Identification of rat alpha1 macroglobulin as an inhibitor of rat Galbeta1-4GlcNAc alpha2-6 sialyltransferase.
Rat serum was found to contain an inhibitor of pure alpha2-6 sialyltransferase (EC 220.127.116.11). The inhibitor was a high Mr protein isolated by molecular filtration on Sephadex G100, followed by anion exchange chromatography on Sephadex DEAE A25, then separation on Sepharose CL 4B, and finally by isoelectric focusing. Electrophoretic separation and subsequent N-terminal sequence analysis of the active inhibitor preparation showed the presence of two protein components, identified as rat C-reactive protein, and rat alpha1 macroglobulin. Pure rat CRP did not inhibit alpha2-6 sialyltransferase. Treatment of the inhibitor preparations with monospecific antibodies against rat alpha1 macroglobulin blocked inhibitory activity in a dose-dependent manner. The results present strong evidence that alpha1 macroglobulin is capable of acting as an inhibitor of alpha2-6 sialyltransferase. No inhibition of galactosyltransferase (EC 188.8.131.52) could be detected, indicating that the interaction with alpha1 macroglobulin may have specificity among the glycosyltransferases. The entrapment of alpha2-6 sialyltransferase by alpha1 macroglobulin presented here occurs in vitro and will require further in vivo investigations to determine the precise physiological significance. Independent of the physiologic significance is the finding that this interaction occurs in vitro, which, pending elucidation of the precise mechanism and specificity, may provide a new tool for investigations into the functional significance of sialylation, and potentially for use or design of new inhibitors of therapeutic value in physiologic conditions involving altered levels of sialylation.


4C/ID in medical education: How to design an educational program based on whole-task learning: AMEE Guide No. 93.
Medical education increasingly stresses that medical students should be prepared to take up multiple roles as a health professional. This requires the integrated acquisition of multiple competences such as clinical reasoning and decision making, communication skills and management skills. To promote such complex learning, instructional design has focused on the use of authentic, real-life learning tasks that students perform in a real or simulated task environment. The four-component instructional design model (4C/ID) model is an instructional design model that starts from the use of such tasks and provides students with a variety of learning tools facilitating the integrated acquisition of knowledge, skills and attitudes. In what follows, we guide the reader on how to implement educational programs based on the 4C/ID model and illustrate this with an example from general practice education. The developed learning environment is in line with the whole-task approach, where a learning domain is considered as a coherent, integrated whole and where teaching progresses from offering relatively simple, but meaningful, authentic whole tasks to more complex tasks. We describe the steps that were taken, from prototype over development to implementation, to build five learning modules (patient with diabetes; the young child with fever; axial skeleton; care for the elderly and physically undefined symptoms) that all focus on the integrated acquisition of the Canadian Medical Education Directives for Specialists roles in general practice. Furthermore, a change cycle for educational innovation is described that encompasses practice-based challenges and pitfalls about the collaboration between different stakeholders (students, developers and teachers) and the transition from traditional, fragmented and classroom-based learning to integrated and blended learning based on sound instructional design principles.


Respiratory syncytial virus infection in patients with phagocyte defects.
Patients with phagocyte defects frequently develop bacterial or fungal pneumonias, but they are not considered to be at increased risk for viral infections. We describe 3 patients with known phagocyte immunodeficiencies who developed lower respiratory tract infections (LRTI) caused by respiratory syncytial virus (RSV). All 3 patients had dense pneumonias as indicated by computed tomography scan of the lungs and RSV was recovered. We conclude that RSV can present as a dense pneumonia in patients with phagocyte defects. Along with common pathogens causing LRTI, RSV should be considered in the differential diagnosis. Viral cultures as well as rapid antigen detection assays for respiratory viruses should be included in the evaluation of LRTI in patients with phagocyte defects. respiratory syncytial virus, phagocyte, immunodeficiency, pneumonia.


[Work process of the nurse who works in child care in family health units].
This is a qualitative research, which purpose was to analyse the working process of nurse in child care actions in family health units. Nurses are the subjects and empirical data was achieved by the means of participant observation, and interviews. Data analysis followed thematic analysis fundaments. Results reveal that working process organization of nurses still remains centered in proceedings with an offert of assistance based in client illness, showing obstacles to puericulture practice in health basic attention.


Paclitaxel Treatment and Proprotein Convertase 1/3 (PC1/3) Knockdown in Macrophages is a Promising Antiglioma Strategy as Revealed by Proteomics and Cytotoxicity Studies.
High grade gliomas are the most common brain tumors in adult. These tumors are characterized by a high infiltration in microglial cells and macrophages. The immunosuppressive tumor environment is known to orient immune cells toward a pro-tumoral and anti-inflammatory phenotype. Therefore, the current challenge for cancer therapy is to find a way to reorient macrophages toward an antitumoral phenotype. Previously, we demonstrated that macrophages secreted antitumoral factors when they were invalidated for the proprotein converstase 1/3 (PC1/3) and treated with LPS. However, achieving an activation of macrophages via LPS/TLR4/Myd88-dependent pathway appears yet unfeasible in cancer patients. On the contrary, the antitumor drug Paclitaxel is also known to activate the TLR4 MyD88-dependent signaling pathway and mimics LPS action. Therefore, we evaluated if PC1/3 knock-down (KD) macrophages could be activated by Paclitaxel and efficient against glioma. We report here that such a treatment of PC1/3 KD macrophages drove to the overexpression of proteins mainly involved in cytoskeleton rearrangement. In support of this finding, we found that these cells exhibited a Ca2+ increase after Paclitaxel treatment. This is indicative of a possible depolymerization of microtubules and may therefore reflect an activation of inflammatory pathways in macrophages. In such a way, we found that PC1/3 KD macrophages displayed a repression of the anti-inflammatory pathway STAT3 and secreted more pro-inflammatory cytokines. Extracellular vesicles isolated from these PC1/3 KD cells inhibited glioma growth. Finally, the supernatant collected from the coculture between glioma cells and PC1/3 KD macrophages contained more antitumoral factors. These findings unravel the potential value of a new therapeutic strategy combining Paclitaxel and PC1/3 inhibition to switch macrophages toward an antitumoral immunophenotype.


Basic dental information needed for the OFM initial occlusal evaluation.
It is incumbent upon the orofacial myologist to evaluate the presenting client's occlusion and detect any behaviors which may be influencing the alignment of the dentition or interfering with the treatment plan of the referral source. In order to accomplish these tasks, it is necessary to share some common terminology and to effectively communicate between all the participants involved in the treatment plan. The purpose of this article is to assist in accomplishing these goals.


Pre-Conception Maternal Food Intake and the Association with Childhood Allergies.
Periconceptional nutrition may have an important function in programming the immune function and allergies, however, there is a lack of studies assessing pre-conception food intake and childhood allergic disorders. The aim of the current study was to identify maternal pre-conception dietary components that may be associated with allergic disorders in children up to 3 years of age. Pregnant women attending their first antenatal visit and who were aged >18 years were invited to participate. Pre-conception food frequency data was retrospectively collected at 18 weeks' gestation. Childhood eczema, current wheeze, and rhinitis was assessed at 36 months of age using a questionnaire and doctor diagnosis (n = 234). Linear discriminant analysis (LDA) was used to explore the combination of dietary food components that best discriminated between allergy status in children. Maternal pre-conception food intake such as low and high fat dairy, fresh fruit, unsaturated spreads, and take-away foods, were protective for any allergy assessed. Non-oily fish was protective for eczema and current wheeze; saturated spreads (e.g., butter) was protective for eczema, current wheeze, and rhinitis; poultry and fruit juice were adversely associated with each allergy. Pre-conception food intakes demonstrate inconsistent and somewhat contrary relationships to the development of child allergies. Whether and how maternal food intake impacts the underlying fetal programming and the mechanisms of childhood allergy warrants further investigation.


Assessing the Potential Contributions of Reduced Immigrant Viability and Fecundity to Reproductive Isolation.
Reduced fitness of immigrants from alternative environments is thought to be an important reproductive isolating barrier. Most studies evaluating the importance of the relative fitness of immigrants to speciation have focused on reduced survival of immigrants (i.e., immigrant inviability). However, variation in fecundity appears to have a greater impact on variation in fitness than does variation in viability, suggesting that reduced fecundity of immigrants could act as an important yet largely overlooked reproductive isolating barrier. Using a model and a survey of studies of local adaptation, we evaluate the relative strength of reduced immigrant viability and fecundity as potential causes of reproductive isolation. We found that reduced fecundity as compared to reduced viability as a reproductive isolating barrier should increase in importance as the relative costs of reproduction increase. Consistent with the elevated demands of reproduction reported in the literature, we found that reproductive isolation from reduced immigrant fecundity was of similar magnitude or greater than that from reduced immigrant viability, particularly in the early stages of speciation. These results suggest that the important role of differential fecundity in local adaptation extends to speciation.


Augmented and virtual reality usage in awake craniotomy: a systematic review.
Augmented and virtual reality (AR, VR) are becoming promising tools in neurosurgery. AR and VR can reduce challenges associated with conventional approaches via the simulation and mimicry of specific environments of choice for surgeons. Awake craniotomy (AC) enables the resection of lesions from eloquent brain areas while monitoring higher cortical and subcortical functions. Evidence suggests that both surgeons and patients benefit from the various applications of AR and VR in AC. This paper investigates the application of AR and VR in AC and assesses its prospective utility in neurosurgery. A systematic review of the literature was performed using PubMed, Scopus, and Web of Science databases in accordance with the PRISMA guidelines. Our search results yielded 220 articles. A total of six articles consisting of 118 patients have been included in this review. VR was used in four papers, and the other two used AR. Tumour was the most common pathology in 108 patients, followed by vascular lesions in eight patients. VR was used for intraoperative mapping of language, vision, and social cognition, while AR was incorporated in preoperative training of white matter dissection and intraoperative visualisation and navigation. Overall, patients and surgeons were satisfied with the applications of AR and VR in their cases. AR and VR can be safely incorporated during AC to supplement, augment, or even replace conventional approaches in neurosurgery. Future investigations are required to assess the feasibility of AR and VR in various phases of AC.


Philadelphia negative, Bcr-Abl positive chronic myeloid leukemia associated with pure red cell aplasia.
Pure red cell aplasia (PRCA) is a rare disorder which is associated with thymoma, viral infections and autoimmune diseases. A few cases of PRCA during the clinical course of CML have been reported and these usually terminate in blastic crisis and death, suggesting a poor prognosis. However, only one case of Philedelphia chromosome negative, Bcr-Abl positive CML associated with PRCA has been reported. Here, we present a second case report of a Philedelphia negative, Bcr-Abl positive CML associated with PRCA who was unresponsive to all the chemotherapeutic regimens. We conclude that the present case supports the idea that the development of PRCA in the course of CML may be a bad prognostic sign.


Acidification of three-dimensional emeraldine polymers: Search for minimum energy paths from base to salt.
We present a numerical simulation of the HCl acidification process of a three-dimensional semiconducting emeraldine base (EB) polymer leading to the corresponding metallic emeraldine salt form. We have searched minimum energy paths connecting the initial configuration, composed of two EB polymer chains per cell each one attached by two HCl molecules, with the Pc2a polaronic configuration which is the final state of the acidification process. For this aim, the variational nudged elastic band method has been adopted. We provide a pictorial representation of the acidification process at T=0 K, monitoring the EB protonation and the evolution of the polymeric chains and of the positions of the Cl(-) counterions on the lowest potential energy surface. To include also temperature effects, we have explored the potential energy surface around the final equilibrium configuration, heating the system and following its dynamics by the Car-Parrinello procedure.


Multicenter retrospective comparative study of laparoscopically assisted and conventional anorectoplasty for male infants with rectoprostatic urethral fistula.
Laparoscopically assisted anorectoplasty (LAARP) was expected to achieve better fecal continence than conventional procedures. However, the issue of which approach is better remains controversial. We compared outcomes between the conventional procedure and LAARP in male infants with rectoprostatic urethral fistula. Institutes belonging to the Japanese Study Group of Anorectal Anomalies (JSGA) were invited to participate. Subjects were male infants with rectoprostatic urethral fistula treated by the conventional approach (abdominoperineal pull-through and PSARP) or LAARP between 2000 and 2006. Medical charts and operative records were reviewed retrospectively. Eighty-one patients (conventional: 36, LAARP: 45) were enrolled from 15 centers. In both groups, the mean Kelly score was 5. The total score of the scoring system was newly developed by the Japanese Study Group of Anorectal Anomalies. Follow-up Project (5-15 points) was 10.7 and 12.1 in the conventional group and the LAARP group, respectively (p=0.07). The incidence of failed rectoanal anastomosis, mucosal prolapse, and anal stenosis was comparable in both groups. Posterior urethral diverticula were detected on cystourethrograms in 7% and 11% (p=1.0) and on MRI in 0% and 34% (p=0.02) of the conventional and the LAARP groups, respectively. Overall, 94% of diverticula were asymptomatic. Fecal continence and complication rates after LAARP were comparable to those observed after the conventional method. Posterior urethral diverticula were detected more frequently after LAARP.


Results of a standardized technique and postoperative care plan for laparoscopic sigmoid colectomy: a 30-month experience.
Laparoscopic sigmoid colectomy has been accepted slowly despite potential advantages because of the perceptions of a steep learning curve and increased operative times and costs. The purpose of this article is to review the outcome of a standardization of all the intraoperative and postoperative processes used in our department for the performance of laparoscopic sigmoid colectomy. A consecutive series of patients requiring laparoscopic sigmoid colectomy from March 1999 through December 2001 at the Cleveland Clinic Foundation, Cleveland, Ohio, was analyzed. Patients requiring sigmoid or rectosigmoid resection for all colonic pathologies were included. Criteria for exclusion from an attempted laparoscopic sigmoid colectomy were body mass index >35 and prior major abdominal surgeries (exclusive of hysterectomy, cholecystectomy, or appendectomy). Data collected included age, gender, indication for surgery, American Society of Anesthesiology class, body mass index, operative duration, length of hospital stay, complications, mortality, and 30-day readmission. The operative steps for laparoscopic sigmoid colectomy were as follows: 1) open insertion of the umbilical port; 2) placement of three operating ports; 3) dissection/division of the vascular pedicle after identification of the left ureter; 4) mobilization of the sigmoid and descending colon; 5) rectal mobilization/division; 6) exteriorization of the specimen; and 7) circular stapled anastomosis. Instrumentation for the procedure was standardized. Conversion was performed when a sequential step could not be completed in a reasonable time frame. A standard perioperative care plan was used. From March 1999 through December 2001, the primary surgeon performed 207 sigmoid colectomies, including 181 (87.4 percent) attempted laparoscopic sigmoid colectomies and 22 (12.1 percent) conversions. Indications for the laparoscopic sigmoid colectomies were diverticular disease (115), colonic neoplasia (32), prolapse (14), endometriosis (10), and other (10). The male/female ratio was 85:96, and the mean body mass index was 27.3 +/- 5.6. Mean operative time was 119 +/- 35 minutes. Mean length of stay was 2.9 +/- 1.2 days for completed cases and 6.4 +/- 1.4 days for converted cases. Anastomotic leaks occurred in two patients (1.1 percent), one of whom died of multisystem organ failure, yielding an operative mortality of 0.6 percent. The overall complication rate was 6.6 percent, and the 30-day readmission rate was 8 percent. The results indicate that a structured approach to laparoscopic sigmoid colectomy provides the surgeon with objective measures of operative progress that limit unduly long operations without increasing conversion rates and that control resource utilization. This approach provides a potential guideline for teaching and mastering laparoscopic sigmoid colectomy, reducing the learning curve, and optimizing results.


Placental pathology reports: A qualitative study in a US university hospital setting on perceived clinical utility and areas for improvement.
To explore how placental pathology is currently used by clinicians and what placental information would be most useful in the immediate hours after delivery. We used a qualitative study design to conduct in-depth, semi-structured interviews with obstetric and neonatal clinicians who provide delivery or postpartum care at an academic medical center in the US (n = 19). Interviews were transcribed and analyzed using descriptive content analysis. Clinicians valued placental pathology information yet cited multiple barriers that prevent the consistent use of pathology. Four main themes were identified. First, the placenta is sent to pathology for consistent reasons, however, the pathology report is accessed by clinicians inconsistently due to key barriers: difficult to find in the electronic medical record, understand, and get quickly. Second, clinicians value placental pathology for explanatory capability as well as for contributions to current and future care, particularly when there is fetal growth restriction, stillbirth, or antibiotic use. Third, a rapid placental exam (specifically including placental weight, infection, infarction, and overall assessment) would be helpful in providing clinical care. Fourth, placental pathology reports that connect clinically relevant findings (similar to radiology) and that are written with plain, standardized language and that non-pathologists can more readily understand are preferred. Placental pathology is important to clinicians that care for mothers and newborns (particularly those that are critically ill) after birth, yet many problems stand in the way of its usefulness. Hospital administrators, perinatal pathologists, and clinicians should work together to improve access to and contents of reports. Support for new methods to provide quick placenta information is warranted.


Positive Allosteric Modulation of A2AR Alters Immune Cell Responses and Ameliorates Psoriasis-Like Dermatitis in Mice.
Psoriasis is an immune cell‒mediated inflammatory disease of the skin with a mixed T helper type 1/T helper type17 cytokine environment combined with an innate immune response engaging toll-like receptors. Inflammatory diseases are characterized by dysregulated immune cell responses and elevated levels of adenosine at disease sites. Adenosine, acting through the A2AR, regulates inflammation, immune response, T-cell homeostasis, and tissue repair. We have identified a unique means to enhance A2AR function using a positive allosteric modulator. We show that oral administration of the A2AR-positive allosteric modulator AEA061 reduced ear swelling, skin thickness, erythema, scale formation, and inflammatory cytokine expression in A2Ar+/+ but not in A2Ar-/- mice with imiquimod-induced psoriasis-like dermatitis. Similar clinical and mRNA improvements were observed with topical administration. AEA061 also reduced clinical scores and cytokine expression in a mouse model of IL-23‒induced psoriasis-like dermatitis. In addition, AEA061 attenuated imiquimod-induced expression of IFN-α in plasmacytoid dendritic cells in vivo and IL-23 and IL-36α in conventional dendritic cells. TCR-mediated IL-17 expression in γδT cells in vivo and IL-17 production by CD4+ T cells enriched for γδT cells in vitro were also inhibited. Thus, the enhancement of A2AR responsiveness to the endogenous agonist adenosine through positive allosteric modulation is sufficient to enhance intrinsic homeostatic mechanisms attenuating disease progression.


Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study.
Low-income and middle-income countries (LMICs) are under-represented in reports on the burden of antimicrobial resistance. We aimed to quantify the clinical effect of carbapenem resistance on mortality and length of hospital stay among inpatients in LMICs with a bloodstream infection due to Enterobacteriaceae. The PANORAMA study was a multinational prospective cohort study at tertiary hospitals in Bangladesh, Colombia, Egypt, Ghana, India, Lebanon, Nepal, Nigeria, Pakistan, and Vietnam, recruiting consecutively diagnosed patients with carbapenem-susceptible Enterobacteriaceae (CSE) and carbapenem-resistant Entero-bacteriaceae (CRE) bloodstream infections. We excluded patients who had previously been enrolled in the study and those not treated with curative intent at the time of bloodstream infection onset. There were no age restrictions. Central laboratories in India and the UK did confirmatory testing and molecular characterisation, including strain typing. We applied proportional subdistribution hazard models with inverse probability weighting to estimate the effect of carbapenem resistance on probability of discharge alive and in-hospital death, and multistate modelling for excess length of stay in hospital. All patients were included in the analysis. Between Aug 1, 2014, and June 30, 2015, we recruited 297 patients from 16 sites in ten countries: 174 with CSE bloodstream infection and 123 with CRE bloodstream infection. Median age was 46 years (IQR 15-61). Crude mortality was 20% (35 of 174 patients) for patients with CSE bloodstream infection and 35% (43 of 123 patients) for patients with CRE bloodstream infection. Carbapenem resistance was associated with an increased length of hospital stay (3·7 days, 95% CI 0·3-6·9), increased probability of in-hospital mortality (adjusted subdistribution hazard ratio 1·75, 95% CI 1·04-2·94), and decreased probability of discharge alive (0·61, 0·45-0·83). Multilocus sequence typing showed various clades, with marginal overlap between strains in the CRE and CSE clades. Carbapenem resistance is associated with increased length of hospital stay and mortality in patients with bloodstream infections in LMICs. These data will inform global estimates of the burden of antimicrobial resistance and reinforce the need for better strategies to prevent, diagnose, and treat CRE infections in LMICs. bioMérieux.


Comparison of Health Information Technology Use Between American Adults With and Without Chronic Health Conditions: Findings From The National Health Interview Survey 2012.
Health information technology (HIT) is utilized by people with different chronic conditions such as diabetes and hypertension. However, there has been no comparison of HIT use between persons without a chronic condition, with one chronic condition, and multiple (≥2) chronic conditions (MCCs). The aim of the study was to assess the difference in HIT use between persons without a chronic condition, with one chronic condition, and with MCCs, to describe the characteristics of HIT use among those with chronic conditions and to identify the predictors of HIT use of the persons with one chronic condition and MCCs. A secondary data analysis was conducted in spring 2017 using the National Health Interview Survey (NHIS) 2012 Family Core and Sample Adult Core datasets that yielded 34,525 respondents aged 18 years and older. Measures included overall HIT use (ie, any use of the following five HIT on the Internet: seeking health information, ordering prescription, making appointment, emailing health provider, and using health chat groups), as well as sociodemographic and health-related characteristics. Sociodemographic and health characteristics were compared between HIT users and nonusers among those who reported having at least one chronic condition using chi-square tests. Independent predictors of HIT use were identified using multiple logistic regression analyses for those with one chronic condition, with MCCs, and without a chronic condition. Analyses were weighted and performed at significance level of .005. In 2012, adults with one health chronic condition (raw count 4147/8551, weighted percentage 48.54%) was significantly higher than among those with MCCs (3816/9637, 39.55%) and those with none of chronic condition (7254/16,337, 44.40%, P<.001). Seeking health information was the most prevalent HIT use. Chi-square tests revealed that among adults with chronic conditions, those who used HIT were significantly different from their counterpart peers who did not use HIT in terms of sociodemographic and health characteristics (P<.001). Overall, the significant factors related to HIT use were similar among the adults with one chronic condition, with MCCs, or without a chronic condition: younger age, female sex, non-Hispanic white, higher education level, and higher income level were shown to be positively related to the HIT use. This study provides a snapshot of HIT use among those with chronic conditions and potential factors related to such use. Clinical care and public health communication efforts attempting to leverage more HIT use should acknowledge differential HIT usage as identified in this study to better address communication inequalities and persistent disparities in socioeconomic status.


Training in microsurgical skills: Does course-based learning deliver?
Practical skill training courses are an increasingly popular method of teaching surgical skills. Few data are available from instructional courses indicating how successful they are at imparting practical skills to those individuals who attend them. We aimed to identify the skill benefits gained by trainee surgeons attending a 5-day microsurgical skills course. A global scoring system was devised to objectively assess the level of skill employed by trainees to complete an arterial microvascular anastamosis. Vessel patency, anastamotic construct, and care of tissue in the surrounding operative field were taken into account. Postoperative tissue viability and physiological vessel function following anastamosis were also investigated. The majority of surgeons (60%) exhibited an increase in their level of microsurgical skill during the course. The remaining candidates remained static or deteriorated. Attendance at this microsurgical training workshop resulted in an improvement in microsurgical skills in most trainees. In-course assessment by training courses would allow identification of individuals requiring further training or skill refinement.


Contents variation analysis of free amino acids, nucleosides and nucleobases in semen sojae praeparatum fermentation using UFLC-QTRAP MS.
UFLC-QTRAP MS was used to develop a sensitive and rapid method of evaluating content variation during Semen sojae praeparatum (SSP) fermentation. It did this through the simultaneous quantification of 22 free amino acids and 16 nucleosides and nucleobases in the raw materials and processed products of SSP. The method was shown to be reproducible and accurate. The limits of detection and quantity values were 0.09-168.75 and 0.31-562.50 ng/mL for the 38 analytes, respectively. The data were examined through principal components analysis to compare the content variations. The quantitative results showed that the ingredients were properly determined in most of the samples and were converted regularly throughout the SSP fermentation process. These results correspond to the morphologic changes and principal components analysis results.


[An epilepsy case presenting temporal aphonia and prosodic deficit with left hemiparesis].
A 53-year-old right-handed woman was admitted to a hospital with a seizure, exhibiting loss of consciousness and paroxysmal myoclonic movement. MRI showed no abnormalities of her brain. Electroencephalography revealed sporadic sharp and slow wave complexes, starting from the right central region. Cerebral perfusion SPECT revealed increased blood supply in the right hemisphere. She received diagnosis of epilepsy and was treated with phenytoin. After she regained her consciousness, she had no voice and presented with left hemiparesis which was interpreted to be Todd's palsy. She gradually recovered in using her voice, to full normalization of affective prosody in 11 days. The left hemiparesis recovered first in the upper and later in the lower extremities. Her symptoms could be interpreted to be vocal and prosodic disturbance, but not aphasia, because she could understand speach and communicate with writing. The lesions responsible for prosodic deficit are still controversial. The symptoms observed and the findings obtained may indicate that the deficiency of the affective prosody may be caused by the dysfunction of the medial surface of the non-dominant frontal lobe in this case.


Bayesian approaches to modeling the conditional dependence between multiple diagnostic tests.
Many analyses of results from multiple diagnostic tests assume the tests are statistically independent conditional on the true disease status of the subject. This assumption may be violated in practice, especially in situations where none of the tests is a perfectly accurate gold standard. Classical inference for models accounting for the conditional dependence between tests requires that results from at least four different tests be used in order to obtain an identifiable solution, but it is not always feasible to have results from this many tests. We use a Bayesian approach to draw inferences about the disease prevalence and test properties while adjusting for the possibility of conditional dependence between tests, particularly when we have only two tests. We propose both fixed and random effects models. Since with fewer than four tests the problem is nonidentifiable, the posterior distributions are strongly dependent on the prior information about the test properties and the disease prevalence, even with large sample sizes. If the degree of correlation between the tests is known a priori with high precision, then our methods adjust for the dependence between the tests. Otherwise, our methods provide adjusted inferences that incorporate all of the uncertainty inherent in the problem, typically resulting in wider interval estimates. We illustrate our methods using data from a study on the prevalence of Strongyloides infection among Cambodian refugees to Canada.


Temporal knowledge representation and reasoning techniques using time Petri nets.
In this paper, we present temporal knowledge representation and reasoning techniques using time Petri nets. A method is also proposed to check the consistency of the temporal knowledge. The proposed method can overcome the drawback of the one presented in Yao (1994). It provides a useful way to check the consistency of the temporal knowledge.


Synergistic apoptosis induction by proteasome and histone deacetylase inhibitors is dependent on protein synthesis.
Proteasome inhibitors are able to efficiently induce apoptosis in many tumor cells while leaving quiescent, untransformed cells largely unharmed. Here we investigated the further enhancement of proteasome inhibitor-mediated apoptosis induction in Bcr-Abl positive K562 CML cells by simultaneous treatment with different histone deacetylase inhibitors (HDIs). Combining proteasome and HDIs resulted in rapid hyperacetylation of histone H3 and accumulation of polyubiquitinated proteins and the synergistic induction of apoptosis. Apoptosis induction was associated with caspase 8, 3 and 9 activation, Bid processing, destruction of the mitochondrial membrane potential, cleavage of PARP and lamin B and extensive DNA fragmentation. The pan-caspase inhibitor Z-VAD-FMK and the caspase-8 inhibitor Z-IETD-FMK could inhibit K562 cell apoptosis. Apoptosis was also delayed by overexpression of Bcl-xL, as well as by crmA, a known inhibitor of caspases 1 and 8. Caspase 8 activity could still be detected in the presence of ectopic Bcl-xL, but not in crmA transfected cells. The most striking anti-apoptotic effect though was obtained by the translational inhibitor cycloheximide, which abolished caspase 8 processing, blocked Bid cleavage and maintained the mitochondrial transmembrane potential. Apoptosis by the combination treatment occurred independently from CD95/Fas receptor stimulation. These results demonstrated that transcriptional activation by HDIs combined with proteasome inhibitor mediated posttranslational stabilization of protein(s) results in significantly enhanced CML apoptosis which was striktly dependent on uninterrupted protein synthesis.


Regulation of thymidine metabolism in Escherichia coli K-12: studies on the inducer and the coordinateness of induction of the enzymes.
A study was made of the regulation of three enzymes that act sequentially in the metabolism of thymidine in Escherichia coli K-12. Under a variety of conditions, two of the enzymes, thymidine phosphorylase and deoxyribose-5-phosphate aldolase, were found to be synthesized coordinately. However, the third enzyme, phosphodeoxyribomutase, was synthesized noncoordinately with the other two enzymes under the same conditions. In addition, the mutase could be fully induced, whereas basal levels of the phosphorylase and the aldolase were maintained. These findings indicate that two operons comprise the genes concerned with the reversible pathway leading from thymidine to acetaldehyde and glyceraldehyde-3-phosphate. In addition to thymidine, it was found that acetaldehyde was an external inducer of these enzymes. The results of induction experiments performed on wild-type cells and mutants defective in the mutase or the aldolase, with thymidine or acetaldehyde as exogenous inducers, strongly suggest that deoxyribose-5-phosphate is more proximal to the intracellular inducer than is thymidine, deoxyribose-1-phosphate, or acetaldehyde.


Adverse impacts of chronic pain on health-related quality of life, work productivity, depression and anxiety in a community-based study.
Chronic pain has major clinical and social consequences. Few studies have examined any variation in the extent of impairment on quality of life and work productivity by site and type of chronic pain. The objective of our study is to examine adverse impacts of chronic pain on physical and psychological health and work productivity. Our community-population study was based on a phone-interview of adults with chronic pain, residing in Olmsted County, MN. Chronic pain groups were categorized into abdominal pain, back pain, joint pain, multisite pain, neuropathic pain or no chronic pain. We used standardized instruments, including the Brief Pain Inventory, the Patients Health Questionnair-9, and Work Productivity and Activity Impairment Questionnaire. We evaluated 591 patients suffering from chronic pain and 150 participants with no chronic pain. Almost one third of patients with multisite pain (33%) and neuropathic pain (32%) reported mild/major depressive symptoms. Patients suffering from chronic pain, particularly from multisite pain and neuropathic pain, reported significant pain interferences with daily activities and impairments in physical function. Chronic pain was significantly associated with reduced performance at work but not with missed work hours. The average reported reduction in work productivity ranged from 2.4 hours (±5.6) per week for adults with joint chronic pain to 9.8 hours (±11.1) per week for adults with multisite chronic pain. Chronic pain, particularly multisite pain and neuropathic pain, significantly affected physical and psychological health. Chronic pain is a multifaceted health condition that requires a multidisciplinary treatment approach.


Reaction graph kernels predict EC numbers of unknown enzymatic reactions in plant secondary metabolism.
Understanding of secondary metabolic pathway in plant is essential for finding druggable candidate enzymes. However, there are many enzymes whose functions are not yet discovered in organism-specific metabolic pathways. Towards identifying the functions of those enzymes, assignment of EC numbers to the enzymatic reactions they catalyze plays a key role, since EC numbers represent the categorization of enzymes on one hand, and the categorization of enzymatic reactions on the other hand. We propose reaction graph kernels for automatically assigning EC numbers to unknown enzymatic reactions in a metabolic network. Reaction graph kernels compute similarity between two chemical reactions considering the similarity of chemical compounds in reaction and their relationships. In computational experiments based on the KEGG/REACTION database, our method successfully predicted the first three digits of the EC number with 83% accuracy. We also exhaustively predicted missing EC numbers in plant's secondary metabolism pathway. The prediction results of reaction graph kernels on 36 unknown enzymatic reactions are compared with an expert's knowledge. Using the same data for evaluation, we compared our method with E-zyme, and showed its ability to assign more number of accurate EC numbers. Reaction graph kernels are a new metric for comparing enzymatic reactions.


A validated stability indicating HPTLC method for simultaneous estimation of irbesartan and hydrochlorothiazide.
Irbesartan, a diazaspiro angiotensin II blocker, is marketed in combination with Hydrochlorothiazide, which is a diuretic acting on distal convoluted tubule; for synergistic anti-hypertensive action. The present study deals with development and validation of a stability indicating HPTLC method for simultaneous estimation of Irbesartan and Hydrochlorothiazide using TLC plates precoated with Silica gel 60F254 and the mobile phase comprising Acetonitrile: Chloroform in the ratio of 5:6 v/v. Irbesartan and Hydrochlorothiazide were well resolved with Rf 0.27 ± 0.03 and 0.45 ± 0.03, respectively. Wavelength selected for the quantization was 270 nm. Inherent stability of these drugs was studied by exposing both drugs to various stress conditions as per ICH guidelines viz. Dry heat, oxidative, photolysis (UV and cool white fluorescent light) and hydrolytic conditions under different pH values. Both the drugs were not degraded under dry heat and photolytic conditions, but showed degradation under hydrolytic condition. The degraded products of Irbesartan and hydrochlorothiazide were well resolved from the individual bulk drug response. The developed method is found to be simple, specific, precise and stability indicating. The specificity of the method was confirmed by peak purity profile of the resolved peaks.


A prospective cohort study of the changing mental health needs of adolescents in custody.
To investigate changes in mental health and other needs, as well as clinical and diagnostic 'caseness', in a sample of adolescents over a 6-month period following entry into a Young Offenders Institution in the UK. Prospective cohort study. One Young Offenders Institution between November 2006 and August 2009. 219 male adolescents aged 15-18 years (M=16.56; SD=0.6) were assessed at baseline (median=4; range 0-26 days following reception into custody) on the Salford Needs Assessment Schedule for Adolescents (SNASA) and Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS). Participants were then reassessed at 3-month and 6-month postbaseline to document any change in mental health. Of the initial baseline sample, 132 were still in the study at 3-month postbaseline and 63 were still available for assessment at 6 months. There were no differences between those who were not available for assessment at the three key stages in terms of demographic and criminological data. Over time there was a general improvement in mental health. While the proportion of participants with a mental health need (SNASA) did not change over time, symptom severity as measured by the SNASA did reduce significantly. When we assessed diagnostic 'caseness' using the K-SADS, three young people showed significant mental health deterioration. In line with previous studies, we found that symptoms in prison generally improved over time. Prison may provide an opportunity for young people previously leading chaotic lifestyles to settle into a stable routine and engage with services; however, it is unclear if these would be maintained either within the prison or on release into the community.


The development of competence in favorable and unfavorable environments. Lessons from research on successful children.
The development of competence holds great interest for parents and society alike. This article considers implications from research on competence and resilience in children and adolescents for policy and interventions designed to foster better outcomes among children at risk. Foundations of competence in early development are discussed, focusing on the role of attachment relationships and self-regulation. Results from studies of competence in the domains of peer relations, conduct, school, work, and activities are highlighted. Lessons are drawn from studies of naturally occurring resilience among children at risk because of disadvantage or trauma and also from efforts to deliberately alter the course of competence through early childhood education and preventive interventions. Converging evidence suggests that the same powerful adaptive systems protect development in both favorable and unfavorable environments.


Eye care in the intensive care unit during the COVID-19 pandemic.
Ocular complications in critical care patients are common. There has been a surge in intensive care admissions following the COVID-19 outbreak. The management of COVID-19 exposes patients to a number of specific risk factors for developing ocular complications, which include non-invasive ventilation, mechanical ventilation and prone positioning. Consequently, it is likely that there will be an increase in the number of ocular complications secondary to the management of COVID-19 patients in the intensive care unit setting, and these complications could lead to permanent visual loss and blindness. Increased awareness of eye care in the intensive care unit setting is therefore vital to help prevent visual loss and maintain quality of life for patients recovering from COVID-19.


MMS sensitivity of all amino acid-requiring mutants in aspergillus and its suppression by mutations in a single gene.
All available amino acid-requiring mutants of Aspergillus nidulans were found to be hypersensitive to MMS (methyl methanesulfonate) to various degrees. On MMS media, secondary mutations could be selected which suppress this MMS sensitivity but do not affect the requirement. Many such mutations were analyzed and found to be alleles of one gene, smsA (= suppressor of MMS sensitivity), which mapped distal on the right arm of chromosome V. This gene is more likely to be involved in general regulation of amino acid biosynthesis than MMS uptake, since a variety of pathway interactions were clearly modified by smsA suppressors in the absence of MMS.


The effects of ambivalent fertility desires on pregnancy risk in young women in the USA.
Many different definitions of the construct of motivational ambivalence have appeared in the literature on reproductive health. Using a theoretical framework in which motivational ambivalence is defined as an interaction between positive and negative pregnancy desires, we propose two hypotheses. The first is that positive and negative pregnancy desires independently predict the risk of an unplanned pregnancy. The second is that ambivalence and three related constructs that are also based on the interaction between positive and negative desires are each important predictors of pregnancy risk. We use weekly journal data collected from a US sample of 1,003 women aged 18-19 years and conduct hazard model analysis to test our hypotheses. Using both dummy and continuous predictors, we report results that confirm both hypotheses. The proposed interaction framework has demonstrated validity, compares favourably with previously reported alternative approaches, and incorporates a set of constructs that have potential importance for further research directed at the prevention of unplanned pregnancy.


Monoclonal Antibodies Counteract Opioid-Induced Behavioral and Toxic Effects in Mice and Rats.
Monoclonal antibodies (mAbs) and vaccines have been proposed as medical countermeasures to treat opioid use disorder (OUD) and prevent opioid overdose. In contrast to current pharmacotherapies (e.g., methadone, buprenorphine, naltrexone, and naloxone) for OUD and overdose, which target brain opioid receptors, mAbs and vaccine-generated polyclonal antibodies sequester the target opioid in the serum and reduce drug distribution to the brain. Furthermore, mAbs offer several potential clinical benefits over approved medications, such as longer serum half-life, higher selectivity, reduced side effects, and no abuse liability. Using magnetic enrichment to isolate opioid-specific B cell lymphocytes prior to fusion with myeloma partners, this study identified a series of murine hybridoma cell lines expressing mAbs with high affinity for opioids of clinical interest, including oxycodone, heroin and its active metabolites, and fentanyl. In mice, passive immunization with lead mAbs against oxycodone, heroin, and fentanyl reduced drug-induced antinociception and the distribution of the target opioid to the brain. In mice and rats, mAb pretreatment reduced fentanyl-induced respiratory depression and bradycardia, two risk factors for opioid-related overdose fatality. Overall, these results support use of mAbs to counteract toxic effects of opioids and other chemical threats. SIGNIFICANCE STATEMENT: The incidence of fatal overdoses due to the widespread access to heroin, prescription opioids, and fentanyl suggests that current Food and Drug Administration-approved countermeasures are not sufficient to mitigate the opioid epidemic. Monoclonal antibodies (mAbs) may provide acute protection from overdose by binding to circulating opioids in serum. Use of mAbs prophylactically, or after exposure in combination with naloxone, may reduce hospitalization and increase survival.


The 'overly-sensitive' heart: sodium channel block and QRS interval prolongation.
Cardiac safety remains of paramount importance in the development of successful clinical drug candidates. Great progress has been made recently in understanding liabilities associated with delayed ventricular repolarization (manifest as QT prolongation) and in predicting (thus avoiding) drugs that delay repolarization based on application of strategic preclinical assays. Following the advances made in clinical electrophysiological monitoring and conduct of thorough QT studies, focus is now shifting towards monitoring of additional drug-induced effects, particularly on ventricular conduction (measured as changes in the QRS interval on the ECG) as part of evolving clinical thorough ECG studies. In this issue of the British Journal of Pharmacology, a study by Harmer et al. proposes provisional safety margins for QRS prolongation in man based on retrospective clinical data and a single in vitro approach to assess potency of block of cardiac sodium current (hNav1.5), the ionic current responsible for ventricular conduction (observed as QRS prolongation). The present commentary places their study in context with evolving preclinical cardiac electrophysiological safety assessments, along with discussions focused on ensuring the proper 'translation' of preclinical findings with potential clinical concerns. Given the extant limitations and uncertainties of presently available data, as well as our limited understanding of the pro-arrhythmic potential associated with these changes, due caution should be applied when considering the proposed in vitro-based margins for drug-induced QRS prolongation measured clinically. Additional validation with multiple preclinical models and more rigorous clinical safety studies will be necessary to substantiate these recommended margins. This article is a commentary on Harmer et al., pp. 260-273 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2011.01415.x.


Molecular mechanism of tissue-specific regulation of mouse renin gene expression by cAMP. Identification of an inhibitory protein that binds nuclear transcriptional factor.
Renin gene expression in the mouse kidney and submandibular gland (SMG) are differentially regulated by cAMP. In this study, we examined the potential molecular mechanism responsible for this tissue-specific regulation. 32P end-labeled synthetic oligonucleotide containing mouse renin cAMP-responsive element (CRE) was incubated with kidney nuclear extracts from either control or cAMP-treated mice and analyzed by gel mobility shift assay. Our results demonstrated that cAMP induced a nuclear protein which complexed with the CRE oligonucleotide in a specific manner. This nuclear protein-DNA binding was competed effectively by the oligonucleotide containing human chorionic gonadotropin alpha-subunit CRE but not by the mouse renin DNA fragment from which the CRE was deleted by site-directed mutagenesis. In contrast, no DNA-protein complex formation could be detected when this [32P]CRE oligonucleotide was incubated with the SMG nuclear extract from control or cAMP-treated mice. However, CRE-binding protein complex formation was demonstrated in the SMG nuclear extract when the incubation was performed in the presence of 0.8% sodium deoxycholate and 1.2% Nonidet P-40, detergents that dissociate protein-protein complexes. Furthermore, in the absence of deoxycholate, we observed that SMG nuclear extract attenuated the binding of the kidney CRE-binding protein to mouse renin CRE in a dose-dependent manner and this inhibitory effect of SMG nuclear extract disappeared in the presence of sodium deoxycholate. This inhibitory nuclear protein in SMG is specific for CRE-binding protein since it does not affect nuclear protein binding to synthetic DNA oligonucleotides of human collagenase AP-1 and human metallothionein AP-2. Our data further suggest that inhibitory nuclear protein is present in lower quantities in other extrarenal tissues, i.e. testes, liver, brain, heart, but is not detectable in the kidney. Taken together, these results suggest that the SMG and certain extrarenal tissues contain nuclear trans-acting factor(s) that interact with CRE-binding protein, thereby interfering with its binding to mouse renin CRE. The presence of this inhibitory protein in the mouse SMG nucleus may contribute to the tissue-specific regulation of the renin gene expression by cAMP.


Developmental exposure to terbutaline and chlorpyrifos: pharmacotherapy of preterm labor and an environmental neurotoxicant converge on serotonergic systems in neonatal rat brain regions.
Developmental exposure to unrelated neurotoxicants can nevertheless produce similar neurobehavioral outcomes. We examined the effects of developmental exposure to terbutaline, a tocolytic beta2-adrenoceptor agonist used to arrest preterm labor, and chlorpyrifos (CPF), a widely used organophosphate pesticide, on serotonin (5HT) systems. Treatments were chosen to parallel periods typical of human developmental exposures, terbutaline (10 mg/kg) on postnatal days (PN) 2-5 and CPF (5 mg/kg) on PN11-14, with assessments conducted on PN45, comparing each agent alone as well as sequential administration of both. Although neither treatment affected growth or viability, each elicited similar alterations in factors that are critical to the function of the 5HT synapse: 5HT1A receptors, 5HT2 receptors, and the presynaptic 5HT transporter (5HTT). Either agent elicited global increases in 5HT receptors and the 5HTT in brain regions possessing 5HT cell bodies (midbrain, brainstem) as well as in the hippocampus, which contains 5HT projections. For both terbutaline and CPF, males were affected more than females, although there were some regional disparities in the sex selectivity between the two agents. Both altered 5HT receptor-mediated cell signaling, suppressing stimulatory effects on adenylyl cyclase and enhancing inhibitory effects. When animals were exposed sequentially to both agents, the outcomes were no more than additive and, for many effects, less than additive, suggesting convergence of the two agents on a common set of developmental mechanisms. Our results indicate that 5HT systems represent a target for otherwise unrelated neuroteratogens.


Diagnosis and treatment of patients with prostatic abscess in the post-antibiotic era.
We reviewed the pathogenesis, clinical presentation, treatment options and outcomes of prostatic abscess in the post-antibiotic era, focusing on how patient risk factors and the emergence of multidrug-resistant organisms influence management of the condition. A MEDLINE search for "prostate abscess" or "prostatic abscess" was carried out. Prostate abscess is no longer considered a consequence of untreated urinary infection; now, men with prostatic abscess are typically debilitated or immunologically compromised, with >50% of patients having diabetes. In younger men, prostatic abscess can be the initial presentation of such chronic conditions. In older men, prostatic abscess is increasingly a complication of benign prostatic hyperplasia or prostate biopsy. Diagnosis is based on a physical examination, leukocytosis, leukocyturia and transrectal ultrasound, with magnetic resonance imaging serving as the preferred confirmatory imaging modality. Treatment of prostatic abscess is changing as a result of the emergence of atypical and drug-resistant organisms, such as extended-spectrum β-lactamase-producing enterobacteriaceae and methicillin-resistant Staphylococcus aureus. As many as 75% of infections are resistant to first-generation antibiotics, necessitating aggressive therapy with broad-spectrum parenteral antibiotics, such as third-generation cephalosporins, aztreonam or antibiotic combinations. A total of 80% of patients require early surgical drainage, frequently through a transurethral approach. In the post-antibiotic era, prostatic abscess is evolving from an uncommon complication of urinary infection to a consequence of immunodeficiency, growing antibiotic resistance and urological manipulation. This condition, primarily affecting patients with chronic medical conditions rendering them susceptible to atypical, drug-resistant organisms, requires prompt aggressive intervention with contemporary antibiotic therapy and surgical drainage.


Binding of subdomains 1/2 of PfEMP1-DBL1α to heparan sulfate or heparin mediates Plasmodium falciparum rosetting.
The capacity of Plasmodium falciparum parasitized erythrocytes (pRBC) to adhere to the endothelial lining in the microvasculature and to red blood cells (RBC) is associated with the virulence of the parasite, the pathogenesis and development of severe malaria. Rosetting, the binding of uninfected RBC to pRBC, is frequently observed in individuals with severe malaria and is mediated by the N-terminal NTS-DBL1α domain of the adhesin Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed at the surface of the pRBC. Heparan sulfate has been suggested to be an important receptor for the NTS-DBL1α variant IT4(var60) expressed by the parasite FCR3S1.2. Here, we have determined the binding site of NTS-DBL1α (IT4(var60)) to the RBC and heparin using a set of recombinant, mutated proteins expressed in and purified from E. coli. All the variants were studied for their ability to bind to RBC, their capacities to disrupt FCR3S1.2 rosettes, their affinities for heparin and their binding to rosette-disruptive mAbs. Our results suggest that NTS-DBL1α mediates binding to RBC through a limited number of basic amino acid residues localized on the surface of subdomains 1 (SD1) and 2 (SD2). The SD2-binding site is localized in close proximity to one of two previously identified binding sites in the rosetting PfEMP1 of the parasite PaloAlto-varO. The binding site in SD2 of NTS-DBL1α could represent a template for the development of anti-rosetting drugs.


Role of 18F-FDG PET/CT in the detection of eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is a rare immune-mediated chronic inflammatory disease of the esophagus. The main symptoms are dysphagia, retrosternal pain, and repeated food impaction. Esophageal eosinophilic infiltration is seen on histopathological examination. Progressive esophageal stenosis and other complications may occur if not detected and treated. We report a patient with pathologically confirmed EoE whose disease was detected on fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). This case demonstrates the important role of 18F-FDG PET/CT in the diagnosis of eosinophilic esophagitis.


Expression of Carboxypeptidase X M14 Family Member 2 Accelerates the Progression of Hepatocellular Carcinoma via Regulation of the gp130/JAK2/Stat1 Pathway.
Carboxypeptidase X, M14 family member 2 (CPXM2) has been reported to be involved with several human malignancies. However, the impact of CPXM2 on human hepatocellular carcinoma (HCC) tumorigenesis has not been studied. Using immunohistochemistry, the detailed CPXM2 expression patterns were examined in HCC cell lines and tissues. Additionally, a hepatic stellate cell line overexpressing CPXM2 and an HCC CPXM2-knockdown cell line were established by lipofection of an expression plasmid or short hairpin RNA, respectively. The transfection efficiencies were confirmed by reverse transcription-quantitative PCR, Western blotting and immunofluorescence. Moreover, Western blotting was conducted to determine the phosphorylation levels of the tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (Stat1) pathway. Furthermore, gp130-specific hairpin RNA was used to knockdown gp130 expression in hepatic stellate cells overexpressing CPXM2. The malignant phenotype of cultured HCC cells was assessed by a Cell Counting Kit-8 (CCK8) assay, plate cloning assay, Matrigel invasion assay and wound-healing assay in vitro. It was demonstrated that CPXM2 was upregulated in HCC, and its upregulation predicted a poor prognosis. Besides, the upregulation of CPXM2 markedly enhanced the metastatic potential of HCC via the gp130/JAK2/Stat1 signaling pathway in vitro. In summary, this evidence suggests a positive role for CPXM2 in HCC progression via modulation of the gp130/JAK2/Stat1 signaling pathway in HCC.


A proposed combination of flat-panel detector and mobile X-ray systems for low-dose image-guided central venous catheter insertion.
A central venous catheter (CVC) should be inserted at the optimum position to infuse medicines, blood products, nutrients, or fluids. Positioning of the catheter tip is commonly performed under landmark or fluoroscopic guidance. However, Japanese regulations do not allow the performing of fluoroscopy-guided procedures outside of the fluoroscopy room. We hypothesized that a new image-guided CVC placement technique by combining a wireless flat-panel detector (FPD) and a mobile X-ray system could be applied at the bedside to support CVC insertion. A CVC attached to a chest phantom in conjunction with the polymethyl methacrylate (PMMA) phantom was imaged, contrast-to-noise ratio (CNR) was measured with images, and radiologists and emergency physicians rated the catheter images using a Likert scale for visual evaluation. The minimum dose of the FPD and mobile X-ray system was reduced by at least 98% compared with that of the X-ray fluoroscopy system. The CNR decreased with the increasing PMMA phantom thickness. However, results of the visual evaluation were maintained at the clinically usable score with low-dose imaging up to a 6-cm thickness of the PMMA phantom. In conclusion, the combination of FPD and mobile X-ray systems is particularly effective in the emergency room setting where such procedures are required to be performed with urgency.


Dehydration and drinking behavior of the marine file snake Acrochordus granulatus.
Dehydration and drinking behaviors were investigated in the little file snake (Acrochordus granulatus) collected from marine populations in the Philippines and in Australia. File snakes dehydrate in seawater and do not drink seawater when dehydrated in air and offered seawater to drink. Dehydrated file snakes drink freshwater, and the threshold of dehydration for first drinking response is a deficit of -7.4% ± 2.73% (mean ± SD) of original body mass. The thirst mechanism in this species is more sensitive than that recently studied in sea snakes. The volume of water ingested increases with increasing dehydration. Mean plasma osmolality was 278.89 ± 33.17 mMol/kg, mean hematocrit was 59% ± 5.45%, and both decreased in snakes that drank freshwater following acclimation in seawater. Snakes always drank freshwater at the water's surface, testing water with tongue flicks between each swallowing of water. Some snakes ingested large volumes of freshwater, approaching 50% of body mass. Visual observations and measurements of osmolality in plasma and stomach fluids suggest that water is taken up from the gut and dilutes body fluids slowly over the course of 48 h or longer. Eighty percent of snakes that were collected during the dry season (following >4 mo of drought) in Australia drank freshwater immediately following their capture, indicating that snakes were dehydrated in their marine environment even when known to have been feeding at the time. Snakes kept in seawater maintained a higher state of body condition when freshwater was periodically available. These results support a growing conclusion that diverse taxa of marine snakes require environmental sources of freshwater to maintain water balance, contrary to earlier belief. Identifying the freshwater requirements of secondarily marine vertebrates is important for better understanding how they maintain water balance in marine habitats, especially with respect to conservation in changing environments.


Enhanced OH in C-Type Shock Waves in Molecular Clouds.
Cosmic-ray and X-ray ionizations in molecular gas produce a weak far-ultraviolet flux through the radiative decay of H2 molecules that have been excited by collisions with energetic electrons (the Prasad-Tarafdar mechanism). I consider the effect of this dissociating flux on the oxygen chemistry in C-type shocks. Typically, a few percent of the water molecules produced within the shock front are dissociated before the gas has cooled to 50 K. The resulting column density of warm OH rises from 1015 to 1016 cm-2 as the ionization rate is increased from 10-17 s-1 (typical of dark clouds) to 10-15 s-1 (adjacent to supernova remnants). These column densities produce substantial emission in the far-infrared rotational transitions of OH and are consistent with the OH/H2O ratios inferred from Infrared Space Observatory observations of emission from molecular shocks. For high ionization rates, the column of warm OH is sufficient to explain the OH(1720 MHz) masers that occur where molecular clouds are being shocked by supernova remnants. The predicted abundance of OH throughout the shock front will enable C-type shocks to be examined with high spectral resolution through radio observations of the four hyperfine ground-state transitions of OH at 18 cm and heterodyne measurements of emission in the far-infrared (e.g., from the Stratospheric Observatory for Infrared Astronomy).


Puckered and JNK signaling in pioneer neurons coordinates the motor activity of the Drosophila embryo.
Central nervous system organogenesis is a complex process that obeys precise architectural rules. The impact that nervous system architecture may have on its functionality remains, however, relatively unexplored. To clarify this problem, we analyze the development of the Drosophila embryonic Ventral Nerve Cord (VNC). VNC morphogenesis requires the tight control of Jun kinase (JNK) signaling in a subset of pioneer neurons, exerted in part via a negative feedback loop mediated by the dual specificity phosphatase Puckered. Here we show that the JNK pathway autonomously regulates neuronal electrophysiological properties without affecting synaptic vesicle transport. Manipulating JNK signaling activity in pioneer neurons during early embryogenesis directly influences their function as organizers of VNC architecture and, moreover, uncovers a role in the coordination of the embryonic motor circuitry that is required for hatching. Together, our data reveal critical links, mediated by the control of the JNK signaling cascade by Puckered, between the structural organization of the VNC and its functional optimization.


A coarse-grained force field for Protein-RNA docking.
The awareness of important biological role played by functional, non coding (nc) RNA has grown tremendously in recent years. To perform their tasks, ncRNA molecules typically unite with protein partners, forming ribonucleoprotein complexes. Structural insight into their architectures can be greatly supplemented by computational docking techniques, as they provide means for the integration and refinement of experimental data that is often limited to fragments of larger assemblies or represents multiple levels of spatial resolution. Here, we present a coarse-grained force field for protein-RNA docking, implemented within the framework of the ATTRACT program. Complex structure prediction is based on energy minimization in rotational and translational degrees of freedom of binding partners, with possible extension to include structural flexibility. The coarse-grained representation allows for fast and efficient systematic docking search without any prior knowledge about complex geometry.


Cave acoustics in prehistory: Exploring the association of Palaeolithic visual motifs and acoustic response.
During the 1980 s, acoustic studies of Upper Palaeolithic imagery in French caves-using the technology then available-suggested a relationship between acoustic response and the location of visual motifs. This paper presents an investigation, using modern acoustic measurement techniques, into such relationships within the caves of La Garma, Las Chimeneas, La Pasiega, El Castillo, and Tito Bustillo in Northern Spain. It addresses methodological issues concerning acoustic measurement at enclosed archaeological sites and outlines a general framework for extraction of acoustic features that may be used to support archaeological hypotheses. The analysis explores possible associations between the position of visual motifs (which may be up to 40 000 yrs old) and localized acoustic responses. Results suggest that motifs, in general, and lines and dots, in particular, are statistically more likely to be found in places where reverberation is moderate and where the low frequency acoustic response has evidence of resonant behavior. The work presented suggests that an association of the location of Palaeolithic motifs with acoustic features is a statistically weak but tenable hypothesis, and that an appreciation of sound could have influenced behavior among Palaeolithic societies of this region.


[Current therapeutic advances in the treatment of non-Hodgkin lymphoma].
Lymphoma is a lymphoid cell cancer that originates in lymphoid tissues. Non Hodgkin (NHL) type represents 90% of cases. In Mexico, NHL constitutes the third most common cancer in males and the sixth among females. NHL treatment has achieved significant advances in the last decade and NHL is currently becoming a disease with a high probability of cure. Rituximab has become an alternative for the treatment of NHL. Rituximab is a monoclonal antibody that targets the CD20 antigen expressed in the mature malignant B cells. It induces NHL B cells destruction by complement-mediated citotoxicity, apoptosis and sensitization to the toxic effect of chemotherapy. Rituximab has revolutionized treatment results by offering patients with aggressive NHL a higher possibility of cure and in the case of the intractable forms of NHL it increases the disease free period. The standard treatment for a patient with NHL is rituximab-CHOP (immunotherapy). In addition, rituximab has pharmacoeconomic advantages as shown in various cost-utility and cost-effectiveness studies.


Staying 'in the zone' but not passing the 'point of no return': embodiment, gender and drinking in mid-life.
Public health approaches have frequently conceptualised alcohol consumption as an individual behaviour resulting from rational choice. We argue that drinking alcohol needs to be understood as an embodied social practice embedded in gendered social relationships and environments. We draw on data from 14 focus groups with pre-existing groups of friends and work colleagues in which men and women in mid-life discussed their drinking behaviour. Analysis demonstrated that drinking alcohol marked a transitory time and space that altered both women's and men's subjective embodied experience of everyday gendered roles and responsibilities. The participants positioned themselves as experienced drinkers who, through accumulated knowledge of their own physical bodies, could achieve enjoyable bodily sensations by reaching a desired level of intoxication (being in the zone). These mid-life adults, particularly women, discussed knowing when they were approaching their limit and needed to stop drinking. Experiential and gendered embodied knowledge was more important in regulating consumption than health promotion advice. These findings foreground the relational and gendered nature of drinking and reinforce the need to critically interrogate the concept of alcohol consumption as a simple health behaviour. Broader theorising around notions of gendered embodiment may be helpful for more sophisticated conceptualisations of health practices.


The predictive value of low-field strength magnetic resonance imaging for intraoperative residual tumor detection. Clinical article.
Neurosurgeons have been utilizing intraoperative MR (iMR) imaging to evaluate the extent of tumor resection since the 1990s. A low-field strength (0.12 T) MR imaging unit (PoleStar N20, Medtronic) is a practical and relatively inexpensive iMR imaging system that has found increased use in neurosurgery. The gold standard for post operative detection of residual tumor has been high-strength MR imaging performed within 48 hours of resection.The object of this study was to determine the predictive concordance of low-strength iMR imaging with standard high-strength MR imaging for detection of residual tumor. The authors retrospectively evaluated the MR images from 74 intracranial tumor resections, comparing the intraoperative images obtained using a 0.12-T iMR imaging unit to the immediate postoperative images obtained using a standard 1.5-T MR imaging unit within 48 hours after surgery. The sensitivity of low-field MR imaging for detection of residual tumor was 0.74 (95% CI 0.58-0.86),and its specificity was 0.97 (95% CI 0.83-1). When only glial tumors (42 of the 74 lesions) were analyzed, the sensitivity was 0.82 (95% CI 0.59-0.94) and the specificity was 0.95 (95% CI 0.73-1). These data could assist the neurosurgeon who has to decide intraoperatively whether the observed iMR images show residual tumor or not.


Physical activity measurements: lessons learned from the pathways study.
High obesity rates in American Indian children led to Pathways, a randomized school- and community-based childhood prevention study. Seven tribes, 5 universities, the National Institutes of Health/National Heart, Lung, and Blood Institute, and 4 elementary schools partnered in the study. Increasing physical activity (PA) was an important intervention target. The PA assessment was based on study objectives, feasibility, and tribal acceptance. A time-segmented analysis was also desired. Two methods, a new PA questionnaire and accelerometry, were developed during pilot testing. Together, the methods provided qualitative and quantitative information and showed that 3 of 4 sites were able to increase average daily PA, although overall the control versus intervention difference was not significant. The main limitation was inability to distinguish PA among individuals. Accelerometer size and some community concerns led to a protocol based on a single day of wearing time. Newer model triaxial accelerometers that are much smaller and allow sampling of multiple days of activity are recommended for future studies.


Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitro and In Vivo Antimalarial Activity.
The Plasmodium falciparum aspartic protease plasmepsin X (PMX) is essential for the egress of invasive merozoite forms of the parasite. PMX has therefore emerged as a new potential antimalarial target. Building on peptidic amino alcohols originating from a phenotypic screening hit, we have here developed a series of macrocyclic analogues as PMX inhibitors. Incorporation of an extended linker between the S1 phenyl group and S3 amide led to a lead compound that displayed a 10-fold improved PMX inhibitory potency and a 3-fold improved half-life in microsomal stability assays compared to the acyclic analogue. The lead compound was also the most potent of the new macrocyclic compounds in in vitro parasite growth inhibition. Inhibitor 7k cleared blood-stage P. falciparum in a dose-dependent manner when administered orally to infected humanized mice. Consequently, lead compound 7k represents a promising orally bioavailable molecule for further development as a PMX-targeting antimalarial drug.


Evidence affirming school supports for Australian transgender and gender diverse students.
Background The United Nations (UN) and related UN bodies have recognised transgender and gender diverse (TGD) students' rights at the global level to full equitable access to education, and specifically sexuality education, repeatedly. This article explores the available support for this equal access in Australia. It discusses TGD student rights in a range of Australian laws and education policies. It shows how the inclusion of TGD students, particularly in sexuality education, is reinforced in the current Australian National Curricula. Finally, it considers research on Australian TGD students' educational attainment, experiences of transphobic abuse and violence, and experiences in contexts where they do and do not have staff (and other) support. It also shows that contrary to the picture of TGD students as victims leading inherently negative lives often seen in research, this group is nevertheless capable of resilience and positive education activism, which promotes their wellbeing and social outcomes. It argues for a shift from harmful approaches of victimising TGD students or treating them only as victims, towards celebrating the contributions of these students to their schools and societies.


Document-level Relation Extraction with Relation Correlations.
Document-level relation extraction faces two often overlooked challenges: long-tail problem and multi-label problem. Previous work focuses mainly on obtaining better contextual representations for entity pairs, hardly address the above challenges. In this paper, we analyze the co-occurrence correlation of relations, and introduce it into the document-level relation extraction task for the first time. We argue that the correlations can not only transfer knowledge between data-rich relations and data-scarce ones to assist in the training of long-tailed relations, but also reflect semantic distance guiding the classifier to identify semantically close relations for multi-label entity pairs. Specifically, we use relation embedding as a medium, and propose two co-occurrence prediction sub-tasks from both coarse- and fine-grained perspectives to capture relation correlations. Finally, the learned correlation-aware embeddings are used to guide the extraction of relational facts. Substantial experiments on two popular datasets (i.e., DocRED and DWIE) are conducted, and our method achieves superior results compared to baselines. Insightful analysis also demonstrates the potential of relation correlations to address the above challenges. The data and code are released at https://github.com/RidongHan/DocRE-Co-Occur.


The N-terminal Z repeat 5 of connectin/titin binds to the C-terminal region of alpha-actinin.
Connectin/titin, a 3000 kDa protein, links the Z line to the myosin filament in striated muscle sarcomeres. Using the yeast two-hybrid system, the present work shows that the N-terminal Z repeat 5 region (amino acids 447-472) of connectin binds to the C-terminal region (amino acids 825-897) of alpha-actinin, the main constituent of the Z line.


Curcuma longa extract associated with white pepper lessens high fat diet-induced inflammation in subcutaneous adipose tissue.
Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity. Mice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation. These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition.


1,2,3-Triazole framework: a strategic structure for C-H⋯X hydrogen bonding and practical design of an effective Pd-catalyst for carbonylation and carbon-carbon bond formation.
1,2,3-Triazole is an interesting N-heterocyclic framework which can act as both a hydrogen bond donor and metal chelator. In the present study, C-H hydrogen bonding of the 1,2,3-triazole ring was surveyed theoretically and the results showed a good agreement with the experimental observations. The click-modified magnetic nanocatalyst Pd@click-Fe3O4/chitosan was successfully prepared, in which the triazole moiety plays a dual role as both a strong linker and an excellent ligand and immobilizes the palladium species in the catalyst matrix. This nanostructure was well characterized and found to be an efficient catalyst for the CO gas-free formylation of aryl halides using formic acid (HCOOH) as the most convenient, inexpensive and environmentally friendly CO source. Here, the aryl halides are selectively converted to the corresponding aromatic aldehydes under mild reaction conditions and low Pd loading. The activity of this catalyst was also excellent in the Suzuki cross-coupling reaction of various aryl halides with phenylboronic acids in EtOH/H2O (1 : 1) at room temperature. In addition, this catalyst was stable in the reaction media and could be magnetically separated and recovered several times.


[Health fitness assessment for recreational diving requires special medical competence].
Recreational diving has become increasingly popular in Sweden over the last years and about half a million dives are made each year. During the same time the health requirements for diving have changed and today we allow asthmatics and diabetics to dive under certain conditions. Chest X-ray, that earlier was compulsory, is not required in the fitness to dive examination, and in the future Europe the minimal requirements will be a health declaration rather than a FTD examination by a doctor. Despite this there will be a need for doctors with competence in diving medicine to handle medical problems in connection to diving and to evaluate all the questions generated by the divers' answers in the health declarations.


Gas-forming pyogenic liver abscess.
Gas-forming pyogenic liver abscess (GPLA) is rare and is associated with a high mortality rate. It is commonly associated with underlying diabetes mellitus (DM). Gas formation occurs as a result of mixed acid fermentation within the abscess by formic hydrogenlyase, an enzyme produced by certain bacteria. Presentations can be nonspecific leading to a delay in diagnosis. Management includes urgent drainage of the abscess. We report three cases of GPLA as a result of Klebsiella spp. and Escherichia coli infections. All three patients had DM and were very sick at presentation. Diagnosis was delayed in one patient and this likely contributed to his death. Hospitalisations were prolonged. These cases highlight the need to consider GPLA in diabetic patients presenting with fever, abdominal pain, nonspecific symptoms or septic shock.


Prolonged islet allograft survival in diabetic NOD mice by targeting CD45RB and CD154.
Clinical islet transplantation is a successful procedure that can improve the quality of life in recipients with diabetes. A drawback of the procedure is the need for chronic administration of immunosuppressive drugs that, among other side effects, are potentially diabetogenic. Definition of immunosuppressive protocols that utilize nondiabetogenic compounds could further improve islet transplantation outcome. We used the NOD mouse to assess the effect of targeting the T-lymphocyte surface receptors CD45RB and CD154 in preventing loss of allogeneic islet grafts as a result of recurrence of autoimmunity and allorejection. Administration of the two antibodies led to significantly prolonged allograft survival, with a percentage of grafts surviving long-term. The therapeutic efficacy of the treatment was paralleled by a shift in CD45RB isoform expression on T-lymphocytes, increased in vitro responsiveness to interleukin-7, and increased in vitro gamma-interferon production after anti-CD3 antibody stimulation. Furthermore, graft infiltration by CD8+ T-cells was remarkably reduced. Recipient mice bearing functioning allografts were otherwise immunocompetent, as assessed in vivo and in vitro by numerous tests, including intragraft cytokine production, responsiveness to polyclonal stimulation and alloantigens, and analysis of cell subset phenotype. These data show that nondiabetogenic regimens of immunomodulation can lead to prolonged islet allograft survival in the challenging NOD mouse model.


[Nurses' interventions in the management of urinary incontinence in the elderly: an integrative review].
The objective of this study was to verify the strategies that nurses use to manage urinary incontinence (UI) in the elderly. An integrative literature review was performed on the following databases: WEB OF SCIENCE, MEDLINE, SCOPUS and CINAHL, in the period from 2006 to 2010. A total of 186 articles were located, and after excluding duplicates and performing a careful reading of the full articles, the sample was comprised of seven articles. Most studies utilize an overall approach to urinary incontinence, without characterizing the type or the subjects' claims. Only one study addressed the management of urinary incontinence in the elderly with dementia; another specified the type (hyperactive bladder). Therefore, there is a need for further clinical nursing studies regarding the management of urinary incontinence, aiming to provide scientific evidence to support this practice.


Effect of diabetes on severity and hospital mortality in patients with acute pancreatitis: a national population-based study.
Diabetes may increase the risk of acute pancreatitis (AP). We aimed to further investigate whether diabetes may also adversely affect outcomes of patients with AP. In this retrospective cohort study, we compared 18,990 first-attack AP with diabetes to 37,980 matched control subjects from Taiwan's National Health Insurance Research Database between 2000 and 2009. Primary outcomes were development of severe AP, defined by a modified Atlanta classification scheme, and hospital mortality. Analyses were performed using univariable and multivariable logistic regression model with generalized estimating equations accounting for hospital clustering effect. After baseline characteristics were adjusted, AP patients with diabetes had a higher risk of a severe attack than their nondiabetic counterparts (adjusted odds ratio [OR] 1.21, 95% CI 1.16-1.26). When severity criteria were analyzed individually, diabetic AP patients had a 58% higher risk of intensive care unit admission and a 30% higher risk of local complications, but a 16% lower risk of gastrointestinal bleeding, than AP patients without diabetes. The risk of organ failure at least one system) was similar between the two groups. Conversely, AP patients with diabetes were associated with a lower risk of hospital mortality (adjusted OR 0.77, 95% CI 0.65-0.91). Although diabetes may adversely affect the disease process of AP, it seems to protect patients from AP-related mortality.


Breathing patterns in children with craniofacial dysostosis and hindbrain herniation.
In the past few years, hindbrain herniation has become recognized as a frequent feature of the child with syndromic craniofacial dysostosis. The clinical significance of hindbrain herniation in these disorders is unclear. Abnormalities of respiratory control have frequently been reported. The aim of the present study was to document the incidence of obstructive and central respiratory abnormalities during sleep in craniofacial syndromes with hindbrain herniation. We performed cardiorespiratory sleep studies during unsedated night-time sleep in a group of 13 children. Hindbrain herniation was confirmed by magnetic resonance imaging (MRI) and ranged 1.5-26.9 mm below the cranial base. Sleep studies revealed central respiratory pauses associated with important reduction of the arterial oxygen saturation (Sa,O2) in only two of 13 cases (minimum Sa,O2 86% and 87%). In contrast 10 of 13 children had some degree of upper airway obstruction (four mild, three moderate and three severe). Of the remaining three children, two had previous long-term tracheostomies. Changes in the breathing pattern were proportional to the severity of the obstruction and comprised increased respiratory efforts and arterial oxygen desaturation. Infrequent mixed apnoeas were observed in five patients, and their severity reflected the severity of the obstructive component. In conclusion, obstruction of the upper airways was the predominant sleep-related respiratory problem in this group of patients. Hindbrain herniation was not associated with a high incidence of central sleep apnoea.


Torque and force production during shoulder external rotation: differences between transverse and sagittal planes.
In joints with 3 degrees of freedom, such as the shoulder joint, the association of different movements results in changes in the behavior of the moment arm of the muscles. The capacity of torque production for the same movement can be changed when movements take place in a different plane. The objective of this study is to quantify differences between torque production and resultant force estimated during the shoulder external rotation in two movement planes: the transverse and sagittal planes (with 90 degrees of shoulder abduction). Eight individuals were evaluated using an isokinetic dynamometer and an eletrogoniometer for movements in the transverse plane and six individuals for movements in the sagittal plane. The results showed that the execution of the external rotation in the sagittal plane allowed greater torque magnitudes and resultant force compared with those in the transverse plane, probably owing to a prestretching of infraspinatus and teres minor.


Muscle calcium transient. Effect of post-stimulus length changes in single fibers.
We examined the effects of post-stimulus length changes on voltage-clamped, aequorin-injected single muscle fibers from the barnacle Balanus nubilus. Extra light (extra calcium) is seen when the fiber is allowed to shorten (a small percentage) during the declining phase of the calcium transient. The opposite is observed when the fiber is stretched. Increasing the extent of shortening increases the amount of extra calcium, as does decreasing the temperature. The extra calcium probably comes from the myofilaments and not from the sarcoplasmic reticulum because (a) there is a strong correlation between the extra calcium and the level of activation; (b) there is a strong correlation between the extra calcium and the amount of force redeveloped after a length change; and (c) the time course of the appearance of the extra calcium is intermediate between that of the free calcium concentration and that of force. We suggest (a) that the calcium binding to the activating myofibrillar proteins is sensitive to muscle length or muscle force, and (b) that there is a pool of bound calcium (activating calcium) that waxes and wanes with a time course intermediate between the free calcium concentration and force.


Fluorescent probes and delivery methods for single-molecule experiments.
The recent explosion in papers utilising single-molecule experiments pushes the envelope further for increased spatial and temporal resolution. In order to achieve this, a combination of novel fluorescent probes and spectroscopy techniques are required. Herein, we provide an overview on our contribution to developments in the field of fluorescent probes along with a palette of alternative delivery methods for introducing the probes into living cells. We discuss probe requirements arising from the use of single-molecule spectroscopy methods and the customisation of probes that depends on the target molecule, the chemical state of the molecule as well as the distance and the type of interaction between sensor and ligand. We explain how Förster resonance energy transfer (FRET) and photon-induced electron transfer (PET) can increase the probe customisation. We also discuss additional requirements that arise when performing experiments in living cells like toxicity and cell permeability. Regarding the latter, we devote a special paragraph on the different ways to introduce the desired probe into the cell and how the different properties of each probe and cell type may require different delivery methods. We offer insights based on our experience working with a variety of single-molecule methods, fluorescent probes and delivery systems. Overall, we encompass the latest developments on probe design and delivery and illustrate that the wealth of information provided by single-molecule studies goes along with increased complexity.


Linking traditional treatments of maternal anaemia to iron supplement use: an ethnographic case study from Pemba Island, Zanzibar.
Iron deficiency anaemia is the most common form of malnutrition in the world. Pregnant women are particularly at risk for anaemia. Insufficient attention has been paid to the reasons underlying the only moderate success of iron supplementation. In this article an additional factor that can affect the use of iron supplements is proposed: their relevance to 'traditional' or nonbiomedical treatments of anaemia. This paper represents what is to our knowledge the first ethnographic description of nonbiomedical treatments for maternal anaemia. The research was conducted over several months on Pemba, one of the islands of the Zanzibar archipelago. Data were collected using a variety of qualitative methods, including in-depth interviews, focus group discussions and participant observation. Informants included 25 mothers and 27 traditional and biomedical health care workers. The resulting ethnography elucidates Pembans' beliefs about the relationship of food, traditional medicine, spirits and biomedical medicine in relation to anaemia. In the analysis of the ethnography, both anthropology and public health perspectives are incorporated to suggest how the understanding of these beliefs is useful for increasing iron supplement use.


Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis.
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is a disorder of development of the vasculature characterized by telangiectases and arteriovenous malformations in specific locations. It is one of most common monogenic disorders, but affected individuals are frequently not diagnosed. The most common features of the disorder, nosebleeds, and telangiectases on the lips, hands, and oral mucosa are often quite subtle. Optimal management requires an understanding of the specific presentations of these vascular malformations, especially their locations and timing during life. Telangiectases in the nasal and gastrointestinal mucosa and brain arteriovenous malformations generally present with hemorrhage. However, complications of arteriovenous malformations in the lungs and liver are generally the consequence of blood shunting through these abnormal blood vessels, which lack a capillary bed and thus result in a direct artery-to-vein connection. Mutations in at least five genes are thought to result in hereditary hemorrhagic telangiectasia, but mutations in two genes (ENG and ACVRL1/ALK1) cause approximately 85% of cases. The frequency of arteriovenous malformations in particular organs and the occurrence of certain rare symptoms are dependent on the gene involved. Molecular genetic testing is used to establish the genetic subtype of hereditary hemorrhagic telangiectasia in a clinically affected individual and family, and for early diagnosis to allow for appropriate screening and preventive treatment.


Assessment of a possible link between hyperhomocysteinemia and hyperuricemia.
Hyperhomocysteinemia and hyperuricemia are both considered risk factors for coronary artery disease. However, the relationship between the 2 has not yet been thoroughly investigated. This study aimed to evaluate this relationship more closely. This study is a retrospective cross-sectional analysis of data from a screening center in Israel assessing 16,477 subjects, within an age range of 20 to 80 years. The mean age of the study sample was 46 years, and 68% were males. Hyperuricemia was found in 24.9% and 14.6% of subjects with elevated and normal homocysteine serum levels, respectively (P < 0.001). A positive association was found between homocysteine serum levels and uric acid serum levels. Compared with subjects with normal homocysteine serum levels, those with hyperhomocysteinemia had an odds ratio (OR) for hyperuricemia of 1.7 (95% confidence interval [CI], 1.5-1.9) and 1.6 (95% CI, 1.1-2.5) for males and females, respectively. After multivariate adjustment for age, hypertension, body mass index, estimated glomerular filtration rate, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and thiazide use, the association remained significant in males (OR, 1.5; 95% CI, 1.3-1.7; P < 0.001) but not in females (OR, 0.9; 95% CI, 0.6-1.6; P = 0.82). This large cohort showed a significant association between hyperhomocysteinemia and hyperuricemia. Sex differences were observed. This study suggests that accelerated atherosclerosis may be a consequence of the combined effect of these 2 factors.