Hypercortisolism revealed by the dexamethasone suppression test in patients [corrected] with acute ischemic stroke.
Using the dexamethasone suppression test, we studied the activity of the hypothalamic-pituitary-adrenal axis within the first week after onset in 62 patients with acute ischemic stroke. Compared with two control groups (one comprising 25 elderly patients with various acute medical disorders and the other comprising 33 80-year-old volunteers), stroke patients had higher postdexamethasone cortisol levels (p = 0.08 and p = 0.001, respectively). By multiple regression analysis, high postdexamethasone cortisol levels in the stroke patients were significantly associated with proximity of the lesion to the frontal pole of the brain (p = 0.008) and with disorientation (p = 0.03), whereas no association with major depression was seen. Many stroke patients are exposed to hypercortisolism, which may have negative consequences upon organ functions. The extent to which dexamethasone administration suppresses cortisol levels seems to be determined mainly by the site of brain lesion and cannot be used as an indicator of major depression early after stroke.


Resistance to tick-borne Francisella tularensis by tick-sensitized rabbits: allergic klendusity.
Mammals become hypersensitive to ticks that feed upon them. That hypersensitivity was thought responsible for an observation that a large number of Francisella tularensis-infected Dermacentor variabilis failed to infect a rabbit previously exposed to ticks of that species. In a series of tests of that hypothesis, rabbits sensitized to ticks were often significantly more resistant than control animals to tick-borne tularemia. The conditions that determine the klendusity are thought to be variable and complex but the phenomenon must be of importance in the epidemiology of some arthropod-borne agents.


A novel approach for inhibition of HIV-1 by RNA interference: counteracting viral escape with a second generation of siRNAs.
RNA interference (RNAi) is an evolutionary conserved gene silencing mechanism in which small interfering RNA (siRNA) mediates the sequence specific degradation of mRNA. The recent discovery that exogenously delivered siRNA can trigger RNAi in mammalian cells raises the possibility to use this technology as a therapeutic tool against pathogenic viruses. Indeed, it has been shown that siRNAs can be used effectively to inhibit virus replication. The focus of this review is on RNA interference strategies against HIV-1 and how this new technology may be developed into a new successful therapy. One of the hallmarks of RNAi, its sequence specificity, also presents a way out for the virus, as single nucleotide substitutions in the target region can abolish the suppression. Strategies to prevent the emergence of resistant viruses have been suggested and involve the targeting of conserved sequences and the simultaneous use of multiple siRNAs, similar to current highly active antiretroviral therapy. We present an additional strategy aimed at preventing viral escape by using a second generation of siRNAs that recognize the mutated target sites.


Lumbosacral multiradiculopathy responsive to antibiotic therapy: description of four patients with lumbar spondylosis and a superimposed Lyme disease.
Lyme disease is a diffuse zoonosis caused by spirochaetes of the Borrelia burgdorferi species complex. Neurological manifestations of the disease, involving central or peripheral nervous system, are common. This study describes four consecutive patients with an MRI-proven lumbosacral spondylosis, who complained of progressive worsening of symptoms in the last months in which serological evaluation suggested a superimposed B. Burgdorferi infection. Four patients, all from the Lazio region, were admitted to the Department of Neurology. Extensive laboratory studies and clinical, anamnestic and neurophysiological evaluation were performed in all cases. In all cases, anamnesis revealed a previous diagnosis of lumbosacral foraminal stenosis. Clinical and neurophysiological findings were consistent with a lumbosacral multiradiculopathy. Considering serological evaluation suggestive of a superimposed B. burgdorferi infection a proper antibiotic therapy was started. All cases showed a marked improvement of symptoms. Clinicians should be aware that in all cases of lumbosacral multiradiculopathy, even if a mechanical cause is documented, B. burgdorferi may be a simply treatable condition.


Population migration and the spread of types 1 and 2 human immunodeficiency viruses.
Over 14 million people are estimated to be infected with the human immunodeficiency viruses (HIV), with nearly three-fourths of the infected persons residing in developing countries. One factor responsible for dissemination of both HIV-1 and HIV-2 worldwide was the intense migration of individuals, from rural to urban centers with subsequent return migration and internationally due to civil wars, tourism, business purposes, and the drug trade. In sub-Saharan Africa, between 1960 and 1980, urban centers with more than 500,000 inhabitants increased from 3 to 28, and more than 75 military coups occurred in 30 countries. The result was a massive migration of rural inhabitants to urban centers concomitant with the spread of HIV-1 to large population centers. With the associated demographic, economic, and social changes, an epidemic of sexually transmitted diseases and HIV-1 was ignited. Migratory patterns were also responsible for the spread of endemic HIV-2 to neighboring West African countries and eventually to Europe, the Americans, and India. Although Southeast Asia was the last region in which HIV-1 was introduced, it has the greatest potential for rapid spread due to population density and inherent risk behaviors. Thus, the migration of poor, rural, and young sexually active individuals to urban centers coupled with large international movements of HIV-infected individuals played a prominent role in the dissemination of HIV globally. The economic recession has aggravated the transmission of HIV by directly increasing the population at risk through increased urban migration, disruption of rural families and cultural values, poverty, and prostitution and indirectly through a decrease in health care provision. Consequently, social and economic reform as well as sexual behavior education need to be intensified if HIV transmission is to be controlled.


Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury.
Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2α. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampal-dependent cognitive deficits induced by TBI in two different injury mouse models-focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head trauma-induced chronic cognitive deficits.


Prevention and management of positional skull deformities in infants.
Positional skull deformities may be present at birth or may develop during the first few months of life. Since the early 1990s, US pediatricians have seen an increase in the number of children with cranial asymmetry, particularly unilateral flattening of the occiput, likely attributable to parents following the American Academy of Pediatrics "Back to Sleep" positioning recommendations aimed at decreasing the risk of sudden infant death syndrome. Positional skull deformities are generally benign, reversible head-shape anomalies that do not require surgical intervention, as opposed to craniosynostosis, which can result in neurologic damage and progressive craniofacial distortion. Although associated with some risk of positional skull deformity, healthy young infants should be placed down for sleep on their backs. The practice of putting infants to sleep on their backs has been associated with a drastic decrease in the incidence of sudden infant death syndrome. Pediatricians need to be able to properly differentiate infants with benign skull deformities from those with craniosynostosis, educate parents on methods of proactively decreasing the likelihood of the development of occipital flattening, initiate appropriate management, and make referrals when necessary. This report provides guidance for the prevention, diagnosis, and management of positional skull deformity in an otherwise normal infant without evidence of associated anomalies, syndromes, or spinal disease.


Parent and Patient Reported Outcomes for Head Shape in Children Undergoing Surgery for Single Suture Synostosis.
Assessing outcomes following surgery for single suture craniosynostosis is important to ensure minimum standards are being met, but also to compare results using different surgical techniques and treatment protocols. What constitutes an "outcome" and how this is measured remains a challenge, particularly when assessment should include consideration of aesthetic, functional, and psychological domains.The Oxford Craniofacial Unit has initiated routine collection of parents' and patients' ratings of 2 factors that are closely associated with psychological adjustment; how noticeable the child's headshape is and how much this bothers the parent and/or child. A brief Surgical Outcome Questionnaire is completed by parents and children (over 7 years) at their outpatient appointment; parents are also asked to rate the extent to which they feel surgery made a difference to their child's headshape.Data are presented for 519 parents and 248 children with single suture craniosynostosis who attended the Oxford Craniofacial Unit in 2018 and 2019; this represents over 80% of patients seen in the clinic indicating the questionnaire is acceptable for families and the potential for rapid, relevant data on a continuous basis. Analysis of the data is presented to demonstrate the utility of the Surgical Outcome Questionnaire in exploring the views of both parents and patients of the noticeability and level of concern about the child's headshape for different age groups and diagnoses.The Surgical Outcome Questionnaire provides a novel method of collecting routine data for patients across their craniofacial care pathway, using variables which are relevant and meaningful for patients and parents.


Links among emotional awareness, somatic awareness and autonomic homeostatic processing.
Emotional awareness and somatic interoceptive awareness are essential processes for human psychosomatic health. A typical trait of lacking emotional awareness related to psychosomatic symptoms is alexithymia. In contrast, alexisomia refers to the trait of lacking somatic awareness. Links between emotional and somatic awareness and homeostatic processing are also significant for the psychosomatic health. The purpose of the present paper is to review the links among emotional awareness, somatic interoceptive awareness and autonomic homeostatic processing. On the basis of the collected evidence, the following arguments were presented(1): (1) The main subcortical neural substrates for these processes are limbic-related systems, which are also responsible for autonomic functions for optimization of homeostatic efficiency. (2) Considerable studies have shown that autonomic activity and/or reactivity to stress correlate with both emotional and interoceptive awareness. A hypothesis was advocated about the links between the two types of awareness and autonomic function: Autonomic dysfunction, especially high sympathetic tone at baseline and/or attenuated reactivity or variability to stress, appears to be involved in disturbance of emotional and interoceptive awareness. (3) Several studies suggest that a link or a cooperative relationship exists between emotional and somatic awareness, and that somatic awareness is the more fundamental of the two types of awareness. Emotional awareness, somatic awareness and autonomic homeostatic processing generally occur in parallel or concurrently. However, some complex features of pathologies include coexistence of reduced interoceptive awareness and somatosensory amplification. The autonomic homeostatic process is fundamentally involved in emotional and somatic awareness. Investigation of these types of awareness with both neuroimaging evaluations and estimation of peripheral autonomic function are required as next steps for exploration of the relationship between awareness and human somatic states including somatic symptoms as well as general psychosomatic health.


Use of color Doppler EUS in assessing azygos blood flow for patients with portal hypertension.
Azygos blood flow is an index of blood flow through gastroesophageal collateral vessels and varices in portal hypertension. Conventional measurement of azygos blood flow involves catheterization of the azygos vein. We studied the feasibility of assessing azygos blood flow with color Doppler endosonography and of monitoring the effects of vasoactive agents on azygos blood flow. Patients with portal hypertension were examined by means of linear array color Doppler endoscopic ultrasonography (EUS). Patients who had taken propranolol or nitrates in the 4 weeks before the day of measurement of azygos blood flow were excluded. After identification of the azygos vein and recording of baseline readings of mean arterial blood pressure, pulse rate, and azygos blood flow, patients were selected in a random manner to receive a bolus injection of 2 mg terlipressin, 250 microg somatostatin, or saline solution (control). Azygos blood flow was measured 1, 5, and 10 minutes after injection (AzBF-1, AzBF-5, AzBF-10). Six patients were recruited in each treatment group. Basal azygos blood flow showed a positive association with the Child-Pugh grade of cirrhosis (p < 0.005). After bolus injection of terlipressin and somatostatin, there was a marked decrease in AzBF-1 (24% and 37%), AzBF-5 (42% and 19%), and AzBF-10 (40% both) compared with baseline. The control group showed no significant change in azygos blood flow. Color Doppler EUS is useful in assessing azygos blood flow in portal hypertension and in monitoring the effects of vasoactive agents.


The effect of the gastrectomy on survival in patients with metastatic gastric cancer: a study of ASMO.
To investigate the role of surgical resection of primary tumor on overall survival (OS) in advanced gastric cancer patients at the time of diagnosis. The survival rates of metastatic gastric cancer patients whose gastric primary tumor was resected at time of diagnosis were compared with metastatic gastric cancer patients whose primary tumor was nonresected. The median progression-free survival and OS in operated and nonoperated group were 10 versus 6, 14 versus 9 months, respectively (p < 0.001). In multivariate analysis, gastric resection of primary tumor, Eastern Cooperative Oncology Group performance status, second-line chemotherapy had a significant effect on OS (hazard ratio [HR]: 0.52 [95% CI: 0.38-0.71], HR: 0.57 [95% CI: 0.42-0.78], HR: 1.48 [1.09-2.01]; p ≤ 0.001, p = 0.001 and p = 0.012, respectively). Subpopulations of patients with metastatic gastric cancer might benefit from surgical removal of primary tumor.


In the clinic. Management of newly diagnosed HIV infection.
This issue provides a clinical overview of management of newly diagnosed HIV infection focusing on prevention, diagnosis, treatment, practice improvement, and patient information. Readers can complete the accompanying CME quiz for 1.5 credits. Only ACP members and individual subscribers can access the electronic features of In the Clinic. Non-subscribers who wish to access this issue of In the Clinic can elect "Pay for View." Subscribers can receive 1.5 category 1 CME credits by completing the CME quiz that accompanies this issue of In the Clinic. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians' Information and Education Resource) and MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing division and with assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult www.acponline.org, http://pier.acponline.org, and other resources referenced within each issue of In the Clinic.


Neighborhoods have little effect on fungal attack or insect predation of developing seeds in a grassland biodiversity experiment.
Numerous observational studies have documented conspecific negative density-dependence that is consistent with the Janzen-Connell Hypothesis (JCH) of diversity maintenance. However, there have been few experimental tests of a central prediction of the JCH: that removing host-specific enemies should lead to greater increases in per capita recruitment in areas of higher host density or lower relative phylogenetic diversity. Using spatially randomized plots of high and low host biomass in a temperate grassland biodiversity experiment, we treated developing seedheads of six prairie perennials to factorial applications of fungicide and insecticide. We measured predispersal seed production, seed viability, and seedling biomass. Results were highly species-specific and idiosyncratic. Effects of insect seed predators and fungal pathogens on predispersal responses varied with neither conspecific biomass nor phylogenetic diversity, suggesting that-at least at the predispersal stage and for the insect and fungal seed predators we were able to exclude-the JCH is not sufficient to contribute to negative conspecific density-dependence for these dominant prairie species.


Prefrontal and striatal dopaminergic genes predict individual differences in exploration and exploitation.
The basal ganglia support learning to exploit decisions that have yielded positive outcomes in the past. In contrast, limited evidence implicates the prefrontal cortex in the process of making strategic exploratory decisions when the magnitude of potential outcomes is unknown. Here we examine neurogenetic contributions to individual differences in these distinct aspects of motivated human behavior, using a temporal decision-making task and computational analysis. We show that two genes controlling striatal dopamine function, DARPP-32 (also called PPP1R1B) and DRD2, are associated with exploitative learning to adjust response times incrementally as a function of positive and negative decision outcomes. In contrast, a gene primarily controlling prefrontal dopamine function (COMT) is associated with a particular type of 'directed exploration', in which exploratory decisions are made in proportion to Bayesian uncertainty about whether other choices might produce outcomes that are better than the status quo. Quantitative model fits reveal that genetic factors modulate independent parameters of a reinforcement learning system.


Interpopulation and intrapopulation maternal lineage genetics of the Lanyu pig (Sus scrofa) by analysis of mitochondrial cytochrome b and control region sequences.
The Lanyu pig is an indigenous breed from the Lanyu Islet, which is southeast of Taiwan. Two herds of Lanyu pigs were introduced from the Lanyu Islet into Taiwan in 1975 and 1980. The current population of conserved Lanyu pigs consists of only 44 animals with unknown genetic lineage. The Lanyu pig possesses a distinct maternal genetic lineage remote from Asian and European pigs. The present study aimed to understand the phylogenetic relationship among conserved Lanyu, Asian, and European type pigs based on the cytochrome b coding gene, to ascertain the maternal lineage and genetic diversity within the conserved Lanyu pigs, and to address whether genetic introgression from exotic or Formosan wild pigs had occurred in the conserved Lanyu pigs. Entire mitochondrial genomes of both types of Lanyu pig comprised 2 ribosomal RNA, 22 transfer RNA, and 13 protein-coding genes. Only 2 haplotypes of the mitochondrial DNA (mtDNA) control region and cytochrome b were identified in the conserved Lanyu pig herds. When maximum likelihood trees were constructed, the Type I Lanyu mitochondrial genes formed a unique clade with a large pairwise distance of both cytochrome b and the control region from Asian and European type breeds, Formosan wild pigs, and exotic breeds. Significant loss of genetic diversity of mtDNA within the conserved Lanyu pigs was demonstrated by low haplotype and nucleotide diversities, supported by Fu and Li's D* neutrality test (1.44055; P < 0.05). The mtDNA control region sequences of extant pigs in the Lanyu Islet, however, showed high haplotype and nucleotide diversity, and clustered with exotic pigs. These results indicate no maternal lineage mtD-NA gene introgression from Formosan wild pigs and introduced exotic pigs to conserved Type I Lanyu pigs, and a severe loss of heterozygosity of mtDNA in conserved Lanyu pigs. The remaining extant pigs on the Lanyu Islet have been introgressed with exotic breeds. Strategies for future conservation of native Lanyu pigs are now even more urgent and important.


Rice dwarf viruses with dysfunctional genomes generated in plants are filtered out in vector insects: implications for the origin of the virus.
Rice dwarf virus (RDV), with 12 double-stranded RNA (dsRNA) genome segments (S1 to S12), replicates in and is transmitted by vector insects. The RDV-plant host-vector insect system allows us to examine the evolution, adaptation, and population genetics of a plant virus. We compared the effects of long-term maintenance of RDV on population structures in its two hosts. The maintenance of RDV in rice plants for several years resulted in gradual accumulation of nonsense mutations in S2 and S10, absence of expression of the encoded proteins, and complete loss of transmissibility. RDV maintained in cultured insect cells for 6 years retained an intact protein-encoding genome. Thus, the structural P2 protein encoded by S2 and the nonstructural Pns10 protein encoded by S10 of RDV are subject to different selective pressures in the two hosts, and mutations accumulating in the host plant are detrimental in vector insects. However, one round of propagation in insect cells or individuals purged the populations of RDV that had accumulated deleterious mutations in host plants, with exclusive survival of fully competent RDV. Our results suggest that during the course of evolution, an ancestral form of RDV, of insect virus origin, might have acquired the ability to replicate in a host plant, given its reproducible mutations in the host plant that abolish vector transmissibility and viability in nature.


Antibody responses during hepatitis B viral infection.
Hepatitis B is a DNA virus that infects liver cells and can cause both acute and chronic disease. It is believed that both viral and host factors are responsible for determining whether the infection is cleared or becomes chronic. Here we investigate the mechanism of protection by developing a mathematical model of the antibody response following hepatitis B virus (HBV) infection. We fitted the model to data from seven infected adults identified during acute infection and determined the ability of the virus to escape neutralization through overproduction of non-infectious subviral particles, which have HBs proteins on their surface, but do not contain nucleocapsid protein and viral nucleic acids. We showed that viral clearance can be achieved for high anti-HBV antibody levels, as in vaccinated individuals, when: (1) the rate of synthesis of hepatitis B subviral particles is slow; (2) the rate of synthesis of hepatitis B subviral particles is high but either anti-HBV antibody production is fast, the antibody affinity is high, or the levels of pre-existent HBV-specific antibody at the time of infection are high, as could be attained by vaccination. We further showed that viral clearance can be achieved for low equilibrium anti-HBV antibody levels, as in unvaccinated individuals, when a strong cellular immune response controls early infection.


Using the interactive systems framework to support a quality improvement approach to dissemination of evidence-based strategies to promote early detection of breast cancer: planning a comprehensive dynamic trial.
Dissemination efforts must optimize interventions for new settings and populations. As such, dissemination research should incorporate principles of quality improvement. Comprehensive Dynamic Trial (CDT) designs examine how information gained during dissemination may be used to modify interventions and improve performance. Although CDT may offer distinct advantages over static designs, organizing the many necessary roles and activities is a significant challenge. In this article, we discuss use of the Interactive Systems Framework for Dissemination and Implementation to systematically implement a CDT. Specifically, we describe "Bronx ACCESS", a program designed to disseminate evidence-based strategies to promote adherence to mammography guidelines. In Bronx ACCESS, the Intervention Delivery System will elicit information needed to adapt strategies to specific settings and circumstances. The Intervention Synthesis and Translation System will use this information to test changes to strategies through "embedded experiments". The Intervention Support System will build local capacities found to be necessary for intervention institutionalization. Simulation modeling will be used to integrate findings across systems. Results will inform on-going policy debate about interventions needed to promote population-level screening. More generally, this project is intended to advance understanding of research paradigms necessary to study dissemination.


Purification and characterization of yeast RNA polymerase II transcription factor b.
Heat treatment of yeast nuclear extracts abolished the capacity to initiate transcription at RNA polymerase II promoters. Activity was restored by the addition of both recombinant yeast TFIID and partially purified factor b, a yeast fraction shown previously to be required for polymerase II transcription. On the basis of this assay with heat-treated extract, factor b was purified to virtual homogeneity. The factor appears to comprise polypeptides of approximately 85, 75, and 50 kDa, since these three polypeptides co-purify with activity, and since a native mass of about 200 kDa is estimated from glycerol gradient sedimentation and gel filtration.


Resonant and non-resonant femtosecond ionization mass spectrometry of organochlorine pesticides.
Thirteen organochlorine pesticides in a standard sample mixture were measured by gas chromatography combined with mass spectrometry using an ultraviolet femtosecond laser (267 nm) as the ionization source, and the observed mass spectra were compared with the corresponding spectra obtained using an electron ionization source. When an ultrashort optical pulse was used for ionization, molecular ions were typically produced which was preferential for reliably identifying the analytes. The ionization mechanism was studied based on three models constructed for resonance-enhanced two-photon ionization, non-resonant two-photon ionization, and non-resonant three-photon ionization. The optimal conditions for observing a molecular ion were investigated using data obtained for three pulse widths. The results suggest that two-photon ionization with minimum excess energy would be optimal for observing a molecular ion.


Scheuermann's disease: non-surgical improvement in whole spine sagittal alignment in the treatment of a symptomatic patient using Chiropractic BioPhysics® technique.
[Purpose] To present the dramatic improvement of sagittal posture in a young male with Scheuermann's disease suffering from pain ailments as treated by Chiropractic BioPhysics® technique. [Participant and Methods] An 18 year old reported low back pain and headaches for several years. Full spine radiographic assessment revealed pronounced thoracic hyperkyphosis, anterior head translation, posterior thoracolumbar sagittal balance, and a reduced sacral base orientation. The patient was treated by Chiropractic BioPhysics methods incorporating mirror image® exercises, traction, as well as spinal manipulation. [Results] Assessment after 35 treatment sessions over 14-weeks revealed a dramatic improvement in postural parameters. The thoracic kyphosis reduced by 13°, and was accompanied by a reduction in forward head posture, reduction in posterior sagittal balance, and an increase in sacral base angle to normal. The low back pain and headaches were alleviated. [Conclusion] This case adds to the accumulating evidence demonstrating CBP methods offers an effective approach to reduce the burden of postural disorders including those with Scheuermann's disease. Since thoracic hyperkyphosis is a serious disorder, the routine comprehensive assessment via full-spine radiography is essential for the quantification of relevant postural parameters.


MAPK-activated protein kinase 2 differentially regulates plasmodium falciparum glycosylphosphatidylinositol-induced production of tumor necrosis factor-{alpha} and interleukin-12 in macrophages.
Proinflammatory responses induced by Plasmodium falciparum glycosylphosphatidylinositols (GPIs) are thought to be involved in malaria pathogenesis. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2) in the regulation of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12, two of the major inflammatory cytokines produced by macrophages stimulated with GPIs. We show that MK2 differentially regulates the GPI-induced production of TNF-alpha and IL-12. Although TNF-alpha production was markedly decreased, IL-12 expression was increased by 2-3-fold in GPI-stimulated MK2(-/-) macrophages compared with wild type (WT) cells. MK2(-/-) macrophages produced markedly decreased levels of TNF-alpha than WT macrophages mainly because of lower mRNA stability and translation. In the case of IL-12, mRNA was substantially higher in MK2(-/-) macrophages than WT. This enhanced production is due to increased NF-kappaB binding to the gene promoter, a markedly lower level expression of the transcriptional repressor factor c-Maf, and a decreased binding of GAP-12 to the gene promoter in MK2(-/-) macrophages. Thus, our data demonstrate for the first time the role of MK2 in the transcriptional regulation of IL-12. Using the protein kinase inhibitors SB203580 and U0126, we also show that the ERK and p38 pathways regulate TNF-alpha and IL-12 production, and that both inhibitors can reduce phosphorylation of MK2 in response to GPIs and other toll-like receptor ligands. These results may have important implications for developing therapeutics for malaria and other infectious diseases.


Successful Treatment of Rhino-Orbital-Cerebral Mucormycosis in a Child With Leukemia.
Rhino-orbital-cerebral mucormycosis (ROCM) is a rare fulminant opportunistic fungal infection that despite relevant treatment has high mortality. We present a case of a 3-year-old girl with acute lymphoblastic leukemia and ROCM, who was treated successfully with excessive surgery, systemic antifungal treatment with amphotericin B (AmB), posaconazole, and terbinafine as well as hyperbaric oxygen. Surgery included, beside extracranial and intracranial removal of infected areas, endoscopic sinus and skull base surgery with local AmB installation and in addition placement of an Ommaya reservoir for 114 intrathecal administrations of AmB. In addition, we review the literature of ROCM in pediatric patients with hematological diseases.


Classification and selective collection of individual aerosol particles using laser-induced fluorescence.
We describe the development and performance evaluation of a system for optical interrogation, subsequent selection, and collection of individual aerosol particles entrained in an inlet air stream. Elastic scatter and laser-induced fluorescence obtained from single particles on-the-fly provide compositional information for classification criteria. Individual particles could then be selectively electrically charged and captured to a conductive substrate with an electric potential. The optical subsystem also includes a novel two-beam velocimeter to provide accurate downstream timing. Good overall quantitative performance values are reported for particles in the size range of 1-8 microm at mean rates up to 4 kHz.


Overall rate, location, and predictive factors for positive surgical margins after robot-assisted laparoscopic radical prostatectomy for high-risk prostate cancer.
We report the overall rate, locations and predictive factors of positive surgical margins (PSMs) in 271 patients with high-risk prostate cancer. Between April 2008 and October 2011, we prospectively collected data from patients classified as D'Amico high-risk who underwent robot-assisted laparoscopic radical prostatectomy. Overall rate and location of PSMs were reported. Stepwise logistic regression models were fitted to assess predictive factors of PSM. The overall rate of PSMs was 25.1% (68 of 271 patients). Of these PSM, 38.2% (26 of 68) were posterolateral (PL), 26.5% (18 of 68) multifocal, 16.2% (11 of 68) in the apex, 14.7% (10 of 68) in the bladder neck, and 4.4% (3/68) in other locations. The PSM rate of patients with pathological stage pT2 was 8.6% (12 of 140), 26.6% (17 of 64) of pT3a, 53.3% (32/60) of pT3b, and 100% (7 of 7) of pT4. In a logistic regression model including pre-, intra-, and post-operative parameters, body mass index (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.01-1.19, P= 0.029), pathological stage (pT3b or higher vs pT2; OR: 5.14; 95% CI: 1.92-13.78; P = 0.001) and percentage of the tumor (OR: 46.71; 95% CI: 6.37-342.57; P< 0.001) were independent predictive factors for PSMs. The most common location of PSMs in patients at high-risk was the PL aspect, which reflects the reported tumor aggressiveness. The only significant predictive factors of PSMs were pathological outcomes, such as percentage of the tumor in the specimen and pathological stage.


The odorant binding protein gene family from the genome of silkworm, Bombyx mori.
Chemosensory systems play key roles in the survival and reproductive success of insects. Insect chemoreception is mediated by two large and diverse gene superfamilies, chemoreceptors and odorant binding proteins (OBPs). OBPs are believed to transport hydrophobic odorants from the environment to the olfactory receptors. We identified a family of OBP-like genes in the silkworm genome and characterized their expression using oligonucleotide microarrays. A total of forty-four OBP genes were annotated, a number comparable to the 57 OBPs known from Anopheles gambiae and 51 from Drosophila melanogaster. As seen in other fully sequenced insect genomes, most silkworm OBP genes are present in large clusters. We defined six subfamilies of OBPs, each of which shows lineage-specific expansion and diversification. EST data and OBP expression profiles from multiple larvae tissues of day three fifth instars demonstrated that many OBPs are expressed in chemosensory-specific tissues although some OBPs are expressed ubiquitously and others exclusively in non-chemosensory tissues. Some atypical OBPs are expressed throughout development. These results reveal that, although many OBPs are chemosensory-specific, others may have more general physiological roles. Silkworms possess a number of OBPs genes similar to other insects. Their expression profiles suggest that many OBPs may be involved in olfaction and gustation as well as general carriers of hydrophobic molecules. The expansion of OBP gene subfamilies and sequence divergence indicate that the silkworm OBP family acquired functional diversity concurrently with functional constraints. Further investigation of the OBPs of the silkworm could give insights in the roles of OBPs in chemoreception.


Meta-analysis: the impact of diabetes mellitus on the immunological response to hepatitis B virus vaccine in dialysis patients.
Patients on maintenance dialysis typically show a suboptimal immune response to hepatitis B virus vaccine compared with the non-uraemic population. A variety of inherited or acquired factors have been implicated in this diminished response. It is well known that patients with diabetes mellitus have a compromised immune system, and diabetic nephropathy is an important cause of chronic kidney disease. However, the impact of diabetes mellitus on the immune response to HBV vaccine in patients receiving long-term dialysis remains unclear. To evaluate the influence of diabetes mellitus on the immune response to HBV vaccine in dialysis population by performing a systematic review of the literature with a meta-analysis of clinical studies. We used the random effects model of DerSimonian and Laird with heterogeneity and sensitivity analyses. The end-point of interest was the rate of patients showing seroprotective antibody against hepatitis B surface antigen at completion of vaccine schedule in the diabetic vs. the nondiabetic dialysis individuals. We identified 12 studies involving 1002 unique patients on long-term dialysis. Aggregation of study results showed a significant decrease in response rates among the diabetic vs. the nondiabetic patients [pooled odds ratio=0.52 (95% CI 0.38-0.71)]. The P-value was 0.29 for our test of study heterogeneity. Stratified analysis in various subgroups of interest did not meaningfully change our results. Our meta-analysis showed a clear association between diabetes mellitus and impaired response to hepatitis B virus vaccine in individuals on long-term dialysis. Such a relationship is biologically plausible. Vaccination schedules with adapted vaccine doses and frequent serum testing for loss of immunity against hepatitis B virus should be considered in patients on maintenance dialysis with diabetes mellitus.


Comparison of preparative transplantation regimens using carmustine/etoposide/cisplatin or busulfan/etoposide/cyclophosphamide in lymphoid malignancies.
Most bone marrow transplantation preparative regimens use total body irradiation as one component. Recently, however, two non-total body irradiation containing autologous bone marrow transplantation preparative regimens have been evaluated in patients with lymphoid malignancies. The first regimen consisted of carmustine, etoposide, and cisplatin; some patients also received involved-field radiotherapy to sites of prior disease. Of the 79 patients with relapsed or refractory lymphoma who participated in this study, 57 (72%) achieved a complete remission and 40 (51%) remain in complete remission. Treatment-related deaths occurred in five patients (6%). The second preparative regimen evaluated consisted of busulfan, etoposide, and cyclophosphamide and included 21 patients with Hodgkin's lymphoma, non-Hodgkin's lymphoma, or acute lymphocytic leukemia. Sixteen patients (76%) achieved complete remission and 12 (57%) remain disease free. The regimen-related mortality rate in this study was 14%. The three treatment-related deaths were all due to pulmonary toxicity. The results of these clinical trials indicate that both the carmustine/etoposide/cisplatin regimen and the busulfan/etoposide/cyclophosphamide regimen are effective in treating lymphoid malignancies. Treatment-related toxicities and deaths are significant, but not prohibitive. Accordingly, these new preparative regimens deserve further evaluation in the treatment of patients with lymphoma or leukemia.


Person-environment relations.
The interaction that occurs between individuals and their environment is central to all work and rehabilitation practice. In the past, rehabilitation has focused more on facilitating personal adaptation and less on understanding the influence of the environment on behavior. Eight person-environment models, developed by other disciplines but of relevance to rehabilitation, are presented and discussed. The way in which each of these models views the person, the environment, the person-environment relationship, and adaptation is compared and contrasted to views inherent in rehabilitation practice. The literature suggests that rehabilitation is gradually moving from an interactive perspective of person-environment fit toward a transaction view that more accurately acknowledges the complexity and the entwined nature of these issues.


Depressive symptoms are associated with higher morning plasma cortisol in primary care subjects.
Cortisol dysregulation has a potential role in depression. We evaluated depressive symptoms using the Hamilton Rating Scale for Depression in 48 primary care subjects without history of previous or current depression and its association with cortisol dysregulation (morning plasma cortisol, 24-hour urinary free cortisol and cortisol metabolites). Presence of metabolic syndrome and inflammatory parameters were also assessed. Hamilton Rating Scale for Depression correlated significantly with morning cortisol, but not with urinary free cortisol or metabolites. A significant increase in morning cortisol by Hamilton groups (asymptomatic ≤8; mild to moderate: 9-18; moderate to severe: ≥19) was observed even when adjusted by age/gender. We observed no association of depressive symptoms with metabolic or inflammatory parameters. Depressive symptoms in primary care subjects not consulting for their mood are associated with higher morning plasma cortisol, but not urinary cortisol or its metabolites. These observations suggest that systemic hypercortisolism and related metabolic disorders are not observed in mild/initial states of depressive disorders.


Mechanistic study of the rhodium-catalyzed carboxylation of simple aromatic compounds with carbon dioxide.
A detailed mechanism of the Rh(i)-catalyzed carboxylation of simple aromatic compounds via C-H bond activation was investigated. Kinetic studies with model compounds of the postulated key intermediates revealed that 14-electron complexes, RhMe(dcype) and RhPh(dcype), participated in the C-H bond activation step and the carboxylation step, respectively. Interestingly, the undesired carboxylation of RhMe(dcype) to give acetic acid was found to be much faster than the desired C-H bond activation reaction under stoichiometric conditions, however, the C-H bond activation reaction could occur under catalytic conditions. Careful controlled experiments revealed that C-H bond activation using RhMe(dcype) became competitive with its direct carboxylation under the condition that the concentration of CO2 in the liquid phase was rather low. This factor could be controlled to some extent by mechanical factors such as the stirring rate and the shape of the reaction vessel. The resting state of the rhodium species under catalytic conditions was found to be [RhCl(dcype)]2, and the proposed intermediates such as RhMe(dcype) and Rh(OBz)(dcype) were readily converted to the most stable state, [RhCl(dcype)]2, via transmetallation with [Al]-Cl species, thus preventing the decomposition of the active catalytic species.


Early intensive behavioral intervention (EIBI) for young children with autism spectrum disorders (ASD).
The rising prevalence of autism spectrum disorders (ASD) increases the need for evidence-based behavioral treatments to lessen the impact of symptoms on children's functioning. At present, there are no curative or psychopharmacological therapies to effectively treat all symptoms of the disorder. Early intensive behavioral intervention (EIBI), a treatment based on the principles of applied behavior analysis delivered for multiple years at an intensity of 20 to 40 hours per week, is one of the more well-established treatments for ASD. To systematically review the evidence for the effectiveness of EIBI in increasing the functional behaviors and skills of young children with ASD. We searched the following databases on 22 November 2011: CENTRAL (2011 Issue 4), MEDLINE (1948 to November Week 2, 2011), EMBASE (1980 to Week 46, 2011), PsycINFO (1806 to November Week 3, 2011), CINAHL (1937 to current), ERIC (1966 to current), Sociological Abstracts (1952 to current), Social Science Citation Index (1970 to current), WorldCat, metaRegister of Controlled Trials, and Networked Digital Library of Theses and Dissertations. We also searched the reference lists of published papers. Randomized control trials (RCTs), quasi-randomized control trials, or clinical control trials (CCTs) in which EIBI was compared to a no-treatment or treatment-as-usual control condition. Participants must have been less than six years of age at treatment onset and assigned to their study condition prior to commencing treatment. Two authors independently selected and appraised studies for inclusion and assessed the risk of bias in each included study. All outcome data were continuous, from which standardized mean difference effect sizes with small sample correction were calculated. We conducted random-effects meta-analysis where possible, which means we assumed individual studies would provide different estimates of treatment effects. One RCT and four CCTs with a total of 203 participants were included. Reliance on synthesis from four CCTs limits the evidential base and this should be borne in mind when interpreting the results. All studies used a treatment-as-usual comparison group. We synthesized the results of the four CCTs using a random-effects model of meta-analysis of the standardized mean differences. Positive effects in favor of the EIBI treatment group were found for all outcomes. The mean effect size for adaptive behavior was g = 0.69 (95% CI 0.38 to 1.01; P < 0.0001). The mean effect size for IQ was g = 0.76 (95% CI 0.40 to 1.11; P < 0.0001). Three measures of communication and language skills all showed results in favor of EIBI: expressive language g = 0.50 (95% CI 0.05 to 0.95; P = 0.03), receptive language g = 0.57 (95% CI 0.20 to 0.94; P = .03), and daily communication skills g = 0.74 (95% CI 0.30 to 1.18; P = 0.0009). The mean effect size for socialization was g = 0.42 (95% CI 0.11 to 0.73; P = 0.0008), and for daily living skills was g = 0.55 (95% CI 0.24 to 0.87; P = 0.0005). Additional descriptive analyses of other aspects related to quality of life and psychopathology are presented. However, due to the inclusion of non-randomized studies, there is a high risk of bias and the overall quality of evidence was rated as 'low' using the GRADE system, which rates the quality of evidence from meta-analyses to determine recommendations for practice. There is some evidence that EIBI is an effective behavioral treatment for some children with ASD. However, the current state of the evidence is limited because of the reliance on data from non-randomized studies (CCTs) due to the lack of RCTs. Additional studies using RCT research designs are needed to make stronger conclusions about the effects of EIBI for children with ASD.


Increased gait variability during robot-assisted walking is accompanied by increased sensorimotor brain activity in healthy people.
Gait disorders are major symptoms of neurological diseases affecting the quality of life. Interventions that restore walking and allow patients to maintain safe and independent mobility are essential. Robot-assisted gait training (RAGT) proved to be a promising treatment for restoring and improving the ability to walk. Due to heterogenuous study designs and fragmentary knowlegde about the neural correlates associated with RAGT and the relation to motor recovery, guidelines for an individually optimized therapy can hardly be derived. To optimize robotic rehabilitation, it is crucial to understand how robotic assistance affect locomotor control and its underlying brain activity. Thus, this study aimed to investigate the effects of robotic assistance (RA) during treadmill walking (TW) on cortical activity and the relationship between RA-related changes of cortical activity and biomechanical gait characteristics. Twelve healthy, right-handed volunteers (9 females; M = 25 ± 4 years) performed unassisted walking (UAW) and robot-assisted walking (RAW) trials on a treadmill, at 2.8 km/h, in a randomized, within-subject design. Ground reaction forces (GRFs) provided information regarding the individual gait patterns, while brain activity was examined by measuring cerebral hemodynamic changes in brain regions associated with the cortical locomotor network, including the sensorimotor cortex (SMC), premotor cortex (PMC) and supplementary motor area (SMA), using functional near-infrared spectroscopy (fNIRS). A statistically significant increase in brain activity was observed in the SMC compared with the PMC and SMA (p < 0.05), and a classical double bump in the vertical GRF was observed during both UAW and RAW throughout the stance phase. However, intraindividual gait variability increased significantly with RA and was correlated with increased brain activity in the SMC (p = 0.05; r = 0.57). On the one hand, robotic guidance could generate sensory feedback that promotes active participation, leading to increased gait variability and somatosensory brain activity. On the other hand, changes in brain activity and biomechanical gait characteristics may also be due to the sensory feedback of the robot, which disrupts the cortical network of automated walking in healthy individuals. More comprehensive neurophysiological studies both in laboratory and in clinical settings are necessary to investigate the entire brain network associated with RAW.


Microwave-assisted preparation of paramagnetic zwitterionic amphiphilic copolymer hybrid molybdenum disulfide for T1-weighted magnetic resonance imaging-guided photothermal therapy.
Magnetic resonance imaging (MRI)-guided photothermal therapy (PTT) has recently attracted tremendous attention. In this study, a paramagnetic zwitterionic amphiphilic copolymer (PZAC) was successfully prepared and utilized as a multifunctional surfactant to form micelles in diethylene glycol to coordinate with a molybdenum disulfide precursor (MoS2). Uniform spherical MoS2 nanohybrids (MoS2@PZAC) were first prepared by a microwave-assisted solvothermal process, which is simpler, easier and more efficient than hydrothermal methods or exfoliation processes. In this nanoplatform, MoS2 serves as a phototherapeutic agent possessing a high photothermal conversion efficiency (33.8%), while PZAC acts as a T1-weighted MRI contrast agent. This nanoplatform has the advantages of ultralow toxicity, prolonged circulation time and bio-imaging guided capability. The cytotoxicity assessment showed the good cytocompatibility of MoS2@PZAC. Furthermore, MoS2@PZAC could effectively kill cancer cells upon 2 W cm-2 808 nm laser irradiation for 10 min in both in vitro and in vivo experiments. This work provides a novel and efficient solution to synthesize a multifunctional and uniform theranostic agent, and the results show that the as-prepared MoS2@PZAC can be used as a promising theranostic agent for T1-weighted MRI-guided PTT of cancer cells.


Diaphragm motor unit recruitment during ventilatory and nonventilatory behaviors.
The forces generated by the cat diaphragm (DIA) during different ventilatory and nonventilatory behaviors were determined by measuring transdiaphragmatic pressures (Pdi). The Pdi generated during eupnea was only approximately 12% of the maximum Pdi (Pdimax) generated by bilateral phrenic nerve stimulation. When the animals breathed a gas mixture of 10% O2 and 5% CO2, the Pdi increased to approximately 28% of Pdimax. During total airway occlusion, the Pdi generated by the diaphragm increased to approximately 49% of Pdimax. Only during the gag reflex and sneezing did Pdi reach maximal levels. A model for diaphragm motor unit recruitment during these different behaviors was presented based on the proportion of different motor unit types within the diaphragm, the relative tetanic tensions produced by each unit type, and the assumption of an orderly pattern of motor unit recruitment.


Medial temporal lobe coding of item and spatial information during relational binding in working memory.
Several models have proposed that different medial temporal lobe (MTL) regions represent different kinds of information in the service of long-term memory. For instance, it has been proposed that perirhinal cortex (PRC), parahippocampal cortex (PHC), and hippocampus differentially support long-term memory for item information, spatial context, and item-context relations present during an event, respectively. Recent evidence has indicated that, in addition to long-term memory, MTL subregions may similarly contribute to processes that support the retention of complex spatial arrangements of objects across short delays. Here, we used functional magnetic resonance imaging and multivoxel pattern similarity analysis to investigate the extent to which human MTL regions independently code for object and spatial information, as well as the conjunction of this information, during working memory encoding and active maintenance. Voxel activity patterns in PRC, temporopolar cortex, and amygdala carried information about individual objects, whereas activity patterns in the PHC and posterior hippocampus carried information about the configuration of spatial locations that was to be remembered. Additionally, the integrity of multivoxel patterns in the right anterior hippocampus across encoding and delay periods was predictive of accurate short-term memory for object-location relationships. These results are consistent with parallel processing of item and spatial context information by PRC and PHC, respectively, and the binding of item and context by the hippocampus.


Combining escitalopram and cognitive-behavioural therapy for social anxiety disorder: randomised controlled fMRI trial.
Selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioural therapy (CBT) are often used concomitantly to treat social anxiety disorder (SAD), but few studies have examined the effect of this combination. To evaluate whether adding escitalopram to internet-delivered CBT (ICBT) improves clinical outcome and alters brain reactivity and connectivity in SAD. Double-blind, randomised, placebo-controlled neuroimaging trial of ICBT combined either with escitalopram (n = 24) or placebo (n = 24), including a 15-month clinical follow-up (trial registration: ISRCTN24929928). Escitalopram+ICBT, relative to placebo+ICBT, resulted in significantly more clinical responders, larger reductions in anticipatory speech state anxiety at post-treatment and larger reductions in social anxiety symptom severity at 15-month follow-up and at a trend-level (P = 0.09) at post-treatment. Right amygdala reactivity to emotional faces also decreased more in the escitalopram+ICBT combination relative to placebo+ICBT, and in treatment responders relative to non-responders. Adding escitalopram improves the outcome of ICBT for SAD and decreased amygdala reactivity is important for anxiolytic treatment response.


Head and neck reconstruction by using extended pectoralis major myocutaneous flap.
Pectoralis major flaps have been the workhorse in head and neck region reconstructions till date. However, pectoralis major flaps have disadvantages, including limitations regarding flap range and less stable blood flow than that in free flaps. Here, we report on the safe reconstruction to the oral cavity and neck area by using extended pectoralis major flaps. These flaps include both the normal vessels that feed pectoralis major flaps (the thoracoacromial artery and vein) and the lateral thoracic artery and vein to stabilize blood flow and expand flap survival area caudally. Eight patients who had undergone reconstruction with extended pectoralis major flaps after the resection of head and neck cancers from June 2009 to March 2013. In all cases, the pectoralis major flap was elevated with a vascular pedicle comprising the thoracoacromial artery and vein and the lateral thoracic artery and vein. No blood circulation disorders, such as ischemia or congestion, were observed after the flaps were elevated and moved to the resected areas. All flaps were sutured on without difficulty. The area the flaps were harvested from was closed in a single stage. No postoperative complications such as hematoma, abscess, or fistula were observed. Extended pectoralis major flaps have a wide range and more stable blood flow, so they are thought to be useful in situations in which free flaps cannot be used for a variety of reasons.


Fluorescent protein voltage probes derived from ArcLight that respond to membrane voltage changes with fast kinetics.
We previously reported the discovery of a fluorescent protein voltage probe, ArcLight, and its derivatives that exhibit large changes in fluorescence intensity in response to changes of plasma membrane voltage. ArcLight allows the reliable detection of single action potentials and sub-threshold activities in individual neurons and dendrites. The response kinetics of ArcLight (τ1-on ~10 ms, τ2-on ~ 50 ms) are comparable with most published genetically-encoded voltage probes. However, probes using voltage-sensing domains other than that from the Ciona intestinalis voltage sensitive phosphatase exhibit faster kinetics. Here we report new versions of ArcLight, in which the Ciona voltage-sensing domain was replaced with those from chicken, zebrafish, frog, mouse or human. We found that the chicken and zebrafish-based ArcLight exhibit faster kinetics, with a time constant (τ) less than 6 ms for a 100 mV depolarization. Although the response amplitude of these two probes (8-9%) is not as large as the Ciona-based ArcLight (~35%), they are better at reporting action potentials from cultured neurons at higher frequency. In contrast, probes based on frog, mouse and human voltage sensing domains were either slower than the Ciona-based ArcLight or had very small signals.


Sacroiliac joint dysfunction: evaluation and management.
Sacroiliac joint dysfunction is believed to be a significant source of low back and posterior pelvic pain. To assess the clinical presentation, diagnostic testing, and treatment options for sacroiliac joint dysfunction, a systematic literature review was performed using MEDLINE. Presently, there are no widely accepted guidelines in the literature for the diagnosis and treatment of sacroiliac instability. Establishing management guidelines for this disorder has been complicated by the large spectrum of different etiologic factors, the variability of patient history and clinical symptoms, limited availability of objective testing, and incomplete understanding of the biomechanics of the sacroiliac joint. A reliable examination technique to identify the sacroiliac joint as a source of low back pain seems to be pain relief following a radiologically guided injection of a local anaesthetic into the sacroiliac joint. Most patients respond to non-operative treatment. Patients who do not respond to non-operative treatment should be considered for operative sacroiliac joint stabilization.


Access to medicines for asthma, diabetes and hypertension in eight counties of Kenya.
To assess access to noncommunicable diseases (NCD) medicines in Kenya for patients diagnosed and prescribed treatment for asthma, diabetes and hypertension. Households in eight purposively chosen counties were randomly selected. To be eligible, a household needed to have at least one member aged 18 years or older who had been previously diagnosed and prescribed medicines for one of the following NCDs: asthma, diabetes or hypertension. Using a logistic regression model, we explored the relationship between patient characteristics and the probability that patients had the medicines available at the time of the survey visit. A total of 627 individuals were included in the analysis. The highest percentage of medicines availability was in households with diabetes patients (83.1%), followed by hypertension (77.1%) patients. The lowest availability of medicines was found in households with asthma patients (53.1%). The median household expenditure on medicines per month was US$7.00 for households with diabetes patients; it was US$4.00 for asthma. In general, strong predictors of having medicines at home was being older, having some education compared to no education, few household members, wealth, being diagnosed at private nonprofit facilities and having only one patient with NCDs in the household. Our study found that nearly three-quarters of patients diagnosed and prescribed a medicine for hypertension, asthma or diabetes had the medicine available at home. Access challenges remain, in particular for patients from low-income households and for those diagnosed with asthma.


No association of primary Sjögren's syndrome with Fcγ receptor gene variants.
The genetic background of primary Sjögren's syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcγ receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fcγ receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N=527) and controls (N=528) were genotyped for the Fcγ receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fcγ receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS.


Personality assessment in DSM-5: empirical support for rating severity, style, and traits.
Despite a general consensus that dimensional models are superior to the categorical representations of personality disorders in DSM-IV, proposals for how to depict personality pathology dimensions vary substantially. One important question involves how to separate clinical severity from the style of expression through which personality pathology manifests. This study empirically distinguished stylistic elements of personality pathology symptoms from the overall severity of personality disorder in a large, longitudinally assessed clinical sample (N = 605). Data suggest that generalized severity is the most important single predictor of current and prospective dysfunction, but that stylistic elements also indicate specific areas of difficulty. Normative personality traits tend to relate to the general propensity for personality pathology, but not stylistic elements of personality disorders. Overall, findings support a three-stage diagnostic strategy involving a global rating of personality disorder severity, ratings of parsimonious and discriminant valid stylistic elements of personality disorder, and ratings of normative personality traits.


Mode- and size-dependent Landau-Lifshitz damping in magnetic nanostructures: evidence for nonlocal damping.
We demonstrate a strong dependence of the effective damping on the nanomagnet size and the particular spin-wave mode that can be explained by the theory of intralayer transverse-spin pumping. The effective Landau-Lifshitz damping is measured optically in individual, isolated nanomagnets as small as 100 nm. The measurements are accomplished by use of a novel heterodyne magneto-optical microwave microscope with unprecedented sensitivity. Experimental data reveal multiple standing spin-wave modes that we identify by use of micromagnetic modeling as having either localized or delocalized character, described generically as end and center modes. The damping parameter of the two modes depends on both the size of the nanomagnet as well as the particular spin-wave mode that is excited, with values that are enhanced by as much as 40% relative to that measured for an extended film. Contrary to expectations based on the ad hoc consideration of lithography-induced edge damage, the damping for the end mode decreases as the size of the nanomagnet decreases. The data agree with the theory for damping caused by the flow of intralayer transverse spin currents driven by the magnetization curvature. These results have serious implications for the performance of nanoscale spintronic devices such as spin-torque-transfer magnetic random access memory.


Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines.
Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials. We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection. We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion. Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty. Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.


Is "Active Surveillance" an Acceptable Alternative?: A Qualitative Study of Couples' Decision Making about Early-Stage, Localized Prostate Cancer.
The objective of our study was to describe decision making by men and their partners regarding active surveillance (AS) or treatment for early-stage, localized prostate cancer. Fifteen couples were recruited from a cancer center multispecialty clinic, which gave full information about all options, including AS. Data were collected via individual, semi-structured telephone interviews. Most patients were white, non-Hispanic, had private insurance, had completed at least some college, and were aged 49-72 years. Ten chose AS. All partners were female, and couples reported strong marital satisfaction and cohesion. All couples described similar sequences of a highly emotional initial reaction and desire to be rid of the cancer, information seeking, and decision making. The choice of AS was built on a nuanced evaluation of the man's condition in which the couple differentiated prostate cancer from other cancers and early stage from later stages, wanted to avoid/delay side effects, and trusted the AS protocol to identify negative changes in time for successful treatment. Treated couples continued to want immediate treatment to remove the cancer. We concluded that having a partner's support for AS may help a man feel more comfortable with choosing and adhering to AS. Using decision aids that address both a man's and his partner's concerns regarding AS may increase its acceptability. Our research shows that some patients want to and do involve their partners in the decision-making process. Ethical issues are related to the tension between desire for partner involvement and the importance of the patient as autonomous decision-maker. The extended period of decision making, particularly for AS, is also an ethical issue that requires additional support for patients and couples in the making of fully informed choices that includes AS.


Downregulation of an Evolutionary Young miR-1290 in an iPSC-Derived Neural Stem Cell Model of Autism Spectrum Disorder.
The identification of several evolutionary young miRNAs, which arose in primates, raised several possibilities for the role of such miRNAs in human-specific disease processes. We previously have identified an evolutionary young miRNA, miR-1290, to be essential in neural stem cell proliferation and neuronal differentiation. Here, we show that miR-1290 is significantly downregulated during neuronal differentiation in reprogrammed induced pluripotent stem cell- (iPSC-) derived neurons obtained from idiopathic autism spectrum disorder (ASD) patients. Further, we identified that miR-1290 is actively released into extracellular vesicles. Supplementing ASD patient-derived neural stem cells (NSCs) with conditioned media from differentiated control-NSCs spiked with "artificial EVs" containing synthetic miR-1290 oligonucleotides significantly rescued differentiation deficits in ASD cell lines. Based on our earlier published study and the observations from the data presented here, we conclude that miR-1290 regulation could play a critical role during neuronal differentiation in early brain development.


Altered terminal Schwann cell morphology precedes denervation in SOD1 mice.
In mice that express SOD1 mutations found in human motor neuron disease, degeneration begins in the periphery for reasons that remain unknown. At the neuromuscular junction (NMJ), terminal Schwann cells (TSCs) have an intimate relationship with motor terminals and are believed to help maintain the integrity of the motor terminal. Recent evidence indicates that TSCs in some SOD1 mice exhibit abnormal functional properties, but other aspects of possible TSC involvement remain unknown. In this study, an analysis of TSC morphology and number was performed in relation to NMJ innervation status in mice which express the G93A SOD1 mutation. At P30, all NMJs of the fast medial gastrocnemius (MG) muscle were fully innervated by a single motor axon but 50% of NMJs lacked TSC cell bodies and were instead covered by the processes of Schwann cells with cell bodies located on the preterminal axons. NMJs in P30 slow soleus muscles were also fully innervated by single motor axons and only 5% of NMJs lacked a TSC cell body. At P60, about 25% of MG NMJs were denervated and lacked labeling for TSCs while about 60% of innervated NMJs lacked TSC cell bodies. In contrast, 96% of P60 soleus NMJs were innervated while 9% of innervated NMJs lacked TSC cell bodies. The pattern of TSC abnormalities found at P30 thus correlates with the pattern of denervation found at P60. Evidence from mice that express the G85R SOD1 mutation indicate that TSC abnormalities are not unique for mice that express G93A SOD1 mutations. These results add to an emerging understanding that TSCs may play a role in motor terminal degeneration and denervation in animal models of motor neuron disease.


Does cannabis use modify the effect of post-traumatic stress disorder on severe depression and suicidal ideation? Evidence from a population-based cross-sectional study of Canadians.
Post-traumatic stress disorder sharply increases the risk of depression and suicide. Individuals living with post-traumatic stress disorder frequently use cannabis to treat associated symptoms. We sought to investigate whether cannabis use modifies the association between post-traumatic stress disorder and experiencing a major depressive episode or suicidal ideation. We used data from the 2012 Canadian Community Health Survey-Mental Health, a nationally representative cross-sectional survey of non-institutionalized Canadians aged ⩾15 years. The relationship between post-traumatic stress disorder and each outcome was modelled using logistic regression with an interaction term for cannabis and post-traumatic stress disorder, controlling for demographic characteristics, mental health, and substance use comorbidities. The ratio of odds ratios and relative excess risk due to interaction was calculated to measure interaction on the multiplicative and additive scales, respectively. Among 24,089 eligible respondents, 420 (1.7%) reported a current clinical diagnosis of post-traumatic stress disorder. In total, 106 (28.2%) people with post-traumatic stress disorder reported past-year cannabis use, compared to 11.2% of those without post-traumatic stress disorder (p < 0.001). In multivariable analyses, post-traumatic stress disorder was significantly associated with recent major depressive episode (adjusted odds ratio = 7.18, 95% confidence interval: 4.32-11.91) and suicidal ideation (adjusted odds ratio = 4.76, 95% confidence interval: 2.39-9.47) among cannabis non-users. post-traumatic stress disorder was not associated with either outcome among cannabis-using respondents (both p > 0.05). This study provides preliminary epidemiological evidence that cannabis use may contribute to reducing the association between post-traumatic stress disorder and severe depressive and suicidal states. There is an emerging need for high-quality experimental investigation of the efficacy of cannabis/cannabinoids for the treatment of post-traumatic stress disorder.


Sexual Harassment at Institutions of Higher Education: Prevalence, Risk, and Extent.
Sexual harassment is a pervasive problem on college campuses. Across eight academic campuses, 16,754 students participated in an online study that included questions about sexual harassment victimization by a faculty/staff member or by a peer since enrollment at their Institution of Higher Education (IHE). Utilizing an intersectional theory and hurdle models, this study explored the effects of gender, race/ethnicity, sexual orientation, age at enrollment, student status, and time spent at institution on students' risk for peer- and faculty/staff-perpetrated sexual harassment victimization, as well as the extent of victimization for students who experience harassment. Across institutions, 19% of students reported experiencing faculty/staff-perpetrated sexual harassment and 30% reported experiencing peer-perpetrated sexual harassment. Hypotheses related to intersectional impacts were partially supported, with most significant findings in main effects. Time at institution was found to increase both risk and extent of victimization of both types of harassment. Traditional undergraduate students, non-Latinx White students, female students, and gender and sexual minority students were found to be at increased risk for harassment. Being female increases the odds of experiencing both faculty/staff and peer sexual harassment by 86% and 147%, respectively. Latinx students and students with an ethnicity other than White reported less victimization, but those who reported sexual harassment faced greater extent of harassing behaviors. A discussion of these findings for institutional program planning and policy is explored.


Characterising Drug Release from Immediate-Release Formulations of a Poorly Soluble Compound, Basmisanil, Through Absorption Modelling and Dissolution Testing.
The study aimed to characterise the mechanism of release and absorption of Basmisanil, a biopharmaceutics classification system (BCS) class 2 compound, from immediate-release formulations via mechanistic absorption modelling, dissolution testing, and Raman imaging. An oral absorption model was developed in GastroPlus® and verified with single-dose pharmacokinetic data in humans. The properties and drug release behaviour of different oral Basmisanil formulations were characterised via biorelevant dissolution and Raman imaging studies. Finally, an in vitro-in vivo correlation (IVIVC) model was developed using conventional and mechanistic deconvolution methods for comparison. The GastroPlus model accurately simulated oral Basmisanil exposure from tablets and granules formulations containing micronized drug. Absorption of oral doses below 200 mg was mostly dissolution rate-limited and thus particularly sensitive to formulation properties. Indeed, reduced exposure was observed for a 120-mg film-coated tablet and the slower dissolution rate measured in biorelevant media was attributed to differences in drug load. This hypothesis was confirmed when Raman imaging showed that the percolation threshold was exceeded in this formulation. This biorelevant dissolution method clearly differentiated between the formulations and was used to develop a robust IVIVC model. The study demonstrates the applicability and impact of mechanistic absorption modelling and biopharmaceutical in vitro tools for rational drug development.


Temporal order judgements as a sensitive measure of the spatial bias in patients with visuospatial neglect.
Visuospatial neglect is not a unitary phenomenon, but can be better considered a syndrome, consisting of a multitude of different spatial and non-spatial components. In this study, we used a temporal order judgement (TOJ) test in a large sample of stroke patients (n = 73) to scrutinize the contribution of a spatial bias to the performance on shape cancellation and line bisection tests. In the TOJ test, patients were presented with two elements, one in each visual field, after which the one needed to indicate which of the two elements was presented earlier. For each visual field, the presentation of the stimuli was determined by a staircase procedure where the interval between the two stimuli was determined by the performance of the patient. Results indicated that the strength of the spatial bias was strongly correlated with an object cancellation test, but not with a line bisection test. We argue that these findings are explained by differences in the extent to which a spatial bias determines performance on both tasks: In contrast to shape cancellation tests, successful performance on line bisection tests depends primarily on an object-based, allocentric representation of space, unrelated to any spatial bias in the detection of elements in the contralesional visual field.


Capacitative Ca2+ entry associated with alpha1-adrenoceptors in rat aorta.
In rat aorta, depletion of internal Ca2+ stores by addition of noradrenaline (1 microM) induces a biphasic response (an initial phasic response and a tonic one) mediated by two different intracellular Ca2+ pools. This response cannot be repeated, suggesting a depletion of internal Ca2+ stores sensitive to noradrenaline. In absence of the agonist, this depletion is the signal for the entry of extracellular Ca2+, not only to refill the stores but also, under our experimental conditions, to activate the contractile proteins thus inducing an increase in the resting tone (IRT) that constitutes functional evidence of this Ca2+ entry. The ionic channels involved in the mechanism of the IRT have been studied in the present work. The fact that the addition of nimodipine (10(-15)-10(-11) M) selectively inhibits the IRT suggests that this mechanical response is mediated by Ca2+ influx through dihydropyridine-sensitive Ca2+ channels. Moreover, the inhibitory action of nimodipine is attenuated by glibenclamide (10 microM). Cromakalim (10(-10)-10(-6) M) also inhibits the IRT concentration dependently, and this inhibition is antagonized by glibenclamide (10 microM). These results relate the ATP-dependent K+ channels to the mechanism of the IRT. The refilling of the two internal Ca2+ compartments sensitive to noradrenaline was, like the IRT, altered in presence of the compounds tested, since the subsequent contractile response to noradrenaline was decreased. The present results suggest that nimodipine treatment inhibits the refilling of the Ca2+ compartment responsible for the tonic contraction induced by noradrenaline in Ca2+-free medium, whereas the refilling of the Ca2+ pool responsible for the phasic response to noradrenaline remained unaltered. Both the phasic and tonic responses to noradrenaline in Ca2+-free medium decreased after treatment with cromakalim. We can therefore assume that the refilling of both Ca2+ compartments sensitive to noradrenaline was inhibited. In conclusion, these results are consistent with the contraction of the rat aorta in response to noradrenaline in Ca2+-free medium consisting of an initial phasic response and a tonic one. The former is due to the release of internal Ca2+ from a compartment refilled through a special channel that is cromakalim but not dihydropyridine sensitive. The tonic response is due to Ca2+ release from another compartment refilled through a cromakalim- and dihydropyridine-sensitive Ca2+ channel. The Ca2+ entry through this latter channel intervenes in the IRT observed during the refilling of these stores previously depleted by noradrenaline, and the opening state of this channel is also modulated by ATP-dependent K2+ channels.


Insulin degludec: a novel ultra-long-acting basal insulin for use in Type 1 and 2 diabetes.
The prevalence of diabetes, a chronic disease that currently poses a significant health burden in both developed and developing countries, is expected to increase significantly over the foreseeable future. In Type 1 diabetes, insulin replacement is absolutely imperative; in Type 2 diabetes, many patients will eventually require insulin replacement therapy to compensate for progressive β-cell failure and maintain blood glucose control. Even though currently available insulin analog preparations more closely mimic physiologic insulin needs when compared with neutral protamine Hagedorn insulin, many patients with diabetes still experience unacceptable glycemic control, in part owing to limitations in insulin therapy, such as hypoglycemia risk, weight gain and the need for patients to adjust their lifestyle to their insulin therapy. Insulin degludec, appropriately labeled as an ultra-long-acting basal insulin, promises to achieve similar blood glucose control to currently available preparations (glargine and detemir insulin), with a reduced risk of hypoglycemia and greater flexibility in the day-to-day timing of insulin administration. Greater flexibility in basal insulin administration and/or reducing hypoglycemia risk in insulin-requiring patients with Type 1 or 2 diabetes may facilitate insulin management for patients and physicians.


Exploration of gynaecological cancer high dose-rate brachytherapy treatment: a pilot study.
Performing brachytherapy on female patients with gynaecological cancer is a sensitive procedure, apart from it being an intricate investigation. The aim of this study: establishing gynaecological cancer patients' expectations, experiences and understandings of the high dose-rate brachytherapy treatment procedure. Exploring these patients' life-worlds provides further insights into improving their preparedness and experiences. A qualitative research design with a descriptive phenomenological research approach was used. Recruitment entailed using purposive sampling. To obtain rich insights into the lived experiences, data was acquired through semi-structured interviews until data saturation. Major challenges were experienced with mixed thoughts and feelings, from negative trauma to desires being fulfilled. These patients should have received more information regarding their upcoming brachytherapy treatment. This would have alleviated some of their fears and anxieties, which would in turn have provided them with a better brachytherapy treatment experience. Envisaged outcomes and desires are used to cope. Patients influence each other negatively, so they rather wanted to "see for themselves". Despite some disappointments and negative experiences throughout the brachytherapy continuum, the patients were left with a positive outlook, saying that it is an excellent and necessary treatment. Further studies should be done to elaborate on fulfilments of recommendations in the brachytherapy department of radiation oncology.


Serum levels of retinol-binding protein-4 are associated with the presence and severity of coronary artery disease.
The interplay between the novel adipokine retinol-binding protein-4 (RBP4) and coronary artery disease (CAD) is still obscure. We investigated the relationship between RBP4 levels and the presence and severity of angiographically proven CAD and determined its possible role in acute myocardial infarction (AMI). 305 individuals with angiographically proven CAD (CAD-patients), were classified into 2 subgroups: 1) acute myocardial infarction (AMI, n = 141), and 2) stable angina (SA, n = 164). Ninety-one age- and sex-matched individuals without CAD, but with at least 2 classical cardiovascular risk factors, served as controls (non-CAD group). RBP4 serum levels were measured at hospital admission and were analyzed in relation to the coronary severity stenosis, assessed by the Gensini-score and the number of coronary narrowed vessels. Other clinical parameters, including insulin levels, HOMA-IR, hsCRP, glycaemic and lipid profile, and left-ventricular ejection fraction were also assessed. Serum RBP4 levels were significantly elevated in patients with CAD compared to non-CAD patients (39.29 ± 11.72 mg/L vs. 24.83 ± 11.27 mg/L, p < 0.001). We did not observe a significant difference in RBP4 levels between AMI and SA subgroups (p = 0.734). Logistic regression analysis revealed an independent association of CAD presence with serum RBP4 (β = 0.163, p = 0.006), and hsCRP (β = 0.122, p = 0.022) levels, in the whole study group. Among variables, hsCRP (β = 0.220), HDL (β = -0.150), and RBP4 (β = 0.297), correlated in both univariate and multivariate analysis with CAD severity (R2 = 0.422, p < 0.001). Similarly, RBP4 concentrations increased with the number of coronary narrowed vessels (p < 0.05). Patients with CAD, both SA and AMI, showed elevated RBP4 serum levels. Notably, increased RBP4 concentration seemed to independently correlate with CAD severity, but no with AMI. The ClinicalTrials.gov Identifier is: NCT00636766.


On nonnegative matrix factorization algorithms for signal-dependent noise with application to electromyography data.
Nonnegative matrix factorization (NMF) by the multiplicative updates algorithm is a powerful machine learning method for decomposing a high-dimensional nonnegative matrix V into two nonnegative matrices, W and H, where V ~ WH. It has been successfully applied in the analysis and interpretation of large-scale data arising in neuroscience, computational biology, and natural language processing, among other areas. A distinctive feature of NMF is its nonnegativity constraints that allow only additive linear combinations of the data, thus enabling it to learn parts that have distinct physical representations in reality. In this letter, we describe an information-theoretic approach to NMF for signal-dependent noise based on the generalized inverse gaussian model. Specifically, we propose three novel algorithms in this setting, each based on multiplicative updates, and prove monotonicity of updates using the EM algorithm. In addition, we develop algorithm-specific measures to evaluate their goodness of fit on data. Our methods are demonstrated using experimental data from electromyography studies, as well as simulated data in the extraction of muscle synergies, and compared with existing algorithms for signal-dependent noise.


Unmasking determinants of specificity in the human kinome.
Protein kinases control cellular responses to environmental cues by swift and accurate signal processing. Breakdowns in this high-fidelity capability are a driving force in cancer and other diseases. Thus, our limited understanding of which amino acids in the kinase domain encode substrate specificity, the so-called determinants of specificity (DoS), constitutes a major obstacle in cancer signaling. Here, we systematically discover several DoS and experimentally validate three of them, named the αC1, αC3, and APE-7 residues. We demonstrate that DoS form sparse networks of non-conserved residues spanning distant regions. Our results reveal a likely role for inter-residue allostery in specificity and an evolutionary decoupling of kinase activity and specificity, which appear loaded on independent groups of residues. Finally, we uncover similar properties driving SH2 domain specificity and demonstrate how the identification of DoS can be utilized to elucidate a greater understanding of the role of signaling networks in cancer (Creixell et al., 2015 [this issue of Cell]).


Microphotography and the kodak research laboratories.
Microphotography is defined as the production of photographs in which the image of the original object has been reduced to extremely small size, but its details are still reproduced with a high degree of clarity. The contributions of the Kodak Research Laboratories to this technology, which is now of considerable commercial importance, have been in the production of sensitized materials having suitable resolution and sensitometric characteristics. These include both silver halide materials and photoresists. Some of the history and characteristics of various products and processes are sketched briefly.


Relating Complexity and Error Rates of Ontology Concepts. More Complex NCIt Concepts Have More Errors.
Ontologies are knowledge structures that lend support to many health-information systems. A study is carried out to assess the quality of ontological concepts based on a measure of their complexity. The results show a relation between complexity of concepts and error rates of concepts. A measure of lateral complexity defined as the number of exhibited role types is used to distinguish between more complex and simpler concepts. Using a framework called an area taxonomy, a kind of abstraction network that summarizes the structural organization of an ontology, concepts are divided into two groups along these lines. Various concepts from each group are then subjected to a two-phase QA analysis to uncover and verify errors and inconsistencies in their modeling. A hierarchy of the National Cancer Institute thesaurus (NCIt) is used as our test-bed. A hypothesis pertaining to the expected error rates of the complex and simple concepts is tested. Our study was done on the NCIt's Biological Process hierarchy. Various errors, including missing roles, incorrect role targets, and incorrectly assigned roles, were discovered and verified in the two phases of our QA analysis. The overall findings confirmed our hypothesis by showing a statistically significant difference between the amounts of errors exhibited by more laterally complex concepts vis-à-vis simpler concepts. QA is an essential part of any ontology's maintenance regimen. In this paper, we reported on the results of a QA study targeting two groups of ontology concepts distinguished by their level of complexity, defined in terms of the number of exhibited role types. The study was carried out on a major component of an important ontology, the NCIt. The findings suggest that more complex concepts tend to have a higher error rate than simpler concepts. These findings can be utilized to guide ongoing efforts in ontology QA.


Shank3-mutant mice lacking exon 9 show altered excitation/inhibition balance, enhanced rearing, and spatial memory deficit.
Shank3 is a postsynaptic scaffolding protein implicated in synapse development and autism spectrum disorders. The Shank3 gene is known to produce diverse splice variants whose functions have not been fully explored. In the present study, we generated mice lacking Shank3 exon 9 (Shank3 (Δ9) mice), and thus missing five out of 10 known Shank3 splice variants containing the N-terminal ankyrin repeat region, including the longest splice variant, Shank3a. Our X-gal staining results revealed that Shank3 proteins encoded by exon 9-containing splice variants are abundant in upper cortical layers, striatum, hippocampus, and thalamus, but not in the olfactory bulb or cerebellum, despite the significant Shank3 mRNA levels in these regions. The hippocampal CA1 region of Shank3 (Δ9) mice exhibited reduced excitatory transmission at Schaffer collateral synapses and increased frequency of spontaneous inhibitory synaptic events in pyramidal neurons. In contrast, prelimbic layer 2/3 pyramidal neurons in the medial prefrontal cortex displayed decreased frequency of spontaneous inhibitory synaptic events, indicating alterations in the ratio of excitation/inhibition (E/I ratio) in the Shank3 (Δ9) brain. These mice displayed a mild increase in rearing in a novel environment and mildly impaired spatial memory, but showed normal social interaction and repetitive behavior. These results suggest that ankyrin repeat-containing Shank3 splice variants are important for E/I balance, rearing behavior, and spatial memory.


Suicidal or homicidal sharp force injuries? A review and critical analysis of the heterogeneity in the forensic literature.
The differential diagnosis between self-inflicted and nonself-inflicted, suicidal and homicidal, injuries is difficult or impossible in many cases and, above all, cannot be made on the basis of information obtained solely from the autopsy or the medicolegal clinical examination. The purpose of this study is to analyze the literature on suicidal and homicidal sharp force injuries and identify the relevant parameters that may help differentiate between suicidal and homicidal deaths. To achieve this goal, a review of 595 potentially relevant articles was performed. After excluding the nonrelevant papers by screening the titles, all abstracts were reviewed, and articles meeting the inclusion criteria underwent a full-text review. The following parameters were compiled into a table: number of cases, localization of the injuries, and number of injuries. The data were statistically analyzed and compared with those available in the forensic literature. On the basis of the heterogeneity of data revealed by the present review, a simple and short checklist of the parameters that should be included when reporting suicides and homicides by sharp force has been proposed.


Insulinlike growth factor (IGF)-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy.
Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by polyglutamine expansion in the androgen receptor. Patients develop slowly progressive proximal muscle weakness, muscle atrophy and fasciculations. Affected individuals often show gynecomastia, testicular atrophy and reduced fertility as a result of mild androgen insensitivity. No effective disease-modifying therapy is currently available for this disease. Our recent studies have demonstrated that insulinlike growth factor (IGF)-1 reduces the mutant androgen receptor toxicity through activation of Akt in vitro, and spinal and bulbar muscular atrophy transgenic mice that also overexpress a noncirculating muscle isoform of IGF-1 have a less severe phenotype. Here we sought to establish the efficacy of daily intraperitoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract. The study was done in a controlled, randomized, blinded fashion, and, to reflect the clinical settings, the injections were started after the onset of disease manifestations. The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle. In comparison to vehicle-treated controls, IGF-1-treated transgenic mice showed improved motor performance, attenuated weight loss and increased survival. Our results suggest that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicate that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease.