Octreotide therapy in meningiomas: in vitro study, clinical correlation, and literature review.
OBJECTIVE Meningiomas express somatostatin receptor subtype 2 (SST2), which is targeted by the somatostatin analog octreotide. However, to date, using somatostatin analog therapy for the treatment of these tumors in clinical practice has been debated. This study aims to clarify the in vitro effects of octreotide on meningiomas for precise clinical applications. METHODS The effects of octreotide were analyzed in a large series of 80 meningiomas, including 31 World Health Organization (WHO) Grade II and 4 WHO Grade III tumors, using fresh primary cell cultures to study the impact on cell viability, apoptosis, and signal transduction pathways. RESULTS SST2 mRNA was detected in 100% of the tested meningiomas at levels similar to those observed in other SST2-expressing tumors, neuroendocrine tumors, or pituitary adenomas. Octreotide significantly decreased cell proliferation in 88% of meningiomas but did not induce cell death. On average, cell proliferation was more inhibited in the meningioma group expressing a high level of SST2 than in the low-SST2 group. Moreover, octreotide response was positively correlated to the level of merlin protein and inversely correlated to the level of phosphorylated p70-S6 kinase, a downstream effector of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway. Octreotide inhibited Akt phosphorylation and activated tyrosine phosphatase without impacting the extracellular regulated kinase (ERK) pathway. CONCLUSIONS Octreotide acts exclusively as an antiproliferative agent and does not promote apoptosis in meningioma in vitro. Therefore, in vivo, octreotide is likely to limit tumor growth rather than induce tumor shrinkage. A meta-analysis of the literature reveals an interest in octreotide for the treatment of WHO Grade I tumors, particularly those in the skull base for which the 6-month progression-free survival level reached 92%. Moreover, somatostatin analogs, which are well-tolerated drugs, could be of interest for use as co-targeting therapies for aggressive meningiomas.


A Somatic HIF2α Mutation-Induced Multiple and Recurrent Pheochromocytoma/Paraganglioma with Polycythemia: Clinical Study with Literature Review.
A syndrome known as pheochromocytomas (PCC)/paragangliomas (PGL) and polycythemia resulted from gain-of-function mutation of hypoxia-inducible factor 2α (HIF2α) has been reported recently. However, clinical features of this syndrome vary from patient to patient. In our study, we described the clinical features of the patient within 15-year follow-up with a literature review. The patient presented with "red face" since childhood and was diagnosed with polycythemia and pheochromocytoma in 2000, and then, tumor was removed at his age of 27 (year 2000). However, 13 years later (2013), he was diagnosed with multiple paragangliomas. Moreover, 2 years later (2015), another two paragangaliomas were also confirmed. Genetic analysis of hereditary PCC/PGL-related genes was conducted. A somatic heterozygous missense mutation of HIF2α (c.1589C>T) was identified at exon 12, which is responsible for the elevated levels of HIF2α and erythropoietin (EPO) and subsequent development of paragangaliomas. However, this mutation was only found in the tumors from three different areas, not in the blood. So far, 13 cases of PCC/PGL with polycythemia have been reported. Among them, somatic mutations of HIF2α at exon 12 are responsible for 12 cases, and only 1 case was caused by germline mutation of HIF2α at exon 9. The HIF2α mutation-induced polycythemia with PCC/PGL is a rare syndrome with no treatment for cure. Comprehensive therapies for this disease include removal of the tumors and intermittent phlebotomies; administration of medications to control blood pressure and to prevent complications or death resulted from high concentration of red blood cell (RBC). Genetic test is strongly recommended for patients with early onset of polycythemia and multiple/recurrent PCC/PGL.


Oculomotor plasticity: are mechanisms of adaptation for reactive and voluntary saccades separate?
Saccadic eye movements are permanently controlled and their accuracy maintained by adaptive mechanisms that compensate for physiological or pathological perturbations. In contrast to the adaptation of reactive saccades (RS) which are automatically triggered by the sudden appearance of a single target, little is known about the adaptation of voluntary saccades which allow us to intentionally scan our environment in nearly all our daily activities. In this study, we addressed this issue in human subjects by determining the properties of adaptation of scanning voluntary saccades (SVS) and comparing these features to those of RS. We also tested the reciprocal transfers of adaptation between the two saccade types. Our results revealed that SVS and RS adaptations disclosed similar adaptation fields, time course and recovery levels, with only a slightly lower after-effect for SVS. Moreover, RS and SVS main sequences both remained unaffected after adaptation. Finally and quite unexpectedly, the pattern of adaptation transfers was asymmetrical, with a much stronger transfer from SVS to RS (79%) than in the reverse direction (22%). These data demonstrate that adaptations of RS and SVS share several behavioural properties but at the same time rely on partially distinct processes. Based on these findings, it is proposed that adaptations of RS and SVS may involve a neural network including both a common site and two separate sites specifically recruited for each saccade type.


Oil massage in neonates: an open randomized controlled study of coconut versus mineral oil.
Oil massage for newborns is reported to improve weight gain by better thermoregulation. A role for transcutaneous absorption has also been suggested. This study was undertaken to compare the effect of massage with coconut oil versus mineral oil and placebo (powder) on growth velocity and neuro-behavior in well term and preterm babies. Open Randomized Controlled trial. The Premature unit and the postnatal wards of a major teaching hospital in a metropolitan city. Intramural preterm appropriate for gestational age babies weighing between 1500 to 2000 grams and term births weighing more than 2500 grams fulfilling the inclusion criteria constituted the two gestation age categories studied. Babies in each group were randomized to receive massage with either coconut oil, mineral oil or with placebo. Oil massage was given by a trained person from day 2 of life till discharge, and thereafter by the mother until 31 days of age, four times a day. Babies were followed up daily till discharge and every week after discharge for anthropometry. Neuro-behavioral outcome was assessed by the Brazelton Score at baseline, day 7 and on day 31. Coconut oil massage resulted in significantly greater weight gain velocity as compared to mineral oil and placebo in the preterm babies group; and in the term baby group, as compared to the placebo. Preterm infants receiving coconut oil massage also showed a greater length gain velocity compared to placebo group. No statistically significant difference was observed in the neurobehavioral assessment between all three subgroups in term babies as well as in preterm babies.


Predicting the response of advanced cervical and ovarian tumors to therapy.
The management of advanced cervical and ovarian cancers remains a significant challenge as many women fail to respond to recommended therapy, resulting in disease progression and ultimately patient death. Because of tumor heterogeneity, it is rare for all cancers of a particular type to respond to a specific therapy; and, as a result, many patients receive treatment from which they derive little or no benefit, leading to increased morbidity and undue costs. A marker that could rapidly predict or forecast disease outcome would clearly be beneficial in allowing the administration of a tailored regime for each patient while reducing toxicity and cost. Traditional prognostic factors of tumor size, grade, and stage are not ideal for predicting patient outcome, whereas the use of in vitro assays to detect chemosensitivity or resistance has not yet translated into routine clinical practice. Similarly, biomarkers and tumor markers vary in their predictive ability. DNA array technology offers great promise in predicting the response to therapy based on gene expression profiles, and can allow for targeted therapies against specific molecular alterations that cause disease. Imaging techniques, particularly those with the ability to characterize biological tissues and provide functional, structural, and molecular information, have the potential to noninvasively integrate physical and metabolic information. These include F-18-fluorodeoxyglucose positron emission tomography, dynamic contrast-enhanced magnetic resonance imaging, and diffusion weighted magnetic resonance imaging, all techniques that attempt to evaluate and predict therapy response and so influence clinical outcome. This review examines different methods of predicting the response to treatment in advanced cervical and ovarian tumors. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to describe why prediction of response to therapy for cervical and ovarian cancers is important, describe obstacles to use of in vitro assays to predict outcomes for therapy for ovarian and cervical cancers, and explain potentially new predictive markers.


Current trends in the development and application of molecular technologies for cancer epigenetics.
Current progress in epigenetic research supports the view that diet and dietary components are important in cancer etiology by enhancing or inhibiting carcinogenesis. Since diet and dietary factors may significantly contribute to the causation and progression of many cancers, it is important to find the molecular mechanisms of action of such dietary factors for cancer prevention and treatment. Recently, the role of epigenetic mechanisms in the cancer development and progression has attracted more attention as additional evidence along with traditional DNA sequence based mechanisms such as mutations and structural re-arrangements. Such an increasing interest in cancer epigenetics has also accelerated the development and application of molecular assays and tools for DNA methylation detection and histone modification enrichment analysis. In this paper, key assays and methods for epigenetic research are reviewed and discussed in terms of their utility and usability. In addition, more advanced methods for genome-wide analysis are introduced as part of upcoming research trends and directions.


Decorrelation of Neutral Vector Variables: Theory and Applications.
In this paper, we propose novel strategies for neutral vector variable decorrelation. Two fundamental invertible transformations, namely, serial nonlinear transformation and parallel nonlinear transformation, are proposed to carry out the decorrelation. For a neutral vector variable, which is not multivariate-Gaussian distributed, the conventional principal component analysis cannot yield mutually independent scalar variables. With the two proposed transformations, a highly negatively correlated neutral vector can be transformed to a set of mutually independent scalar variables with the same degrees of freedom. We also evaluate the decorrelation performances for the vectors generated from a single Dirichlet distribution and a mixture of Dirichlet distributions. The mutual independence is verified with the distance correlation measurement. The advantages of the proposed decorrelation strategies are intensively studied and demonstrated with synthesized data and practical application evaluations.


Impact of GLUT1 and Ki-67 expression on early‑stage lung adenocarcinoma diagnosed according to a new international multidisciplinary classification.
High expression levels of glucose transporter isoform 1 (GLUT1) and Ki-67 are reportedly associated with malignancy-related clinicopathological factors in malignant tumors. Recently, a new histological IASLC/ATS/ERS classification for lung adenocarcinoma was proposed. In this study, we investigated the clinicopathological impact of GLUT1 and Ki-67 expression on early-stage lung adenocarcinoma classified according to the IASLC/ATS/ERS classification. One hundred and five patients with completely resected stage IA lung adenocarcinoma were retrospectively classified into two groups, a 'non-invasive type' (n=31) or an 'invasive type' (n=74), based on the IASLC/ATS/ERS classification. GLUT1 and Ki-67 expression status was evaluated using immunohistochemistry. The epidermal growth factor receptor (EGFR) and KRAS mutation status was determined using PCR-based assays. Positive GLUT1 and Ki-67 expression and EGFR and KRAS mutations were detected in 28 (27%), 33 (31%), 51 (49%) and 5 (8%) cases, respectively. Positive GLUT1 expression was significantly associated with a wild-type EGFR and mutant KRAS status. A multivariate analysis revealed that positive GLUT1 expression was independently associated with the 'invasive type'. In multivariate analyses for overall survival (OS) and disease-free survival (DFS), positive Ki-67 and GLUT1 expression was the only independent factor for a poor OS (P=0.012) and DFS (P=0.040), respectively. In addition, when stratified according to the GLUT1 and Ki-67 status, double-positive cases had the poorest DFS and OS times, compared with the other categories. Positive GLUT1 expression is associated with the invasive character of early-stage lung adenocarcinoma and with early disease relapse. Our results strongly suggest that GLUT1 and Ki-67 play important roles in acquiring biological malignant potential in early-stage lung adenocarcinoma.


Advancing computational biology and bioinformatics research through open innovation competitions.
Open data science and algorithm development competitions offer a unique avenue for rapid discovery of better computational strategies. We highlight three examples in computational biology and bioinformatics research in which the use of competitions has yielded significant performance gains over established algorithms. These include algorithms for antibody clustering, imputing gene expression data, and querying the Connectivity Map (CMap). Performance gains are evaluated quantitatively using realistic, albeit sanitized, data sets. The solutions produced through these competitions are then examined with respect to their utility and the prospects for implementation in the field. We present the decision process and competition design considerations that lead to these successful outcomes as a model for researchers who want to use competitions and non-domain crowds as collaborators to further their research.


Researcher readiness for participating in community-engaged dissemination and implementation research: a conceptual framework of core competencies.
Participating in community-engaged dissemination and implementation (CEDI) research is challenging for a variety of reasons. Currently, there is not specific guidance or a tool available for researchers to assess their readiness to conduct CEDI research. We propose a conceptual framework that identifies detailed competencies for researchers participating in CEDI and maps these competencies to domains. The framework is a necessary step toward developing a CEDI research readiness survey that measures a researcher's attitudes, willingness, and self-reported ability for acquiring the knowledge and performing the behaviors necessary for effective community engagement. The conceptual framework for CEDI competencies was developed by a team of eight faculty and staff affiliated with a university's Clinical and Translational Science Award (CTSA). The authors developed CEDI competencies by identifying the attitudes, knowledge, and behaviors necessary for carrying out commonly accepted CE principles. After collectively developing an initial list of competencies, team members individually mapped each competency to a single domain that provided the best fit. Following the individual mapping, the group held two sessions in which the sorting preferences were shared and discrepancies were discussed until consensus was reached. During this discussion, modifications to wording of competencies and domains were made as needed. The team then engaged five community stakeholders to review and modify the competencies and domains. The CEDI framework consists of 40 competencies organized into nine domains: perceived value of CE in D&I research, introspection and openness, knowledge of community characteristics, appreciation for stakeholder's experience with and attitudes toward research, preparing the partnership for collaborative decision-making, collaborative planning for the research design and goals, communication effectiveness, equitable distribution of resources and credit, and sustaining the partnership. Delineation of CEDI competencies advances the broader CE principles and D&I research goals found in the literature and facilitates development of readiness assessments tied to specific training resources for researchers interested in conducting CEDI research.


ENT problems in Dutch children: trends in incidence rates, antibiotic prescribing and referrals 2002-2008.
BACKGROUND. Ear, nose, and throat (ENT) problems are common in childhood and are important reasons to visit the general practitioner. OBJECTIVE. To examine trends in incidence rates, antibiotic prescribing, and referrals of five common ENT problems in children. DESIGN. Netherlands Information Network of General Practice (LINH), a nationally representative general practice database. Setting. A total of 50 000 children, aged 0-17 years, registered in Dutch general practice over the period 2002-2008. METHODS. Incidence rates were calculated and trends were analysed using linear regression analysis, with incidence rates per age group, proportion treated with antibiotics, and referrals as dependent variables and year of observation as independent variable. RESULTS. In general, incidence rates of acute otitis media, serous otitis, sinusitis, tonsillitis, and tonsil hypertrophy remained stable over the period 2002-2008. An increasing trend was observed for serous otitis media in children aged 0-4 years (RR = 1.04, p < 0.001). A decreasing trend was observed for sinusitis in children aged 5-11 and for tonsillitis in children aged 11-17 years (RR 0.99, p < 0.001 and RR 0.94, p < 0.001, respectively). Antibiotics were prescribed in 10-60% of the diagnoses. An increasing trend for antibiotic prescription was found for acute otitis media (beta = 0.07, p < 0.001), mainly on account of amoxicillin. Although antibiotic treatment of tonsillitis remained stable, pheneticillin prescriptions showed a downward trend (beta = -0.10, p < 0.001). First-choice antibiotics were prescribed in >80% of cases. CONCLUSIONS. This study showed remarkably stable trends in incidence rates, antibiotic prescribing, and referrals of common ENT problems. The low proportion of antibiotic treatment in ENT problems did not show negative consequences.


Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice.
Proximal spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Traditionally, SMA has been described as a motor neuron disease; however, there is a growing body of evidence that arrhythmia and/or cardiomyopathy may present in SMA patients at an increased frequency. Here, we ask whether SMA model mice possess such phenotypes. We find SMA mice suffer from severe bradyarrhythmia characterized by progressive heart block and impaired ventricular depolarization. Echocardiography further confirms functional cardiac deficits in SMA mice. Additional investigations show evidence of both sympathetic innervation defects and dilated cardiomyopathy at late stages of disease. Based upon these data, we propose a model in which decreased sympathetic innervation causes autonomic imbalance. Such imbalance would be characterized by a relative increase in the level of vagal tone controlling heart rate, which is consistent with bradyarrhythmia and progressive heart block. Finally, treatment with the histone deacetylase inhibitor trichostatin A, a drug known to benefit phenotypes of SMA model mice, produces prolonged maturation of the SMA heartbeat and an increase in cardiac size. Treated mice maintain measures of motor function throughout extended survival though they ultimately reach death endpoints in association with a progression of bradyarrhythmia. These data represent the novel identification of cardiac arrhythmia as an early and progressive feature of murine SMA while providing several new, quantitative indices of mouse health. Together with clinical cases that report similar symptoms, this reveals a new area of investigation that will be important to address as we move SMA therapeutics towards clinical success.


Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species.
Autophagy is a self-digestion process important for cell survival during starvation. It has also been described as a form of programmed cell death. Mitochondria are important regulators of autophagy-induced cell death and damaged mitochondria are often degraded by autophagosomes. Inhibition of the mitochondrial electron transport chain (mETC) induces cell death through generating reactive oxygen species (ROS). The role of mETC inhibitors in autophagy-induced cell death is unknown. Herein, we determined that inhibitors of complex I (rotenone) and complex II (TTFA) induce cell death and autophagy in the transformed cell line HEK 293, and in cancer cell lines U87 and HeLa. Blocking the expression of autophagic genes (beclin 1 and ATG5) by siRNAs or using the autophagy inhibitor 3-methyladenine (3-MA) decreased cell death that was induced by rotenone or TTFA. Rotenone and TTFA induce ROS production, and the ROS scavenger tiron decreased autophagy and cell death induced by rotenone and TTFA. Overexpression of manganese-superoxide dismutase (SOD2) in HeLa cells decreased autophagy and cell death induced by rotenone and TTFA. Furthermore, blocking SOD2 expression by siRNA in HeLa cells increased ROS generation, autophagy and cell death induced by rotenone and TTFA. Rotenone- and TTFA-induced ROS generation was not affected by 3-MA, or by beclin 1 and ATG5 siRNAs. By contrast, treatment of non-transformed primary mouse astrocytes with rotenone or TTFA failed to significantly increase levels of ROS or autophagy. These results indicate that targeting mETC complex I and II selectively induces autophagic cell death through a ROS-mediated mechanism.


Probing chemical induced cellular stress by non-Faradaic electrochemical impedance spectroscopy using an Escherichia coli capacitive biochip.
A new capacitive biochip was developed using carboxy-CNT activated gold interdigitated (GID) capacitors immobilized with E. coli cells for the detection of cellular stress caused by chemicals. Here, acetic acid, H(2)O(2) and NaCl were employed as model chemicals to test the biochip and monitored the responses under AC electrical field by non-Faradaic electrochemical impedance spectroscopy (nFEIS). The electrical properties of E. coli cells under different stresses were studied based on the change in surface capacitance as a function of applied frequency (300-600 MHz) in a label-free and noninvasive manner. The capacitive response of the E. coli biochip under normal conditions exhibited characteristic dispersion peaks at 463 and 582 MHz frequencies. Deformation of these signature peaks determined the toxicity of chemicals to E. coli on the capacitive biochip. The E. coli cells were sensitive to, and severely affected by 166-498 mM (1-3%) acetic acid with declined capacitance responses. The E. coli biochip exposed to H(2)O(2) exhibited adaptive responses at lower concentrations (<2%), while at a higher level (882 mM, 3%), the capacitance response declined due to oxidative toxicity in cells. However, E. coli cells were not severely affected by high NaCl levels (513-684 mM, 3-4%) as the cells tend to resist the salt stress. Our results demonstrated that the biochip response at a particular frequency enabled the determination of the severity of the stress imposed by chemicals and it can be potentially applied for monitoring unknown chemicals as an indicator of cytotoxicity.


Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states.
Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory signaling in the nervous system. Despite the profound importance of iGluRs to neurotransmission, little is known about the structures and dynamics of intact receptors in distinct functional states. Here, we elucidate the structures of the intact GluA2 AMPA receptor in an apo resting/closed state, in an activated/pre-open state bound with partial agonists and a positive allosteric modulator, and in a desensitized/closed state in complex with fluorowilliardiine. To probe the conformational properties of these states, we carried out double electron-electron resonance experiments on cysteine mutants and cryoelectron microscopy studies. We show how agonist binding modulates the conformation of the ligand-binding domain "layer" of the intact receptors and how, upon desensitization, the receptor undergoes large conformational rearrangements of the amino-terminal and ligand-binding domains. We define mechanistic principles by which to understand antagonism, activation, and desensitization in AMPA iGluRs.


Improved method for determination of optical constants of organic thin films from reflection and transmission measurements.
A new technique for determining the optical properties of organic thin films is presented. A detailed evaluation of the accuracy of the determined optical constants has been performed, and the best combination of measured values yielding the smallest errors in the index of refraction for realistic experimental uncertainties has been found. The proposed method utilizes the fact that optical constants are smooth continuous functions, which reduces the possibility of encountering multiple solutions. The method consists of two steps. In the first step the optical constants at all wavelengths and the film thickness are determined. In the second step the thickness and the imaginary part of the index of refraction are kept fixed while we reevaluate the real part of the index of refraction by using a different objective function with improved sensitivity to the refractive index. After verifying that the proposed method is capable of an accurate estimation of optical constants, we determine the index of refraction data of vanadyl-phthalocyanine in the visible spectral range.


The management of minor degrees of cervical dysplasia associated with the human papilloma virus.
This report attempts to define further the natural history of minor degrees of cervical dysplasia associated with human papilloma virus (HPV). Five hundred and twenty-five patients with a diagnosis of mild to moderate cervical dysplasia and HPV effects were followed without treatment for six months to five years. Those patients who progressed to a greater degree of dysplasia were removed from follow-up and treated appropriately. Those patients who regressed to a non-dysplastic state were returned to the original referring physician to be followed with annual cytology. Regression to a non-dysplastic state was 30.5 percent at six months, 50.4 percent at 1 1/2 years, 60.5 percent at 2 1/2 years, 70.9 percent at 3 1/2 years, 77.3 percent at 4 1/2 years, 7.8 percent have progressed to a greater degree of cervical dysplasia, removed from follow-up, and treated, and 22 patients have recurred, all with minor degrees of dysplasia. No invasive cancer has been diagnosed in this group of patients. From these results, we conclude that patients with minor degrees of dysplasia associated with HPV can be followed in a routine screening program with the anticipation that the great majority will, over time, convert to a non-dysplastic state. A small number of patients will progress to a higher degree of dysplasia and will be effectively identified, to be referred for colposcopic assessment and appropriate treatment.


Diabetes Complications and Depressive Symptoms: Prospective Results From the Montreal Diabetes Health and Well-Being Study.
Prospective studies testing the potential impact of diabetes complications on depression are limited. The present study examined the longitudinal associations between diabetes complications and the risk and recurrence/persistence of depressive symptoms. Data were from a prospective community cohort telephone survey of adults with diabetes (N = 1314). Diabetes complications and depressive symptoms were assessed via self-report (Diabetes Complications Index and Patient Health Questionnaire-9, respectively) at baseline and annually for 5 years. Statistical models adjusted for sociodemographic, lifestyle, and diabetes characteristics. The number of diabetes complications at baseline was positively associated with a greater risk of elevated depressive symptoms, with the highest risk found for those with four to six complications at baseline (risk ratio = 2.73, 95% confidence interval = 1.64-4.56). Cerebrovascular disease was the complication most strongly associated with incident depressive symptoms (risk ratio = 2.22, 95% confidence interval = 1.59-3.10). Coronary artery disease, peripheral vascular disease, and neuropathy were also associated with the risk of depression, whereas foot problems and eye problems were not. In addition, a greater number of diabetes complications were associated with recurrent/persistent depression, though with a small effect size (Δr = .02). A parallel process latent growth curve model indicated that increases in diabetes complications were associated with increases in depressive symptoms during the course of the follow-up period (β = .74, p < .001). This study demonstrates the temporal relation between diabetes complications and depressive symptoms and underscores the psychological burden of diabetes complications by prospectively demonstrating the increased risk and recurrence of depressive symptoms associated with diabetes complications.


Disability, atrophy and cortical reorganization following spinal cord injury.
The impact of traumatic spinal cord injury on structural integrity, cortical reorganization and ensuing disability is variable and may depend on a dynamic interaction between the severity of local damage and the capacity of the brain for plastic reorganization. We investigated trauma-induced anatomical changes in the spinal cord and brain, and explored their relationship to functional changes in sensorimotor cortex. Structural changes were assessed using cross-sectional cord area, voxel-based morphometry and voxel-based cortical thickness of T1-weighted images in 10 subjects with cervical spinal cord injury and 16 controls. Cortical activation in response to right-sided (i) handgrip; and (ii) median and tibial nerve stimulation were assessed using functional magnetic resonance imaging. Regression analyses explored associations between cord area, grey and white matter volume, cortical activations and thickness, and disability. Subjects with spinal cord injury had impaired upper and lower limb function bilaterally, a 30% reduced cord area, smaller white matter volume in the pyramids and left cerebellar peduncle, and smaller grey matter volume and cortical thinning in the leg area of the primary motor and sensory cortex compared with controls. Functional magnetic resonance imaging revealed increased activation in the left primary motor cortex leg area during handgrip and the left primary sensory cortex face area during median nerve stimulation in subjects with spinal cord injury compared with controls, but no increased activation following tibial nerve stimulation. A smaller cervical cord area was associated with impaired upper limb function and increased activations with handgrip and median nerve stimulation, but reduced activations with tibial nerve stimulation. Increased sensory deficits were associated with increased activations in the left primary sensory cortex face area due to median nerve stimulation. In conclusion, spinal cord injury leads to cord atrophy, cortical atrophy of primary motor and sensory cortex, and cortical reorganization of the sensorimotor system. The degree of cortical reorganization is predicted by spinal atrophy and is associated with significant disability.


How does acculturation affect the use of complementary and alternative medicine providers among Mexican- and Asian-Americans?
Researchers have found that immigrants in the United States gradually relinquish cultural practices and adopt health behaviors similar to native born individuals as they acculturate. Few studies have looked at acculturation and Complementary and Alternative Medicine (CAM) use, particularly ethnic forms of CAM. This study uses data from the 2001 California Health Interview Survey-Complementary and Alternative Medicine (CHIS-CAM) supplement to estimate the prevalence of CAM provider use among Mexican- and Asian- Americans and examine the relationship of acculturation on use. Multinomial logistic regression models were used to predict the probability of provider use based on socio-demographic variables, health status and acculturation. Mexican- and Asian- Americans who have spent more time in the US were more likely to use chiropractors or massage therapists compared to no CAM provider. Both groups were less likely to use ethnic-specific CAM providers with more time in the US compared to chiropractors or massage therapists.


[Usefulness of intracranial pressure continuous monitoring in pseudotumor cerebri].
To analyse the usefulness of intracranial pressure (ICP) monitoring in pseudotumor cerebri (PTC). Ten patients with suspected PTC, but having incomplete criteria for the syndrome, on whom ICP monitoring was performed. Demographic, clinical and radiological data were collected, as well as ICP monitoring data and related complications. Results were evaluated 6 months after surgery. In relation to demographics, all patients were young females. Mean ICP was less than 250 mmH2O in 5 of 8 patients with pathological monitoring. Most patients (62.5%) showed A waves; these were related with higher mean ICP, but not always with papilloedema. All recordings showed high amplitude B waves. Most pathological recordings showed wave amplitudes superior to 5 mmHg. There were no complications related to the monitoring technique. Clinical and lumbar opening pressure data are not enough to establish PTC diagnosis correctly, especially if patient has been treated previously. Monitoring using ICP is a valuable, safe tool, and very useful in this syndrome. Mean ICP could be normal even with pathological recordings. Morphological analysis is necessary to establish diagnosis. A and B waves are highly related to shunt response. Wave amplitude is related to brain compliance and to shunt response as well.


A simple and distinctive microbiota associated with honey bees and bumble bees.
Specialized relationships with bacteria often allow animals to exploit a new diet by providing a novel set of metabolic capabilities. Bees are a monophyletic group of Hymenoptera that transitioned to a completely herbivorous diet from the carnivorous diet of their wasp ancestors. Recent culture-independent studies suggest that a set of distinctive bacterial species inhabits the gut of the honey bee, Apis mellifera. Here we survey the gut microbiotae of diverse bee and wasp species to test whether acquisition of these bacteria was associated with the transition to herbivory in bees generally. We found that most bee species lack phylotypes that are the same or similar to those typical of A. mellifera, rejecting the hypothesis that this dietary transition was symbiont-dependent. The most common bacteria in solitary bee species are a widespread phylotype of Burkholderia and the pervasive insect associate, Wolbachia. In contrast, several social representatives of corbiculate bees do possess distinctive bacterial phylotypes. Samples of A. mellifera harboured the same microbiota as in previous surveys, and closely related bacterial phylotypes were identified in two Asian honey bees (Apis andreniformis and Apis dorsata) and several bumble bee (Bombus) species. Potentially, the sociality of Apis and Bombus species facilitates symbiont transmission and thus is key to the maintenance of a more consistent gut microbiota. Phylogenetic analyses provide a more refined taxonomic placement of the A. mellifera symbionts.


A Retrospective Multicenter Evaluation of Clozapine Use in Pediatric Patients Admitted for Acute Psychiatric Hospitalization.
Clozapine is the drug of choice for treatment-resistant schizophrenia. While pediatric clozapine use is not contraindicated, the literature describing its clinical application is limited. The primary objective of this study was to assess the use of clozapine in a child and adolescent population by characterizing the documented safety and clinical benefits of the medication. A multicenter retrospective study at sites in the United States and Australia included children and adolescents admitted to a psychiatric unit who were administered at least one dose of clozapine. Information related to demographics, patient history, past treatments, clozapine, and adverse events was collected. Eighty-two patients from eight sites were included in this study. Patients were predominantly clozapine naive (76.8%), and most had a discharge diagnosis of a primary psychotic disorder (61%) or bipolar disorder (25.6%). Four clozapine discontinuations occurred during hospitalization due to severe neutropenia, ileus, need for diagnostic clarification, and significant psychomotor retardation. The remainder (n = 78) were discharged on a mean clozapine dose of 218.1 ± 142.2 mg. Sedation (26.8%) and sialorrhea (17.1%) were the most common documented adverse events. The mean number of previously trialed antipsychotics before clozapine was 3.5 ± 1.4 (range 1-10). Improvement with clozapine was documented as significant (31.7%), moderate (32.9%), minimal (12.2%), no improvement (2.4%), and not described (20.7%). In this cohort, 95% of pediatric patients admitted with or started on clozapine during an acute psychiatric hospitalization were discharged on the medication. The high incidence of adverse events should reinforce to clinicians the need for vigilant monitoring. Pediatric guidelines recommend clozapine for refractory schizophrenia but stress the critical need to ensure an accurate diagnosis. Limited data exist for the use of clozapine in pediatric patients with other diagnoses.


Kinetics of reactions of the Actinomadura R39 DD-peptidase with specific substrates.
The Actinomadura R39 DD-peptidase catalyzes the hydrolysis and aminolysis of a number of small peptides and depsipeptides. Details of its substrate specificity and the nature of its in vivo substrate are not, however, well understood. This paper describes the interactions of the R39 enzyme with two peptidoglycan-mimetic substrates 3-(D-cysteinyl)propanoyl-D-alanyl-D-alanine and 3-(D-cysteinyl)propanoyl-D-alanyl-D-thiolactate. A detailed study of the reactions of the former substrate, catalyzed by the enzyme, showed DD-carboxypeptidase, DD-transpeptidase, and DD-endopeptidase activities. These results confirm the specificity of the enzyme for a free D-amino acid at the N-terminus of good substrates and indicated a preference for extended D-amino acid leaving groups. The latter was supported by determination of the structural specificity of amine nucleophiles for the acyl-enzyme generated by reaction of the enzyme with the thiolactate substrate. It was concluded that a specific substrate for this enzyme, and possibly the in vivo substrate, may consist of a partly cross-linked peptidoglycan polymer where a free side chain N-terminal un-cross-linked amino acid serves as the specific acyl group in an endopeptidase reaction. The enzyme is most likely a DD-endopeptidase in vivo. pH-rate profiles for reactions of the enzyme with peptides, the thiolactate named above, and β-lactams indicated the presence of complex proton dissociation pathways with sticky substrates and/or protons. The local structure of the active site may differ significantly for reactions of peptides and β-lactams. Solvent kinetic deuterium isotope effects indicate the presence of classical general acid/base catalysis in both acylation and deacylation; there is no evidence of the low fractionation factor active site hydrogen found previously in class A and C β-lactamases.


Can we use ionized calcium in the evaluation of post-thyroidectomy hypocalcemia?
The postoperative hypocalcaemia has the higher incidence as complications related to thyroidectomy. From 1 June 2006 to 30 June 2008, we examined 492 patients operated on consecutively in our unit with a total thyroidectomy for thyroid disease. We evaluated the values of ionized calcium in all the cases, matching these with the preoperative and postoperative values of serum calcium. The pre- and postoperative (24 hours after treatment) data for ionized calcium and serum calcium were examined statistically with the Student's t-test; results with a P-value <0.05 were considered to be statistically significant. Two-hundred-and-twenty-three of the 492 patients (45.2%) treated with total thyroidectomy had preoperative values of ionized calcium lower than 1.13 mmol/L (normal values 1.13-1.32 mmol/L), while the ionized calcium values were lower than 1.10 mmol/L in 154 of the 223 patients. The mean value of ionized calcium in all 223 cases was 1.04+/-0.07 mmol/L. The mean serum calcium value in these patients was 9.13+/-0.291 mg/dL (normal values 8.3-10.5 mg/dL). In the other 259 cases, the values of ionized calcium and serum calcium were 1.21+/-0.03 mmol/L and 9.1+/-0.29 mg/dL, respectively. In 75 cases on 223 with symptomatic hypocalcemia, the mean value of ionized calcium was 0.88+/-0.05 mmol/L, while, in the remaining 148 cases, the mean value was equal to 0.97+/-0.08 mmol/L (P<0.001). We compared this, in both groups, with the values of postoperative serum calcium; in the 75 cases with clinical hypocalcemia, the value of serum calcium was 7.32+/-0.35 mg/dL, while the value was equal to 8.4+/-0.34 mg/dL in the other cases (P<0.001). The values of ionized calcium must not be used as marker of hypocalcemia but must be seen as a diagnostic aid linked to others laboratory values, such as serum calcium.


No long-term persistence of bacterial pollution-induced community tolerance in tylosin-polluted soil.
Pollution-induced community tolerance (PICT) of soil bacteria to the antibiotic tylosin was studied over 95 days. Tylosin was added at increasing concentrations, together with different amounts of alfalfa to study the effects of substrate addition on PICT and bacterial growth in soil. The leucine incorporation technique was used to estimate bacterial growth and as a detection method in the PICT concept. Direct inhibition of the bacterial growth rates, resulting in a dose-response curve, was found above 50 mg of tylosin kg(-1) of soil two days after tylosin addition (IC50 value of 960 mg tylosin kg(-1)). After 10 days of exposure to at least 50 mg of tylosin kg(-1), the PICT was observed and correlated to inhibition of bacterial growth by tylosin. A return of the PICT to control levels was found over time, and after 95 days at 1500 mg of tylosin kg(-1), essentially no PICT was found, as compared to the unpolluted control soil. The return of PICT to pre-exposure levels was not totally reflected in the recovery of bacterial growth. Alfalfa addition did not affect the inhibitory effect of tylosin on bacterial growth rates; neither did it alter the PICT. Since tylosin is relatively rapidly degraded in soil, our results indicate that the PICT will return to prepollution levels when the selective pressure of the toxicant is removed and will thus be a useful technique for monitoring remediation measures.


'Before you teach me, I cannot know': immigrant women's barriers and enablers with regard to cervical cancer screening among different ethnolinguistic groups in Canada.
To describe the similarities and differences among multiple groups of immigrant women and Canadian-born women of low socio-economic status regarding barriers and enablers associated with cervical cancer screening, in order to inform core elements of a strategy that would be acceptable across multiple underscreened groups. Within a health behaviour framework, we used a qualitative explanatory multiple-case study approach consisting of focus group interviews (n = 11) in Hamilton, Canada. Participants were newly immigrated (1-5 years) women and a group of Canadian-born women of low socio-economic status; all participants were in the age range 35-69 years and married. Language groups were Arabic, Cantonese, Somali, Dari (Afghanistan) and Spanish (Latin America). Two separate focus groups for each ethnolinguistic group were conducted; one in English and one in the native language. A template approach to analysis was used. All groups indicated a strong need for information on necessity of screening and on how the procedure is done. Use of a video and a group discussion format were desired strategies. Women had positive feelings about being proactive for their health even if prevention had not been the norm in their home countries. There were differences between groups with respect to preferring a female clinician, which was a higher priority than language congruence with the provider. Only Chinese and Arabic groups discussed embarrassment and modesty as barriers. Addressing key knowledge gaps around cervical cancer screening through personal approaches, educational videos and invitations may be useful core strategies to remove stigma and fear around screening and improve uptake across multiple ethnic groups and in women of lower socioeconomic status.


Moral distress among community pharmacists: causes and achievable remedies.
This study aims to explore the incidence of moral distress experienced by UK community pharmacists through the deployment of a previously developed and validated survey instrument to a national sample. An e-mail inviting pharmacists to complete an on-line questionnaire developed to measure moral distress was successfully delivered via the mailing list of a nationwide support organisation for the pharmacy profession. Completed questionnaires were subjected to statistical analysis to determine to what extent common practice scenarios generated moral distress in community pharmacists. Time constraints represent the greatest source of moral distress for United Kingdom (UK) community pharmacists, scoring highest for both frequency and intensity of distress. The supply of emergency hormonal contraception (EHC) in opposition to religious beliefs scored lowest. Possible underlying causes of moral distress are discussed in the light of our results, and potential mechanisms for reducing the incidence of moral distress for this professional group are considered. The reduction in the frequency and occurrence of moral distress is best achieved by the creation of morally habitable workplaces, where possible triggers can be identified and avoided. Structured undergraduate ethics education and accessible postgraduate training and resources could provide a meaningful opportunity to support pharmacists in exercising their moral competency or moral agency. Moral distress provides a reliable indicator of constraints in the form of policies, legislation and regulations, and the structural and relational aspects of the working environment in which pharmacists practise. This provides invaluable information in the search for strategies to reduce the recurrence of this phenomenon.


Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.
Improving and targeting nicotine replacement therapy (NRT) are cost-effective strategies for reducing adverse health consequences for smokers. Treatment studies document the efficacy of precessation NRT and support important roles for level of nicotine dependence and precessation smoking reduction in successful quitting. However, prior work has not identified the optimal precessation dose or means for personalizing NRT. Genome-wide association has identified groups of genomic markers associated with successful quitting, allowing us to develop a v1.0 "quit-success" genotype score. We now report influences of v1.0 quit-success genotype score, level of dependence and precessation smoking reduction in a smoking cessation trial that examined effects of 21 versus 42 mg/24 h precessation NRT. Four hundred seventy-nine smokers were randomized to 21 or 42 mg NRT, initiated 2 wks prior to target quit dates. We monitored self-reported abstinence and end-expired air carbon monoxide (CO). Genotyping used Affymetrix arrays (Santa Clara, CA, USA). The primary outcome was 10-wk continuous smoking abstinence. NRT dose, level of nicotine dependence and genotype scores displayed significant interactive effects on successful quitting. Successful abstinence also was predicted by CO reductions during precessation NRT. These results document ways in which smoking cessation strategies can be personalized based on levels of nicotine dependence, genotype scores and CO monitoring. These assessments, taken together, can help match most smokers with optimal NRT doses and help rapidly identify some who may be better treated using other methods.


Renal Function and Transplantation in Liver Disease.
Kidney injury is associated with increased morbidity and mortality in liver transplant recipients. Since the introduction of the model for end-stage liver disease for the allocation of organs for liver transplantation in 2002, the heavy weighting of serum creatinine in the model for end-stage liver disease score has significantly increased the incidence of renal dysfunction seen among patients undergoing liver transplantation. As a result, the frequency of simultaneous liver-kidney (SLK) transplantation compared to liver transplantation alone (LTA) has also increased. The decision to perform SLK rather than LTA is an important one because the benefits to the liver transplant recipient receiving a kidney transplant must be balanced with the benefits of using that organ for a patient with end-stage renal disease. However, predicting whether or not a patient with liver failure has reversible kidney disease, and therefore does not also need a kidney transplant, is difficult. The severity and duration of pretransplant renal dysfunction, hepatitis c, diabetes, and other risk factors for kidney disease are associated with an increased risk of posttransplant end-stage renal disease. However, there are currently no clinical findings that accurately predict renal recovery post liver transplant. As a result, the rate of SLK versus LTA differs significantly between transplant centers. To increase consistency across centers, multiple guidelines have been proposed to guide the decision between SLK and LTA, but their poor predictive value has limited their uniform adoption. Nevertheless, adoption of uniform rules for the allocation of kidneys would reduce the variability between centers in rates of SLK transplant.


Ten-year experience with the artificial urinary sphincter in children.
To assess the efficacy of the artificial urinary sphincter survival and continence were first evaluated 5 years ago. We now evaluated the effects of the artificial urinary sphincter more than a decade after implantation. Before 1985 an artificial urinary sphincter was implanted in 22 male and 14 female consecutive patients 4 to 30 years old (median age 12). In addition, between 1985 and 1990, 18 other children underwent artificial urinary sphincter implantation. Results of both series were compared. Of the 25 sphincters in the original series that were functioning after 5 years 1 was removed and 2 patients were lost to followup, resulting in 22 functioning implants (61% of the patients). Mean survival time of the prostheses was 12.1 years and average followup for functioning sphincters was 13.7 years. There was no statistically significant difference in artificial urinary sphincter survival between the original group at 5 years and the second group treated after 1985. Of the patients in both groups with sphincters in place 32 of 39 (82%) were dry. Augmentation cystoplasty was performed in 9 of 18 patients (50%) in the second series (5 preoperatively and 4 postoperatively) compared to 10 of 36 (28%) in the original series at 5 years (3 preoperatively and 7 postoperatively). Renal failure developed in 6 patients from both series. The artificial urinary sphincter is a durable long-term solution for children with intractable incontinence. Long-term surveillance of the urinary tract is mandatory because of the potential for renal failure in patients who have bladder hypertonicity after placement of the device.


Properties of polyplexes formed through interaction between hydrophobically-modified poly(ethylene imine)s and calf thymus DNA in aqueous solution.
Polycationic polymers and DNA form soluble complexes in aqueous solution, which allows the transfer of genetic material into cells. Therefore, these chemically-modified polymers are of interest for use in studies aimed at better transfection efficiency and gene expression along with reduced cytotoxicity. In this study, branched poly(ethylene imine) (PEI) was modified by alkylation with n-alkyl groups (n = 4, 6, 8 and 12 carbons). The polyplexes formed through interaction of the modified PEIs and calf thymus DNA (ctDNA) were investigated using UV-Vis spectrophotometry, ethidium bromide fluorescence emission, circular dichroism spectroscopy, dynamic light scattering, and small-angle X-ray scattering techniques along with the determination of the zeta potential and viscosity. According to the results obtained, the formation of ctDNA-PEI polyplexes occurs in three steps. Firstly, when a small amount of polyelectrolyte is present the ctDNA chains are partially compacted. Subsequently, with the addition of more polyelectrolyte, the complexes have a null charge density and micrometric size. Lastly, with a higher concentration of PEI, the ctDNA is fully compacted by the PEI chains, leading to positively charged complexes with Rh values in the range of 52.0-86.0 nm. The viscosity and SAXS analysis suggested that the unmodified PEI exhibits the strongest interaction and promotes the best ctDNA condensation.


Oncometabolic Nuclear Reprogramming of Cancer Stemness.
By impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modeling, computation, and proof-of-concept studies with live cells, we found that an oncometabolite-driven pathological version of nuclear reprogramming increases the speed and efficiency of dedifferentiating committed epithelial cells into stem-like states with only a minimal core of stemness transcription factors. Our biomathematical model, which introduces nucleosome modification and epigenetic regulation of cell differentiation genes to account for the direct effects of oncometabolites on nuclear reprogramming, demonstrates that oncometabolites markedly lower the "energy barriers" separating non-stem and stem cell attractors, diminishes the average time of nuclear reprogramming, and increases the size of the basin of attraction of the macrostate occupied by stem cells. These findings establish the concept of oncometabolic nuclear reprogramming of stemness as a bona fide metabolo-epigenetic mechanism for generation of cancer stem-like cells.


Contextual predictive factors of child sexual abuse: the role of parent-child interaction.
To determine the prevalence of child sexual abuse in the Colombian coasts, as well as to assess the role of parent-child interactions on its occurrence and to identify factors from different environmental levels that predict it. This cross-sectional study explores the results of 1,089 household interviews responded by mothers. Descriptive analyses and multivariate logistic regressions were conducted, with child sexual abuse regressed on parent-child interactions, children's characteristics, maternal characteristics, family characteristics, and community characteristics. 1.2% of the mothers reported that their children had been sexually abused. Families that communicated with their children were less likely to report child sexual abuse, each additional standard deviation of communication reduced child sexual abuse 3.5 times. Affection and negative treatment to the children were not associated with child sexual abuse. Families who experienced intimate partner violence and violent communities were more likely to experience child sexual abuse. Interventions are needed to address the problem of child sexual abuse.


Autonomous subpixel satellite track end point determination for space-based images.
An algorithm for determining satellite track end points with subpixel resolution in spaced-based images is presented. The algorithm allows for significant curvature in the imaged track due to rotation of the spacecraft capturing the image. The motivation behind the subpixel end point determination is first presented, followed by a description of the methodology used. Results from running the algorithm on real ground-based and simulated spaced-based images are shown to highlight its effectiveness.


Homeostatic dysregulation proceeds in parallel in multiple physiological systems.
An increasing number of aging researchers believes that multi-system physiological dysregulation may be a key biological mechanism of aging, but evidence of this has been sparse. Here, we used biomarker data on nearly 33, 000 individuals from four large datasets to test for the presence of multi-system dysregulation. We grouped 37 biomarkers into six a priori groupings representing physiological systems (lipids, immune, oxygen transport, liver function, vitamins, and electrolytes), then calculated dysregulation scores for each system in each individual using statistical distance. Correlations among dysregulation levels across systems were generally weak but significant. Comparison of these results to dysregulation in arbitrary 'systems' generated by random grouping of biomarkers showed that a priori knowledge effectively distinguished the true systems in which dysregulation proceeds most independently. In other words, correlations among dysregulation levels were higher using arbitrary systems, indicating that only a priori systems identified distinct dysregulation processes. Additionally, dysregulation of most systems increased with age and significantly predicted multiple health outcomes including mortality, frailty, diabetes, heart disease, and number of chronic diseases. The six systems differed in how well their dysregulation scores predicted health outcomes and age. These findings present the first unequivocal demonstration of integrated multi-system physiological dysregulation during aging, demonstrating that physiological dysregulation proceeds neither as a single global process nor as a completely independent process in different systems, but rather as a set of system-specific processes likely linked through weak feedback effects. These processes--probably many more than the six measured here--are implicated in aging.


Molecular high harmonic generation in a two-color field.
We experimentally investigate the high harmonic generation (HHG) from CH4 molecules and Xe atoms in a two-color field (using the 800 nm laser and the tunable laser with the longer wavelength from 1500 nm to 1900 nm), and observe that the longer wavelength component can destructively suppress the HHG from CH4 molecules. By controlling the time delay between the two color laser pulses or tuning the laser intensity of the longer wavelength component, the suppressions of the HHG from CH4 molecules and the enhancements of the HHG from Xe atoms at the same laser condition are observed. The results indicate that the longer wavelength component around the molecular infrared absorption can suppress the molecular HHG process.


Encoding predictive reward value in human amygdala and orbitofrontal cortex.
Adaptive behavior is optimized in organisms that maintain flexible representations of the value of sensory-predictive cues. To identify central representations of predictive reward value in humans, we used reinforcer devaluation while measuring neural activity with functional magnetic resonance imaging. We presented two arbitrary visual stimuli, both before and after olfactory devaluation, in a paradigm of appetitive conditioning. In amygdala and orbitofrontal cortex, responses evoked by a predictive target stimulus were decreased after devaluation, whereas responses to the nondevalued stimulus were maintained. Thus, differential activity in amygdala and orbitofrontal cortex encodes the current value of reward representations accessible to predictive cues.


Transcriptomics Analysis of Porcine Caudal Dorsal Root Ganglia in Tail Amputated Pigs Shows Long-Term Effects on Many Pain-Associated Genes.
Tail amputation by tail docking or as an extreme consequence of tail biting in commercial pig production potentially has serious implications for animal welfare. Tail amputation causes peripheral nerve injury that might be associated with lasting chronic pain. The aim of this study was to investigate the short- and long-term effects of tail amputation in pigs on caudal DRG gene expression at different stages of development, particularly in relation to genes associated with nociception and pain. Microarrays were used to analyse whole DRG transcriptomes from tail amputated and sham-treated pigs 1, 8, and 16 weeks following tail treatment at either 3 or 63 days of age (8 pigs/treatment/age/time after treatment; n = 96). Tail amputation induced marked changes in gene expression (up and down) compared to sham-treated intact controls for all treatment ages and time points after tail treatment. Sustained changes in gene expression in tail amputated pigs were still evident 4 months after tail injury. Gene correlation network analysis revealed two co-expression clusters associated with amputation: Cluster A (759 down-regulated) and Cluster B (273 up-regulated) genes. Gene ontology (GO) enrichment analysis identified 124 genes in Cluster A and 61 genes in Cluster B associated with both "inflammatory pain" and "neuropathic pain." In Cluster A, gene family members of ion channels e.g., voltage-gated potassium channels (VGPC) and receptors e.g., GABA receptors, were significantly down-regulated compared to shams, both of which are linked to increased peripheral nerve excitability after axotomy. Up-regulated gene families in Cluster B were linked to transcriptional regulation, inflammation, tissue remodeling, and regulatory neuropeptide activity. These findings, demonstrate that tail amputation causes sustained transcriptomic expression changes in caudal DRG cells involved in inflammatory and neuropathic pain pathways.


Thickness measurement for volume holograms by analysis of first-order diffraction.
We present a method for measuring the thickness of volume holograms by analyzing the variations of the diffraction efficiency as a function of angle of incidence. This method can be justified theoretically within the Born approximation for gratings with small modulation. But we prove experimentally that the method can work surprisingly well even for strongly modulated volume holograms. The principle of the method consists of the determination of angles of incidence for which the first-order diffraction efficiency takes its extreme (maxima and minima) values: these angles are related to the thickness of the grating.


Prognostic factors for return to work, sickness benefits, and transitions between these states: a 4-year follow-up after work-related rehabilitation.
The aim of this study was to examine if age, gender, medical diagnosis, occupation, and previous sick leave predicted different probabilities for being at work and for registered sickness benefits, and differences in the transitions between any of these states, for individuals that had participated in an interdisciplinary work-related rehabilitation program. 584 individuals on long-term sickness benefits (mean 9.3 months, SD = 3.4) were followed with official register data over a 4-year period after a rehabilitation program. 66 % were female, and mean age was 44 years (SD = 9.3). The majority had a mental (47 %) or a musculoskeletal (46 %) diagnosis. 7 % had other diagnoses. Proportional hazards regression models were used to analyze prognostic factors for the probability of being on, and the intensity of transitions between, any of the following seven states during follow-up; working, partial sick leave, full sick leave, medical rehabilitation, vocational rehabilitation, partial disability pension (DP), and full DP. In a fully adjusted model; women, those with diagnoses other than mental and musculoskeletal, blue-collar workers, and those with previous long-term sick leave, had a lower probability for being at work and a higher probability for full DP during follow-up. DP was also associated with high age. Mental diagnoses gave higher probability for being on full sick leave, but not for transitions to full sick leave. Regression models based on transition intensities showed that risk factors for entering a given state (work or receiving sickness benefits) were slightly different from risk factors for leaving the same state. The probabilities for working and for receiving sickness benefits and DP were dependent on gender, diagnoses, type of work and previous history of sick leave, as expected. The use of novel statistical methods to analyze factors predicting transition intensities have improved our understanding of how the processes to and from work, and to and from sickness benefits may differ between groups. Further research is required to understand more about differences in prognosis for return to work after intensive work-related rehabilitation efforts.


Influence of relative humidity and suspending menstrua on survival of Acinetobacter spp. on dry surfaces.
Acinetobacter spp. are being reported with increasing frequency as a cause of nosocomial infection and have been isolated from the skin of healthy individuals, patients, hospital staff, dry nonbiotic objects, and different pieces of medical equipment. Factors affecting the survival of Acinetobacter spp. under conditions closely similar to those found in the hospital environment were investigated in the present study to help us understand the epidemiology of nosocomial Acinetobacter infection. Bacterial cells were suspended in distilled water or bovine serum albumin and were dried onto glass coverslips and kept at different relative humidities. Cells washed from coverslips were used to determined viable counts. Freshly isolated strains of Acinetobacter spp. belonging to the clinically important Acinetobacter calcoaceticus-Acinetobacter baumannii complex were found to be more resistant to drying conditions (e.g., 30 days for A. baumannii 16/49) than American Type Culture Collection strains (e.g., 2 days for A. baumannii ATCC 9955). The majority of strains belonging to the Acb complex had survival times similar to those observed for the gram-positive organism Staphylococcus aureus tested in the experiment. Survival times were prolonged for almost all the strains tested when they were suspended in bovine serum albumin (e.g., 60 days for A. baumannii R 447) compared with those for strains suspended in distilled water (11 days for R 447). The survival times for strains at higher relative humidity (31 or 93%) were longer than those for strains of Acinetobacter kept at a relative humidity of 10% (11 days at 31% relative humidity and 4 days at 10% relative humidity for R447). These findings are consistent with the observed tendency of Acinetobacter spp. to survive on dry surfaces, and they can be transferred not only by moist vectors but also under dry conditions in a hospital environment during nosocomial infection outbreaks. The results obtained in the experiment support the previously suggested airborne spread of Acinetobacter spp. in hospital wards and repeated outbreaks after incomplete disinfection of contaminated dry surfaces.


Tumors Alter Inflammation and Impair Dermal Wound Healing in Female Mice.
Tissue repair is an integral component of cancer treatment (e.g., due to surgery, chemotherapy, radiation). Previous work has emphasized the immunosuppressive effects of tumors on adaptive immunity and has shown that surgery incites cancer metastases. However, the extent to which and how tumors may alter the clinically-relevant innate immune process of wound healing remains an untapped potential area of improvement for treatment, quality of life, and ultimately, mortality of cancer patients. In this study, 3.5 mm full-thickness dermal excisional wounds were placed on the dorsum of immunocompetent female mice with and without non-malignant flank AT-84 murine oral squamous cell carcinomas. Wound closure rate, inflammatory cell number and inflammatory signaling in wounds, and circulating myeloid cell concentrations were compared between tumor-bearing and tumor-free mice. Tumors delayed wound closure, suppressed inflammatory signaling, and altered myeloid cell trafficking in wounds. An in vitro scratch "wounding" assay of adult dermal fibroblasts treated with tumor cell-conditioned media supported the in vivo findings. This study demonstrates that tumors are sufficient to disrupt fundamental and clinically-relevant innate immune functions. The understanding of these underlying mechanisms provides potential for therapeutic interventions capable of improving the treatment of cancer while reducing morbidities and mortality.


Drinking water sources, mortality and diarrhoea morbidity among young children in northern Ghana.
In the Upper East Region of Ghana, considerable resources have been invested in the provision of boreholes. As part of the Ghana Vitamin A Supplementation Trials' Survival Study which was carried out in one of the districts of the Upper East Region between January 1989 and December 1991, data were collected over a period of one calendar year on the drinking water sources used by approximately 13,000 mothers/guardians of over 20,000 children and on the morbidity and mortality experiences of these children. These data were used to describe seasonal and geographical variations in drinking water sources; to look for other predictors of water source use; and to establish whether the drinking water source was associated with the risk of child death or the period prevalence of diarrhoea among young children. Boreholes were used as the main source of drinking water by about 60-70% of respondents. They were used slightly more frequently in the dry season. In the rainy season, the use increased of more traditional sources such as rainwater or holes dug in stream beds. The use of boreholes was greatest in the northern zone of the study area and was more common in those who had had some formal education and were of higher socioeconomic status. Some association was found between reported drinking water source and diarrhoeal morbidity, although this association appeared to be seasonal. No significant association was found between drinking water source and child mortality.


Public attitudes and beliefs about living kidney donation: focus group study.
With the rising prevalence of end-stage kidney disease worldwide, the proportion of the general community who might subsequently be called upon to consider living related kidney donation is also increasing. Knowledge about the attitudes and beliefs among the general public about living kidney donation is limited. We aimed to describe public perspectives on living kidney donation. Participants were recruited from three states in Australia to participate in 12 focus groups (n=113). Transcripts were analyzed thematically. We identified six themes: expected benefits (saving and improving life, societal gain, donor satisfaction, reassurance and control), consciousness of donor risks (compromised health, lifestyle limitations, financial consequences, relationship tensions, devastation), social precariousness (fear of the unknown, exploitative connotation, recipient deservingness, protecting conscience, potential regret), upholding fairness (equal access to transplantation, reciprocity, prevent prejudice, donor safety net), decisional autonomy (body ownership, right to know, valid relationships), and assumed duty of care (facilitate informed decision-making, safeguard against coercion, ensure psychological safety, justifiable risk, objectivity, warranted disclosure). The expected benefits for recipients bolster public support for living kidney donor transplantation; however, ethical dilemmas and concerns for the donor instilled ambivalence about living donation. Protecting equity and autonomy, and an implicit trust in health professionals to protect donors and recipients mitigated some of these uncertainties. Developing interventions, practices, and policies that address community skepticism and values may promote awareness and trust in living kidney donation.


Measurement of net electric charge and dipole moment of dust aggregates in a complex plasma.
Understanding the agglomeration of dust particles in complex plasmas requires knowledge of basic properties such as the net electrostatic charge and dipole moment of the dust. In this study, dust aggregates are formed from gold-coated mono-disperse spherical melamine-formaldehyde monomers in a radiofrequency (rf) argon discharge plasma. The behavior of observed dust aggregates is analyzed both by studying the particle trajectories and by employing computer models examining three-dimensional structures of aggregates and their interactions and rotations as induced by torques arising from their dipole moments. These allow the basic characteristics of the dust aggregates, such as the electrostatic charge and dipole moment, as well as the external electric field, to be determined. It is shown that the experimental results support the predicted values from computer models for aggregates in these environments.


Multiple displacement amplification for malaria parasite DNA.
Multiple displacement amplification (MDA) using Phi29 has proved to be an efficient, high-fidelity method for whole genome amplification in many organisms. This project was designed to evaluate this approach for use with the malaria parasite Plasmodium falciparum. In particular, we were concerned that the AT richness and presence of contaminating human DNA could limit efficiency of MDA in this system. We amplified 60 DNA samples using phi29 and scored 14 microsatellites, 9 single-nucleotide polymorphisms (SNPs), and gene copy number at GTP-cyclohydrolase I both before and after MDA. We observed 100% concordance in 829 microsatellite genotypes and in 499 SNP genotypes. Furthermore, copy number estimates for the GTP-cyclohydrolase I gene were correlated (r(2) = 0.67) in pre- and postamplification samples. These data confirm that MDA permits scoring of a range of different types of polymorphisms in P. falciparum malaria and can be used to extend the life of valuable DNA stocks.


Global Matrix 2.0: Report Card Grades on the Physical Activity of Children and Youth Comparing 38 Countries.
The Active Healthy Kids Global Alliance organized the concurrent preparation of Report Cards on the physical activity of children and youth in 38 countries from 6 continents (representing 60% of the world's population). Nine common indicators were used (Overall Physical Activity, Organized Sport Participation, Active Play, Active Transportation, Sedentary Behavior, Family and Peers, School, Community and the Built Environment, and Government Strategies and Investments), and all Report Cards were generated through a harmonized development process and a standardized grading framework (from A = excellent, to F = failing). The 38 Report Cards were presented at the International Congress on Physical Activity and Public Health in Bangkok, Thailand on November 16, 2016. The consolidated findings are summarized in the form of a Global Matrix demonstrating substantial variation in grades both within and across countries. Countries that lead in certain indicators often lag in others. Average grades for both Overall Physical Activity and Sedentary Behavior around the world are D (low/poor). In contrast, the average grade for indicators related to supports for physical activity was C. Lower-income countries generally had better grades on Overall Physical Activity, Active Transportation, and Sedentary Behaviors compared with higher-income countries, yet worse grades for supports from Family and Peers, Community and the Built Environment, and Government Strategies and Investments. Average grades for all indicators combined were highest (best) in Denmark, Slovenia, and the Netherlands. Many surveillance and research gaps were apparent, especially for the Active Play and Family and Peers indicators. International cooperation and cross-fertilization is encouraged to address existing challenges, understand underlying determinants, conceive innovative solutions, and mitigate the global childhood inactivity crisis. The paradox of higher physical activity and lower sedentary behavior in countries reporting poorer infrastructure, and lower physical activity and higher sedentary behavior in countries reporting better infrastructure, suggests that autonomy to play, travel, or chore requirements and/or fewer attractive sedentary pursuits, rather than infrastructure and structured activities, may facilitate higher levels of physical activity.


Suggestive evidence for association of human chromosome 18q12-q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases.
Some immune system disorders, such as type 1 diabetes, multiple sclerosis (MS), and rheumatoid arthritis (RA), share common features: the presence of autoantibodies and self-reactive T-cells, and a genetic association with the major histocompatibility complex. We have previously published evidence, from 1,708 families, for linkage and association of a haplotype of three markers in the D18S487 region of chromosome 18q21 with type 1 diabetes. Here, the three markers were typed in an independent set of 627 families and, although there was evidence for linkage (maximum logarithm of odds score [MLS] = 1.2; P = 0.02), no association was detected. Further linkage analysis revealed suggestive evidence for linkage of chromosome 18q21 to type 1 diabetes in 882 multiplex families (MLS = 2.2; lambdas = 1.2; P = 0.001), and by meta-analysis the orthologous region (also on chromosome 18) is linked to diabetes in rodents (P = 9 x 10(-4)). By meta-analysis, both human chromosome 18q12-q21 and the rodent orthologous region show positive evidence for linkage to an autoimmune phenotype (P = 0.004 and 2 x 10(-8), respectively, empirical P = 0.01 and 2 x 10(-4), respectively). In the diabetes-linked region of chromosome 18q12-q21, a candidate gene, deleted in colorectal carcinoma (DCC), was tested for association with human autoimmunity in 3,380 families with type 1 diabetes, MS, and RA. A haplotype ("2-10") of two newly characterized microsatellite markers within DCC showed evidence for association with autoimmunity (P = 5 x 10(-6)). Collectively, these data suggest that a locus (or loci) exists on human chromosome 18q12-q21 that influences multiple autoimmune diseases and that this association might be conserved between species.


Relief of suffering and regard for personhood: nurses' ethical concerns in Japan and the USA.
The ethical concerns of Japanese nurses are compared with those of previously described nurses from the USA. Patient comfort was a primary concern of nurses from both countries. Participants described an ethical imperative to provide adequate pain medication for patients and prevent unnecessary and uncomfortable invasive tests and procedures, especially at the end of life as the focus changed from 'cure' to 'care'. The notion of regard for personhood varied, based on the communication styles and definition of the self inherent in the different cultures of the nurses. A common meaning centred around knowing patients as persons, listening to their needs and preferences, supporting their everyday choices through advocacy, and maintaining their dignity. Despite background cultural differences, there are common ethical concerns between nurses in Japan and the USA. This article invites readers to reflect on everyday nursing practices that exemplify ethical expertise, and the significance of this expertise in uncovering and articulating nursing ethics across cultures.


Multivessel coronary artery disease: quantifying how recent trials should influence clinical practice.
The majority (70%) of coronary revascularizations concern patients with multivessel disease (MVD). Treatment options include medical therapy, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). CABG surgery has been shown to improve survival compared with medical therapy. PCI relieves angina compared with medical therapy and is equivalent to CABG in low complex MVD. Other benefits are currently being evaluated in ongoing trials. In complex MVD, CABG results in lower rates of long-term mortality, myocardial infarction and repeat revascularization compared with PCI. These results are more pronounced in diabetics and in patients with lesions that are anatomically more complex. The application of the results of clinical trials may be limited due to restrictive eligibility criteria. Comparative effectiveness studies are, therefore, needed to complement the results of trials, but also have inherent limitations. Inappropriateness criteria provide an important tool to measure how evidence from trials, large registries and guidelines is integrated in clinical practice. Checklists and decision aids may also lead to better application of the latest evidence and lower rates of inappropriate use. Decision-making is centered around heart team discussions and risk scores. Economic considerations will increasingly be included in decision-making, since the economic impact of ischemic heart disease is high and the growth of healthcare expenditure is unsustainable. In this context, CABG is associated with higher upfront costs, but is economically attractive at long-term follow-up.


Vaginal pH as a Diagnostic Tool for Menopause: A Preliminary Analysis.
Menopause is defined as the permanent cessation of menstruation, as a result of decrease in ovarian follicles and the loss of ovarian activity. There is decrease in inhibin B level which causes decrease in negative feedback on the serum follicle-stimulating hormone (FSH), which in turn increases the level of serum FSH. Serum FSH is routinely used as a marker of menopause. Decline in the estrogen level causes thinning of vaginal epithelium, resulting in less exfoliation of the vaginal epithelial cells, lesser available glycogen, and decreased substrate for acid production, leading to increase in vaginal pH. The aim of this study is to compare the sensitivity of vaginal pH versus serum FSH level to diagnose menopause. This is a cross-sectional study, performed in obstetrics and gynecology outpatient department of a teaching hospital of central Gujarat. A total of 120 women who had their last menstrual period >1 year back (menopause) were included in the study. Vaginal pH was measured and serum sample was taken to measure FSH level. Sensitivity of both vaginal pH and serum FSH to diagnose menopause was compared. McNemar test was used to analyze the convergence of the two methods for the diagnosis of menopause. In the absence of vaginal infection, sensitivity of vaginal pH to diagnose menopause was 90%, while sensitivity of the serum FSH was 85%. Sensitivity of the vaginal pH is similar to the serum FSH for diagnosis of menopause.


Association between plasma 25-hydroxyvitamin D and breast cancer risk.
Vitamin D has been associated with decreased risk of several cancers. In experimental studies, vitamin D has been shown to inhibit cell proliferation and induce differentiation and apoptosis in normal and malignant breast cells. Using a population-based case-control study on Long Island, New York, we examined the association of breast cancer with plasma 25-hydroxyvitamin D (25-OHD) levels, a measure of vitamin D body stores. In-person interviews and blood specimens were obtained from 1,026 incident breast cancer cases diagnosed in 1996 to 1997 and 1,075 population-based controls. Plasma 25-OHD was measured in batched, archived specimens by Diasorin RIA. The mean (SD) plasma 25-OHD concentration was 27.1 (13.0) and 29.7 (15.1) ng/mL in the cases and controls, respectively (P < 0.0001). Plasma 25-OHD was inversely associated with breast cancer risk in a concentration-dependent fashion (P(trend) = 0.002). Compared with women with vitamin D deficiency (25-OHD, <20 ng/mL), levels above 40 ng/mL were associated with decreased breast cancer risk (odds ratio, 0.56; 95% confidence interval, 0.41-0.78). The reduction in risk was greater among postmenopausal women (odds ratio, 0.46; 95% confidence interval, 0.09-0.83), and the effect did not vary according to tumor hormone receptor status. In summary, these results add to a growing body of evidence that adequate vitamin D stores may prevent breast cancer development. Whereas circulating 25-OHD levels of >32 ng/mL are associated with normal bone mineral metabolism, our data suggest that the optimal level for breast cancer prevention is >or=40 ng/mL. Well-designed clinical trials are urgently needed to determine whether vitamin D supplementation is effective for breast cancer chemoprevention.


Site-Specific Characteristics of Bone Marrow Mesenchymal Stromal Cells Modify the Effect of Aging on the Skeleton.
Bone is a self-renewing tissue. Bone marrow mesenchymal stromal cells (BMSCs) are located in the adult skeleton and are believed to be involved in the maintenance of skeletal homeostasis throughout life. With increasing age, the ability of the skeleton to repair itself decreases, possibly due to the reduced functional capacity of BMSCs. Recent evidence has suggested the existence of at least two populations of BMSCs with different embryonic origins that cannot be interchanged during stem cell recruitment: craniofacial BMSCs (neural crest origin) and appendicular BMSCs (mesoderm origin). Questions arise as to whether the site-specific characteristics alter the effect of aging on the skeleton. In this study, the effects of biological aging on human BMSCs were compared with BMSCs derived from the craniofacial bone versus those derived from the appendicular skeleton. The phenotype, proliferation, and functional characteristics (osteogenic differentiation, cytokine secretion, and bone formation in vivo) of the BMSCs were investigated. The results demonstrated that the proliferative capacity and osteogenic differentiation of the BMSCs decrease significantly with age both in vitro and in vivo. For age-matched groups, the osteogenic differentiation capacity of alveolar BMSCs was higher than that of femoral BMSCs in the middle-aged and old groups, while there was no significant difference for the young groups. Compared with old alveolar BMSCs, old femoral BMSCs had a significantly longer population doubling time, a smaller colony-forming population, and less bone formation in vivo, while there was no significant difference for the young and middle-aged groups. Distinct differences in the expression of cytokine factors were also found. In conclusion, human BMSCs display an age-related decrease in functional capacity, and embryonic origins may play a critical role in mediating the aging rate of BMSCs. These data provide novel insights into the skeletal site-specific characteristics of aged BMSCs.


Antiviral activity of the bicyclam derivative JM3100 against drug-resistant strains of human immunodeficiency virus type 1.
Bicyclams have recently been identified as potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication. The prototype of this series, JM3100 exhibits anti-HIV potency at concentrations ranging from 0.001 to 0.01 micrograms/ml. JM3100 proved to be active when tested against HIV strains resistant to the reverse transcriptase (RT) inhibitors 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (DDI), 3TC, alpha APA and TIBO, at roughly the same concentrations as for the wild-type strain. The virus was passaged in vitro in the presence of increasing concentrations of either TIBO or alpha APA alone or in combination with JM3100. The combination between TIBO, or alpha APA, and JM3100 delayed the development of TIBO- and alpha APA-resistant strains, without emergence of resistance to JM3100. In separate experiments, it took more than 60 passages (300 days) in MT-4 cells and 20 passages (140 days) in peripheral blood lymphocyte (PBL) cells for the virus to become resistant to JM3100. The JM3100-resistant virus showed cross-resistance to sulfated polysaccharides such as dextran sulfate (DS), pentosan sulfate (PS), heparin and cyclodextrin sulfate (CDS), suggesting that these compounds may share a common mechanism of action. Furthermore, the inhibitory effect of JM3100 on virus-induced syncytium formation was enhanced in the presence of heparin. The results presented here provide further support for the bicyclams as attractive candidate drugs for the chemotherapy of HIV infections.


Fine scale spatial urban land cover factors associated with adult mosquito abundance and risk in Tucson, Arizona.
It is currently unclear what role microhabitat land cover plays in determining the seasonal spatial distribution of Aedes aegypti and Culex quinquefasciatus, disease vectors of dengue and West Nile Virus, respectively, in Tucson, AZ. We compared mosquito abundance to sixteen land cover variables derived from 2010 NAIP multispectral data and 2008 LiDAR height data. Mosquitoes were trapped with 30-9 traps from May to October of 2010 and 2011. Variables were extracted for five buffer zones (10-50 m radii at 10 m intervals) around trapping sites. Stepwise regression was performed to determine the best scale for observation and the influential land cover variables. The 30 m radius buffer was determined to be the best for observing the land cover-mosquito abundance relationship. Ae. aegypti presence was positively associated with structure and medium height trees and negatively associated with bare earth; Cx. quinquefasciatus presence was positively associated with pavement and medium height trees and negatively associated with shrubs. These findings emphasize vegetation, impervious surfaces, and soil influences on mosquito presence in an urban setting. Lastly, the land cover-mosquito abundance relationships were used to produce risk maps of seasonal presence that highlight high risk areas in Tucson, which may be useful for focusing mosquito control program actions.


Anxiety and the Neurobiology of Temporally Uncertain Threat Anticipation.
When extreme, anxiety-a state of distress and arousal prototypically evoked by uncertain danger-can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala-the two major subdivisions of the extended amygdala-play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety.SIGNIFICANCE STATEMENT Anxiety-an emotion prototypically associated with the anticipation of uncertain harm-has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear.


Inhibitors of phosphodiesterase IV (PDE IV) increase acid secretion in rabbit isolated gastric glands: correlation between function and interaction with a high-affinity rolipram binding site.
In this report, we describe the ability of selective inhibitors of phosphodiesterase (PDE) isozymes to increase aminopyrine accumulation in rabbit isolated gastric glands. Aminopyrine accumulation in the presence of histamine was increased by the nonselective PDE inhibitor isobutylmethylxanthine (EC50 = 4.8 microM) and by two selective PDE IV inhibitors, rolipram and Ro 20-1724 (EC50 = 0.013 and 0.07 microM, respectively) but not by selective PDE III inhibitors (siguazodan and SK&F 94120) or by a selective PDE V inhibitor (zaprinast). These results suggest that PDE IV is an important regulator of acid secretion in response to histamine. One of the more fascinating properties of PDE IV is the expression of a high-affinity binding site for [3H]-rolipram in addition to cAMP catalytic activity. Although agents that inhibit PDE IV catalytic activity also appear to bind to the high-affinity rolipram-binding site, the rank-order potencies of compounds for these two effects are poorly correlated. Also, certain pharmacological actions of PDE IV inhibitors appear to be related to an interaction with this binding site. In this study, we observed that the ability of PDE IV inhibitors to enhance acid secretion was not associated with their ability to inhibit PDE IV catalytic activity but did show a strong correlation with their ability to compete for [3H]-rolipram binding. Furthermore, we were able to detect [3H]-rolipram binding sites in gastric glands that had characteristics similar to those of the [3H]-rolipram binding sites in rat brain microsomes and human recombinant PDE IV.


What is normal black African hair? A light and scanning electron-microscopic study.
The hair of normal black Africans forms a mat of tightly interwoven hair shafts. The effect of this on the structure of the hair shaft and the response to grooming is unknown. Our purpose was to use light and scanning electron microscopy (SEM) to examine the structure of Negroid-type hairs and effects of combing in black African volunteers. Hair samples were collected, by combing, from Africans and compared with those from Caucasian and Asian volunteers. The volunteers had never used chemical treatments. Their hair had not been cut for at least 1 year and grooming had been limited to shampooing, drying, and combing. More than 2000 hairs in 12 African volunteers were examined by light microscopy. The hairs appear as a tight coiled springlike structure. Many shafts exhibited knots (10%-16% vs 0.15%) and appear broken compared with hair shafts from other ethnic groups. SEM of African hairs showed features consistent with repeated breaks of the shaft. Examination of hairs in situ showed interlocking of hair shafts. These observations provide an understanding of the physical nature of, and effect of combing on, black African hair.


Immunopathogenesis and neurological manifestations associated to HTLV-1 infection.
The human T lymphotropic virus type-1 (HTLV-1) was the first human retrovirus identified. The virus is transmitted through sexual intercourse, blood transfusion, sharing of contaminated needles or syringes and from mother to child, mainly through breastfeeding. In addition to the well-known association between HTLV-1 and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), several diseases and neurologic manifestations have been associated with the virus. This review was conducted through a PubMed search of the terms HTLV-1, immune response and neurological diseases. Emphasis was given to the most recent data regarding pathogenesis and clinical manifestations of HTLV-1 infection. The aim of the review is to analyze the immune response and the variety of neurological manifestations associated to HTLV-1 infection. A total of 102 articles were reviewed. The literature shows that a large percentage of HTLV-1 infected individuals have others neurological symptoms than HAM/TSP. Increased understanding of these numerous others clinical manifestations associated to the virus than adult T cell leukemia/lymphoma (ATLL) and HAM/TSP has challenged the view that HTLV-1 is a low morbidity infection.