effects of insulin sensitising agents such as D-chiro-inositol (DCI) on ovulation and insulin resistance in women with PCOS. This was a systematic review done in an Academic Department of Obstetrics and Gynaecology in the UK of all studies published on PCOS and DCI up till May 2010. Patients were women with PCOS receiving DCI or where the relationship between insulin resistance and DCI had been investigated. Ovulation rates and changes in insulin sensitivity were the main outcome measures. Less DCI-IPG was released in PCOS women compared to controls and this seems to correlate positively with insulin resistance and hyperinsulinemia evident in these patients. DCI administration had beneficial effects on ovulation, anthropometric and metabolic markers in PCOS women by enhancing insulin. The effects of metformin in improving insulin action in PCOS women was achieved though the release of DCI-IPG mediators. Heterogeneity observed in the methodologies of each study, the scarcity of relevant studies and the small sample sizes used prohibit reliable conclusions to be drawn. Therefore, more studies must be conducted in the future to evaluate accurately the effects of DCI in PCOS.


Development of a condensed locus control region cassette and testing in retrovirus vectors for A gamma-globin.
Retrovirus vectors for A gamma-globin are being developed for the treatment of beta chain hemoglobinopathies. Toward the goal of achieving therapeutic expression levels, core elements of the beta-globin locus control region (LCR) hypersensitive sites (HS) were screened for enhancer activity in erythroid MEL and K562 cell lines using a drug-resistant colony assay. When used alone, core elements of HS1, HS3, and HS4 showed no activity and a fragment for HS2 showed only modest activity in the colony assay. However, a 1.1 kb combination of fragments for HS2, HS3, and HS4 (termed a nLCR) enhanced colony formation 17-fold in K562 cells and 94-fold in MEL cells. Addition of an HS1 fragment enhanced nLCR activity only modestly in MEL cells. When linked to a beta-globin gene, the 1.1 kb nLCR enhanced globin mRNA expression to 82% per copy of mouse alpha-globin in transfected MEL cells. Inclusion of a nLCR in retrovirus vectors containing a beta-globin promoter and various A gamma-globin gene expression cassettes resulted in extreme genetic instability and reduced titers. Specific deletions were abrogated by removing homologous sequences, but random recombinations were still observed at significant frequencies. In MEL cells containing intact provirus, A gamma-globin mRNA produced by an optimal vector containing the nLCR was only 2-fold higher (8.5% vs. 3.9% per copy of mouse alpha-globin) compared to the same vector without the nLCR. These data suggest that vector elements detract from the ability of the nLCR to enhance expression of the beta pr.A gamma cassettes.


Distribution of vasoactive intestinal polypeptide (VIP) binding in circular muscle and characterization of VIP binding in canine small intestinal mucosa.
The present study examined the localization and characterization of [125I]vasoactive intestinal polypeptide (VIP) binding to synaptosomes and enterocyte membranes using preparations made from homogenized canine intestinal mucosa and compared it to [3H]saxitoxin binding and VIP-immunoreactive content (markers for synaptosomes). The highest [125I]VIP binding was located in the P2 fraction and was correlated with the locations of maximal [3H]saxitoxin binding and VIP-immunoreactive content. This correlation indicates that VIP receptors are present on synaptosomes of canine small intestinal mucosa. A fraction enriched in synaptosomes contained a high density of saturable VIP receptors (352 +/- 26.40 fmol/mg) having high affinity (Kd, 0.23 nM) for [125I]VIP. Studies of association and dissociation of [125I]VIP to this site revealed that binding was fully reversible and yielded a Kd value similar to that from equilibrium binding. Competition binding experiments suggested the presence of two binding sites, a high and a low affinity binding site. The order of competition potency was VIP greater than peptide histidine isoleucine greater than secretin greater than peptide histidine methionine greater than or equal to [D-Ala4]VIP greater than or equal to [Phe1]VIP greater than VIP10-28 greater than [4-Cl-D-Phe6-Leu17]VIP. All these competitors displaced all specifically bound VIP. VIP, peptide histidine isoleucine and secretin interacted differentially with each of the two binding sites. Peptide histidine methionine, [D-Ala4]VIP, [Phe1]VIP, VIP10-28 and [4-Cl-D-Phe6-Leu17]VIP interacted with a single low affinity at all binding sites. Other VIP binding sites were sought in circular muscle and submucosa.(ABSTRACT TRUNCATED AT 250 WORDS)


Matrix metalloproteinase levels in children with aggressive periodontitis.
Matrix metalloproteinases (MMPs) are a family of host-derived proteinases reported to mediate multiple functions associated with periodontal destruction and inflammation. Most of the existing data have been gathered from adults with chronic periodontitis. The purpose of this study was to determine the MMP levels in a cohort of African American children with and without aggressive periodontitis. Gingival crevicular fluid (GCF) was collected in a cohort of 44 African American children, 7 to 19 years of age, with and without aggressive periodontitis (AgP) and compared to healthy unrelated children and to adults with chronic periodontitis (CP). GCF volume was determined with a calibrated gingival fluid meter. The samples were assayed for MMP-1, -2, -3, -8, -9, -12, and -13 using fluorimetric substrates. The MMP levels from diseased sites in the subjects with AgP were statistically higher (P <0.05) in almost all instances than those associated with the unrelated controls or with the subjects with CP. MMP-8 was significantly elevated in the diseased sites of the children with AgP relative to non-diseased sites in the same children (P = 0.002), as well as the siblings, non-diseased controls, and subjects with CP (P < or =0.0001). There was no positive correlation between probing depth and any MMP level. MMP levels were elevated in AgP sites relative to non-diseased sites in the same subjects, in siblings, and in unrelated controls. MMPs associated with the AgP sites in children were generally elevated compared to an adult cohort with a history of CP.


Reengineering lipid biosynthetic pathways of Aspergillus oryzae for enhanced production of γ-linolenic acid and dihomo-γ-linolenic acid.
Biological significance of 18-carbon polyunsaturated fatty acids, γ-linolenic acid (GLA; C18:3 n-6) and dihomo-γ-linolenic acid (DGLA; C20:3 n-6) has gained much attention in the systematic development of optimized strains for industrial applications. In this work, a n-6 PUFAs-producing strain of Aspergillus oryzae was generated by manipulating metabolic reactions in fatty acid modification and triacylglycerol biosynthesis. The codon-optimized genes coding for Δ6-desaturase and Δ6-elongase of Pythium sp., and diacylglycerol acyltransferase 2 (mMaDGAT2) of Mortierella alpina were co-transformed in a single vector into A. oryzae BCC14614, yielding strain TD6E6-DGAT2. Comparative phenotypic analysis showed that a 70% increase of lipid titer was found in the engineered strain, which was a result of a significant increase in triacylglycerol (TAG) content (52.0 ± 1.8% of total lipids), and corresponded to the increased size of lipid particles observed in the fungal cells. Interestingly, the proportions of GLA and DGLA in neutral lipids of the engineered strain were similar, with the highest titers obtained in the high C:N culture (29:0; 6% glucose) during the lipid-accumulating stage of growth. Time-course expression analysis of the engineered strain revealed transcriptional control of TAG biosynthesis through a co-operation between the native DGAT2 of A. oryzae and the transformed mMaDGAT2.


The prenatal use of antibiotics and the development of allergic disease in one year old infants. A preliminary study.
Recent research has suggested that the protective effect of natural infections may be due to their influence on the development of the immune system in early life. The purpose of the study was to determine whether maternal use of antibiotics during pregnancy is a risk factor for wheezing and allergy in early infancy. Nonsmoking women, aged 18-35 years, were enrolled in 2000/2001 from prenatal clinics during the second or third trimester of pregnancy. After delivery, newborns were followed-up every three months over one year and trained interviewers conducted a standardized interview with mothers on infants' health at each visit held every three-month. In total, 102 infants were followed over a one-year period and questionnaires on the use of various medications during pregnancy and potential risk factors for allergy and asthma were completed. Relative risk for persistent wheezing (9+ days over the follow-up) adjusted for potential confounders was significantly associated with the duration of antibiotic therapy, however, it was significant only if the antibiotic treatment took place in the second and the third trimester. The adjusted relative risk was increasing by 14% with each day of using antibiotics compared with the reference group (RR = 1.14; 95% CI: 1.01-1.27). When usage of antibiotics was regarded as a dichotomous variable in the logistic model (cut-off point at 5 days), the estimated adjusted risk for persistent wheezing was 4.42 (95% CI: 1.05-18.8). The risk for hay fever due to exposure to antibiotics was 2.65 (95% CI: 1.03-6.81) and a corresponding estimate for eczema was 2.30 (95% CI: 0.91-5.80). The study suggests that maternal use of antibiotics during pregnancy may prove to be a risk factor for persistent wheezing and development of allergy in early infancy.


Mass Spectrometry Analysis of Shark Skin Proteins.
The mucus layer covering the skin of fish has several roles, including protection against pathogens and mechanical damage in which proteins play a key role. While proteins in the skin mucus layer of various common bony fish species have been explored, the proteins of shark skin mucus remain unexplored. In this pilot study, we examine the protein composition of the skin mucus in spiny dogfish sharks and chain catsharks through mass spectrometry (NanoLC-MS/MS). Overall, we identified 206 and 72 proteins in spiny dogfish (Squalus acanthias) and chain catsharks (Scyliorhinus retifer), respectively. Categorization showed that the proteins belonged to diverse biological processes and that most proteins were cellular albeit a significant minority were secreted, indicative of mucosal immune roles. The secreted proteins are reviewed in detail with emphasis on their immune potentials. Moreover, STRING protein-protein association network analysis showed that proteins of closely related shark species were more similar as compared to a more distantly related shark and a bony fish, although there were also significant overlaps. This study contributes to the growing field of molecular shark studies and provides a foundation for further research into the functional roles and potential human biomedical implications of shark skin mucus proteins.