Osteotomy, compression and other modifications of surgical techniques for internal fixation of extracapsular hip fractures.
Many different surgical techniques have been described for the internal fixation of extracapsular hip fractures. To compare different aspects of surgical technique used in operations for internal fixation of extracapsular hip fractures in adults. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (January 2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 1), MEDLINE, EMBASE, CINAHL, Current Controlled Trials, orthopaedic journals, conference proceedings and reference lists of articles. Date of last search was January 2008. No language restriction was applied. All randomised and quasi-randomised trials investigating operative techniques used in operations for the treatment of extracapsular hip fractures in adults. Two review authors independently selected trials, assessed trial quality and extracted data. Wherever appropriate, data were pooled. Predominantly older people with trochanteric fractures were treated in the 11 included trials.One trial (65 participants undergoing fixation with a fixed nail-plate) found no statistically significant differences between osteotomy versus anatomical reduction. Four trials, involving 465 participants undergoing fixation with a sliding hip screw (SHS), compared osteotomy versus anatomical reduction. Osteotomy was associated with an increased operative blood loss and length of surgery. There were no statistically significant differences for mortality, morbidity or measures of anatomical deformity.Two trials (138 participants) compared SHS fixation of a trochanteric hip fracture augmented with cement against a standard fixation. There were no reoperations even for the four cases of fixation failure in the cement group. The cement group had significantly better quality of life scores at six months. One trial (200 participants) comparing compression versus no compression of a trochanteric fracture in conjunction with SHS fixation found no significant differences between the two groups. One trial (120 participants) found a tendency to improved outcomes with a hydroxyapatite coated lag screw, but none reached statistical significance. One trial (19 participants) reported reduced temperatures when using a modified reaming method. Another trial (50 participants) found reduced bone marrow intravascular embolism, detected by oesophageal ultrasound, when a Gamma nail was inserted with a distal pressure venting hole in the femur. There is inadequate evidence to support the use of osteotomy for internal fixation of a trochanteric hip fracture. Similarly, there is insufficient evidence to support the use of the other techniques examined in the trials included in this review.


The value of cytokeratin immunohistochemistry in the evaluation of axillary sentinel lymph nodes in patients with lobular breast carcinoma.
Cytokeratin immunohistochemistry (IHC) reveals a higher rate of occult lymph node metastases among lobular carcinomas than among ductal breast cancers. IHC is widely used but is seldom recommended for the evaluation of sentinel lymph nodes in breast cancer patients. To assess the value of cytokeratin IHC for the detection of metastases in sentinel lymph nodes of patients with invasive lobular carcinoma. The value of IHC, the types of metastasis found by this method, and the involvement of non-sentinel lymph nodes were analysed in a multi-institutional cohort of 449 patients with lobular breast carcinoma, staged by sentinel lymph node biopsy and routine assessment of the sentinel lymph nodes by IHC when multilevel haematoxylin and eosin staining revealed no metastasis. 189 patients (42%) had some type of sentinel node involvement, the frequency of this increasing with increasing tumour size. IHC was needed for identification of 65 of these cases: 17 of 19 isolated tumour cells, 40 of 64 micrometastases, and 8 of 106 larger metastases were detected by this means. Non-sentinel-node involvement was noted in 66 of 161 cases undergoing axillary dissection. Although isolated tumour cells were not associated with further lymph node involvement, sentinel node positivity detected by IHC was associated with further nodal metastases in 12 of 50 cases (0.24), a proportion that is higher than previously reported for breast cancer in general. IHC is recommended for the evaluation of sentinel nodes from patients with lobular breast carcinoma, as the micrometastases or larger metastases demonstrated by this method are often associated with a further metastatic nodal load.


The interplay between inflammation and neurodegeneration in CNS disease.
This review considers the manner in which inflammation in the CNS contributes to, and protects against, neurodegeneration. A series of questions are posed, first about primarily inflammatory diseases and the causes of neurodegeneration that occurs in them, and then about neurodegenerative diseases and stroke and the role that inflammation plays there. Common themes as well as disease-specific differences are highlighted in this survey of the recent human disease and animal model literature.


History of autoimmune conditions and lymphoma prognosis.
Autoimmune conditions are strong risk factors for developing lymphoma, but their role in lymphoma prognosis is less clear. In a prospective cohort study, we evaluated self-reported history of eight autoimmune conditions with outcomes in 736 diffuse large B-cell, 703 follicular, 302 marginal zone (MZL), 193 mantle cell (MCL), 297 Hodgkin lymphoma (HL), and 186 T-cell lymphomas. We calculated event-free survival (EFS) and overall survival (OS), and estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for sex, prognostic score, and treatment. History of any of the eight autoimmune conditions ranged from 7.4% in HL to 18.2% in MZL, and was not associated with EFS or OS for any lymphoma subtype. However, there was a positive association of autoimmune conditions primarily mediated by B-cell responses with inferior EFS in MCL (HR = 2.23, CI: 1.15-4.34) and HL (HR = 2.63, CI: 1.04-6.63), which was largely driven by rheumatoid arthritis. Autoimmune conditions primarily mediated by T-cell responses were not found to be associated with EFS or OS in any lymphoma subtype, although there were few events for this exposure. Our results indicate that distinguishing autoimmune conditions primarily mediated by B-cell/T-cell responses may yield insight regarding the impact of this comorbid disease, affecting ~10% of lymphoma patients, on survival.


Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child.
Central and peripheral nervous system symptoms and complications are being increasingly recognized among individuals with pandemic SARS-CoV-2 infections, but actual detection of the virus or its RNA in the central nervous system has rarely been sought or demonstrated. Severe or fatal illnesses are attributed to SARS-CoV-2, generally without attempting to evaluate for alternative causes or co-pathogens. A five-year-old girl with fever and headache was diagnosed with acute SARS-CoV-2-associated meningoencephalitis based on the detection of its RNA on a nasopharyngeal swab, cerebrospinal fluid analysis, and magnetic resonance imaging findings. Serial serologic tests for SARS-CoV-2 IgG and IgA showed seroconversion, consistent with an acute infection. Mental status and brain imaging findings gradually worsened despite antiviral therapy and intravenous dexamethasone. Decompressive suboccipital craniectomy for brain herniation with cerebellar biopsy on day 30 of illness, shortly before death, revealed SARS-CoV-2 RNA in cerebellar tissue using the Centers for Disease Control and Prevention 2019-nCoV Real-Time Reverse Transcriptase-PCR Diagnostic Panel. On histopathology, necrotizing granulomas with numerous acid-fast bacilli were visualized, and Mycobacterium tuberculosis complex DNA was detected by PCR. Ventricular cerebrospinal fluid that day was negative for mycobacterial DNA. Tracheal aspirate samples for mycobacterial DNA and culture from days 22 and 27 of illness were negative by PCR but grew Mycobacterium tuberculosis after 8 weeks, long after the child's passing. She had no known exposures to tuberculosis and no chest radiographic findings to suggest it. All 6 family members had normal chest radiographs and negative interferon-γ release assay results. The source of her tuberculous infection was not identified, and further investigations by the local health department were not possible because of the State of Michigan-mandated lockdown for control of SARS-CoV-2 spread. The detection of SARS-CoV-2 RNA in cerebellar tissue and the demonstration of seroconversion in IgG and IgA assays was consistent with acute SARS-CoV-2 infection of the central nervous infection. However, the cause of death was brain herniation from her rapidly progressive central nervous system tuberculosis. SARS-CoV-2 may mask or worsen occult tuberculous infection with severe or fatal consequences.


The Legal Implications of HIPAA Privacy and Public Health Reporting for Correctional Facilities.
Inmates in cramped living quarters, a situation common to correctional facilities, are especially vulnerable to disease. Cramped living conditions, coupled with above-average rates of HIV, tuberculosis, and other communicable diseases, increase inmates' risk of problematic health outcomes. Thus, high-quality health care and sustained efforts to prevent disease are especially important to improve inmate health within correctional facilities. Compliance with federal privacy restrictions pursuant to the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule and state disease reporting requirements will foster inmate health and assist efforts to prevent the spread of disease. This article examines the interplay between HIPAA rules and state reporting laws to preserve health information privacy and to control the spread of disease.


A Relational Approach to Genetic Counseling for Hereditary Breast and Ovarian Cancer.
Ethical issues arise for genetic counselors when a client fails to disclose a genetic diagnosis of hereditary disease to family: they must consider the rights of the individual client to privacy and confidentiality as well as the rights of the family to know their genetic risk. Although considerable work has addressed issues of non-disclosure from the client's perspective, there is a lack of qualitative research into how genetic counselors address this issue in practice. In this study, a qualitative approach was taken to investigate whether genetic counselors in Australia use a relational approach to encourage the disclosure of genetic information from hereditary breast and ovarian cancer (HBOC) clients among family members; and if so, how they use it. Semi-structured qualitative interviews were conducted with 16 genetic counselors from selected states across Australia. Data collection and analysis were guided by a basic iterative approach incorporating a hybrid methodology to thematic analysis. The findings provide indicative evidence of genetic counselors employing a relational approach in three escalating stages--covert, overt and authoritative--to encourage the disclosure of genetic information. The findings lend credence to the notion that genetic counselors envision a form of relational autonomy for their clients in the context of sharing genetic information, and they depart from individualistic conceptions of care/solely client-centered counseling when addressing the needs of other family members to know their genetic status.


Referent expressions and gaze: reference type influences real-world gaze cue utilization.
Gaze cues are used alongside language to communicate. Lab-based studies have shown that people reflexively follow gaze cue stimuli, however it is unclear whether this affect is present in real interactions. Language specificity influences the extent to which we utilize gaze cues in real interactions, but it is unclear whether the type of language used can similarly affect gaze cue utilization. We aimed to (a) investigate whether automatic gaze following effects are present in real-world interactions, and (b) explore how gaze cue utilization varies depending on the form of concurrent language used. Wearing a mobile eye-tracker, participants followed instructions to complete a real-world search task. The instructor varied the determiner used (featural or spatial) and the presence of gaze cues (absent, congruent, or incongruent). Congruent gaze cues were used more when provided alongside featural references. Incongruent gaze cues were initially followed no more than chance. However, unlike participants in the no-gaze condition, participants in the incongruent condition did not benefit from receiving spatial instructions over featural instructions. We suggest that although participants selectively use informative gaze cues and ignore unreliable gaze cues, visual search can nevertheless be disrupted when inherently spatial gaze cues are accompanied by contradictory verbal spatial references.


Structural insights into the function of aminoglycoside-resistance A1408 16S rRNA methyltransferases from antibiotic-producing and human pathogenic bacteria.
X-ray crystal structures were determined of the broad-spectrum aminoglycoside-resistance A1408 16S rRNA methyltransferases KamB and NpmA, from the aminoglycoside-producer Streptoalloteichus tenebrarius and human pathogenic Escherichia coli, respectively. Consistent with their common function, both are Class I methyltransferases with additional highly conserved structural motifs that embellish the core SAM-binding fold. In overall structure, the A1408 rRNA methyltransferase were found to be most similar to a second family of Class I methyltransferases of distinct substrate specificity (m(7)G46 tRNA). Critical residues for A1408 rRNA methyltransferase activity were experimentally defined using protein mutagenesis and bacterial growth assays with kanamycin. Essential residues for SAM coenzyme binding and an extended protein surface that likely interacts with the 30S ribosomal subunit were thus revealed. The structures also suggest potential mechanisms of A1408 target nucleotide selection and positioning. We propose that a dynamic extended loop structure that is positioned adjacent to both the bound SAM and a functionally critical structural motif may mediate concerted conformational changes in rRNA and protein that underpin the specificity of target selection and activation of methyltransferase activity. These new structures provide important new insights that may provide a starting point for strategies to inhibit these emerging causes of pathogenic bacterial resistance to aminoglycosides.


Conversion of acetylcholinesterase to butyrylcholinesterase: modeling and mutagenesis.
Torpedo acetylcholinesterase (AcChoEase, EC 220.127.116.11) and human butyrylcholinesterase (BtChoEase, EC 188.8.131.52), while clearly differing in substrate specificity and sensitivity to inhibitors, possess 53% sequence homology; this permitted modeling human BtChoEase on the basis of the three-dimensional structure of Torpedo AcChoEase. The modeled BtChoEase structure closely resembled that of AcChoEase in overall features. However, six conserved aromatic residues that line the active-site gorge, which is a prominent feature of the AcChoEase structure, are absent in BtChoEase. Modeling showed that two such residues, Phe-288 and Phe-290, replaced by leucine and valine, respectively, in BtChoEase, may prevent entrance of butyrylcholine into the acyl-binding pocket. Their mutation to leucine and valine in AcChoEase, by site-directed mutagenesis, produced a double mutant that hydrolyzed butyrylthiocholine almost as well as acetylthiocholine. The mutated enzyme was also inhibited well by the bulky, BtChoEase-selective organophosphate inhibitor (tetraisopropylpyrophosphoramide, iso-OMPA). Trp-279, at the entrance of the active-site gorge in AcChoEase, is absent in BtChoEase. Modeling designated it as part of the "peripheral" anionic site, which is lacking in BtChoEase. The mutant W279A displayed strongly reduced inhibition by the peripheral site-specific ligand propidium relative to wild-type Torpedo AcChoEase, whereas inhibition by the catalytic-site inhibitor edrophonium was unaffected.


Psychometric properties of the Cannabis Abuse Screening Test in Hungarian samples of adolescents and young adults.
The aim of our study was to analyze psychometric properties of the Cannabis Abuse Screening Test (CAST). Our sample comprised Hungarian high school (n = 476; male 56.3%; mean age 19.0 years, SD = 0.65 years) and college students (n = 439; male 65.1%; mean age 23.9 years, SD = 1.56 years) who reported cannabis use in the past year. The sample covered the five biggest universities of Hungary. Besides the CAST, participants responded to the Munich-Composite International Diagnostic Interview. Factor structure was analyzed by a confirmatory factor analysis. Receiver operating characteristic curve analysis was made to assess cut-off scores. Data collection took place in 2010. CAST proved to be a reliable (Cronbach's α 0.71 and 0.76) one-dimensional measure. Regarding both cannabis dependence and cannabis use disorders, a cut-off of 2 points proved to be ideal in both samples, resulting in optimal specificity, negative predictive values and accuracy, but less than optimal positive predictive values (dependence) and low sensitivity (cannabis use disorder). In line with former results, the CAST proved to be an adequate measure for the screening of cannabis-related problems among adolescents and young adults in an Eastern European country where this scale has not been studied before.


Molecular evolution of A-kinase anchoring protein (AKAP)-7: implications in comparative PKA compartmentalization.
A-Kinase Anchoring Proteins (AKAPs) are molecular scaffolding proteins mediating the assembly of multi-protein complexes containing cAMP-dependent protein kinase A (PKA), directing the kinase in discrete subcellular locations. Splice variants from the AKAP7 gene (AKAP15/18) are vital components of neuronal and cardiac phosphatase complexes, ion channels, cardiac Ca2+ handling and renal water transport. Shown in evolutionary analyses, the formation of the AKAP7-RI/RII binding domain (required for AKAP/PKA-R interaction) corresponds to vertebrate-specific gene duplication events in the PKA-RI/RII subunits. Species analyses of AKAP7 splice variants shows the ancestral AKAP7 splice variant is AKAP7α, while the ancestral long form AKAP7 splice variant is AKAP7γ. Multi-species AKAP7 gene alignments, show the recent formation of AKAP7δ occurs with the loss of native AKAP7γ in rats and basal primates. AKAP7 gene alignments and two dimensional Western analyses indicate that AKAP7γ is produced from an internal translation-start site that is present in the AKAP7δ cDNA of mice and humans but absent in rats. Immunofluorescence analysis of AKAP7 protein localization in both rat and mouse heart suggests AKAP7γ replaces AKAP7δ at the cardiac sarcoplasmic reticulum in species other than rat. DNA sequencing identified Human AKAP7δ insertion-deletions (indels) that promote the production of AKAP7γ instead of AKAP7δ. This AKAP7 molecular evolution study shows that these vital scaffolding proteins developed in ancestral vertebrates and that independent mutations in the AKAP7 genes of rodents and early primates has resulted in the recent formation of AKAP7δ, a splice variant of likely lesser importance in humans than currently described.


High affinity sugar ligands of C-type lectin receptor langerin.
Langerin, a C-type lectin receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized. Based on a recent discovery that the disaccharide L4, a KS component that contains 6-sulfo-Gal, exhibits anti-inflammatory activity in mouse lung, we hypothesized that L4-related compounds are useful tools for characterizing the langerin-ligand interactions and their therapeutic application. We performed binding analysis between purified long and short forms of langerin and a series of KS disaccharide components. We also chemically synthesized oligomeric derivatives of L4 to develop a new high-affinity ligand of langerin. We show that the binding critically requires the 6-sulfation of Gal and that the long form of langerin displays higher affinity than the short form. The synthesized trimeric (also designated as triangle or Tri) and polymeric (pendant) L4 derivatives displayed over 1000-fold higher affinity toward langerin than monomeric L4. The pendant L4, but not the L4 monomer, was found to effectively transduce langerin signaling in a model cell system. L4 is a specific ligand for langerin. Oligomerization of L4 unit increased the affinity toward langerin. These results suggest that oligomeric L4 derivatives will be useful for clarifying the langerin functions and for the development of new glycan-based anti-inflammatory drugs.


Self-reported family socioeconomic status, the 5-HTTLPR genotype, and delinquent behavior in a community-based adolescent population.
Twin and adoption studies have demonstrated a significant contribution of both genetic and environmental factors to antisocial and delinquent behavior. Associations have been reported between the serotonin transporter (5-HTT) and aggression, and between socioeconomic status (SES), aggression, and serotonergic functions of the brain. We aimed to investigate associations between the 5-HTTLPR genotype and family SES in relation to delinquent behavior among adolescents. A total of 1,467 17- to 18-year-old students in the county of Västmanland, Sweden, anonymously completed a questionnaire and gave a saliva sample. Family SES had a U-shaped relation to delinquency, where adolescents with low and high family SES were the most delinquent. There were curvilinear interactions between the 5-HTTLPR genotype and family SES in relation to delinquency. Among individuals having high family SES, boys with the LL (homozygous for the long allele) or LS (heterozygous) genotypes and girls with the SS (homozygous for the short allele) or LS (heterozygous) genotypes showed the highest delinquency scores. Among individuals having low family SES, boys with the LL (homozygous for the long allele) genotype and girls with the LS (heterozygous) genotype showed the highest delinquency scores. The present study suggests evidence for an interaction between family SES and the 5-HTTLPR genotype in relation to juvenile delinquency.


Phylogenetic diversity does not capture body size variation at risk in the world's mammals.
Mammals contribute to important ecosystem processes and services, but many mammalian species are threatened with extinction. We compare how global patterns in three measures of mammalian diversity--species richness, phylogenetic diversity (PD) and body mass variance (BMV)--would change if all currently threatened species were lost. Given that many facets of species' ecology and life history scale predictably with body mass, the BMV in a region roughly reflects the diversity of species' roles within ecosystems and so is a simple proxy for functional diversity (FD). PD is also often considered to be a proxy for FD, but our results suggest that BMV losses within ecoregions would be much more severe than losses of PD or species richness, and that its congruence with the latter two measures is low. Because of the disproportionate loss of large mammals, 65 per cent of ecoregions would lose significantly more BMV than under random extinction, while only 11 per cent would lose significantly more PD. Ecosystem consequences of these selective losses may be profound, especially throughout the tropics, but are not captured by PD. This low surrogacy stresses a need for conservation prioritization based on threatened trait diversity, and for conservation efforts to take an ecosystem perspective.


Potential association of metabolic and musculoskeletal disorders with lumbar intervertebral disc degeneration: Cross-sectional study using medical checkup data.
The pathogenesis of intervertebral disc (IVD) degeneration is complex and involves the interaction of multiple factors. However, few systemic studies have explored the associations of metabolic disorders and age-related musculoskeletal disorders with the development of IVD degeneration. We analyzed clinical data obtained from healthy individuals who had undergone a musculoskeletal checkup. In total, 276 subjects comprising 142 males and 134 females were enrolled. The subjects were divided into two groups based on the degree of IVD degeneration according to Pfirrmann grading: those with grades 1-3, the group with non-degenerative discs; and grades 4 and 5, the group with degenerative discs. The subjects underwent examinations including abdominal circumference, blood pressure, bilateral hand grip strength, abdominal computed tomography, magnetic resonance imaging of the lumbar spine, and dual X-ray absorptiometry. To examine the independent association with IVD degeneration at L3/4, L4/5, and L5/S levels, we constructed a Poisson regression model and estimated relative risks (RRs) and 95% confidence intervals (CIs) of IVD degeneration. Multivariable analysis showed that advanced age was markedly associated with IVD degeneration at all levels and that men had an inverse association with the IVD degeneration, particularly at the L4/5 level (RR = 0.7, 95% CI = 0.6-0.9). In addition, metabolic syndrome was significantly associated with IVD degeneration at the L5/S level (RR = 1.4, 95% CI = 1.1-1.8). Meanwhile, sarcopenia showed no significant association with IVD degeneration at any level. Osteoporosis was inversely associated with IVD degeneration, particularly at the L4/5 level (RR = 0.7, 95% CI = 0.6-0.9). Our data suggest that advanced age, female sex, and metabolic syndrome are associated with IVD degeneration. In addition, osteoporosis showed an inverse association with IVD degeneration. Our data should promote understanding of the etiology of lumbar IVD degeneration.


Imaging-based identification of a critical regulator of FtsZ protofilament curvature in Caulobacter.
FtsZ is an essential bacterial GTPase that polymerizes at midcell, recruits the division machinery, and may generate constrictive forces necessary for cytokinesis. However, many of the mechanistic details underlying these functions are unknown. We sought to identify FtsZ-binding proteins that influence FtsZ function in Caulobacter crescentus. Here, we present a microscopy-based screen through which we discovered two FtsZ-binding proteins, FzlA and FzlC. FzlA is conserved in α-proteobacteria and was found to be functionally critical for cell division in Caulobacter. FzlA altered FtsZ structure both in vivo and in vitro, forming stable higher-order structures that were resistant to depolymerization by MipZ, a spatial determinant of FtsZ assembly. Electron microscopy revealed that FzlA organizes FtsZ protofilaments into striking helical bundles. The degree of curvature induced by FzlA depended on the nucleotide bound to FtsZ. Induction of FtsZ curvature by FzlA carries implications for regulating FtsZ function by modulating its superstructure.


Nodular pulmonary light chain deposition disease: an entity associated with Sjögren syndrome or marginal zone lymphoma.
Light chain deposition disease (LCDD) is usually a systemic disorder characterised by non-amyloid monoclonal immunoglobulin light chain deposition in tissues. Localised nodular pulmonary (NP) LCDD is a rare and poorly characterised entity and, owing to the difficulties in diagnosis, limited data are available. We investigated the clinical, radiological and pathological characteristics of a series of six confidently diagnosed cases of NPLCDD. There were three men and three women with ages ranging from 33 to 74 years. In all cases there were single or multiple pulmonary nodules, in one case associated with cysts. Two patients had no previous history of a lymphoproliferative or autoimmune disorder, two had Sjögren syndrome (SS) and two had extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Lung biopsies led to diagnoses of MALT lymphoma in four patients, including both of those with a previous history of lymphoma and one with SS. In five cases the diagnosis was confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and in one by electron microscopy. There was no evidence of systemic LCDD in any of the cases. Five patients had an indolent course in spite of limited therapeutic intervention while, in the patient who died, the cause of death was related to the spread of the lymphoma and was not due to the pulmonary lesions. NPLCDD is an indolent disease, in most cases associated with MALT lymphoma or autoimmune disease.


Reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring.
An intracranial pressure (ICP) monitor, from which cerebral perfusion pressure (CPP) is estimated, is recommended in the care of severe traumatic brain injury (TBI). Nevertheless, optimal ICP and CPP management may not always prevent cerebral ischemia, which adversely influences patient outcome. The authors therefore determined whether the addition of a brain tissue oxygen tension (PO2) monitor in the treatment of TBI was associated with an improved patient outcome. Patients with severe TBI (Glasgow Coma Scale [GCS] score < 8) who had been admitted to a Level I trauma center were evaluated as part of a prospective observational database. Patients treated with ICP and brain tissue PO2 monitoring were compared with historical controls matched for age, pathological features, admission GCS score, and Injury Severity Score who had undergone ICP monitoring alone. Therapy in both patient groups was aimed at maintaining an ICP less than 20 mm Hg and a CPP greater than 60 mm Hg. Among patients whose brain tissue PO2 was monitored, oxygenation was maintained at levels greater than 25 mm Hg. Twenty-five patients with a mean age of 44 +/- 14 years were treated using an ICP monitor alone. Twenty-eight patients with a mean age of 38 +/- 18 years underwent brain tissue PO2-directed care. The mean daily ICP and CPP levels were similar in each group. The mortality rate in patients treated using conventional ICP and CPP management was 44%. Patients who also underwent brain tissue PO2 monitoring had a significantly reduced mortality rate of 25% (p < 0.05). The use of both ICP and brain tissue PO2 monitors and therapy directed at brain tissue PO2 is associated with reduced patient death following severe TBI.


Concordance of chronic conditions in older Mexican American couples.
There is substantial evidence that marriage is beneficial to health, but evidence on whether the health status of one spouse is similar, or concordant, with the other spouse is limited. This study assessed whether a chronic condition of one spouse is a risk factor for the same chronic condition in the other spouse. The study used baseline data from the Hispanic Established Populations for the Epidemiologic Studies of the Elderly on 553 couples (1106 individuals) who are representative of approximately 500,000 older (> or =65 years) Mexican Americans living in the southwestern United States. Logistic regression was used to predict six chronic conditions among couples: heart condition, stroke, hypertension, diabetes, arthritis, and cancer. Analyses were adjusted for age, education, U.S. nativity, blood pressure, body mass index, smoking, and alcohol consumption. The wife's history of hypertension, diabetes, arthritis, and cancer was associated with higher odds that the husband would have these conditions. A history of hypertension, arthritis, and cancer in the husband was associated with higher odds that the wife would have these conditions. These results provide preliminary evidence that chronic conditions in one spouse are associated with an increased risk of developing like conditions in the other spouse among older Mexican American couples. We propose that the reciprocal influence that marital partners have on each other may be caused by shared living arrangements and shared health risks. Health promotion activities should target family systems. In particular, health providers should gather health histories not only from patients and their genetic family members but also from spouses.


Measurement of social capital in relation to health in low and middle income countries (LMIC): a systematic review.
Social capital is a neglected determinant of health in low and middle income countries. To date, majority of evidence syntheses on social capital and health are based upon high income countries. We conducted this systematic review to identify the methods used to measure social capital in low and middle-income countries and to evaluate their relative strengths and weaknesses. An electronic search was conducted using Pubmed, Science citation index expanded, Social science citation index expanded, Web of knowledge, Cochrane, Trip, Google scholar and selected grey literature sources. We aimed to include all studies conducted in low and middle-income countries, published in English that have measured any aspect of social capital in relation to health in the study, from 1980 to January 2013. We extracted data using a data extraction form and performed narrative synthesis as the measures were heterogeneous. Of the 472 articles retrieved, 46 articles were selected for the review. The review included 32 studies from middle income countries and seven studies from low income countries. Seven were cross national studies. Most studies were descriptive cross sectional in design (n = 39). Only two randomized controlled trials were included. Among the studies conducted using primary data (n = 32), we identified18 purposely built tools that measured various dimensions of social capital. Validity (n = 11) and reliability (n = 8) of the tools were assessed only in very few studies. Cognitive constructs of social capital, namely trust, social cohesion and sense of belonging had a positive association towards measured health outcome in majority of the studies. While most studies measured social capital at individual/micro level (n = 32), group level measurements were obtained by aggregation of individual measures. As many tools originate in high income contexts, cultural adaptation, validation and reliability assessment is mandatory in adapting the tool to the study setting. Evidence on causality and assessing predictive validity is a problem due to the scarcity of prospective study designs. We recommend Harpham et al. s' Adapted Social Capital Assessment Tool (A-SCAT), Hurtado et al. s' six item tool and Elgar et al. s' World Value Survey Social Capital Scale for assessment of social capital in low and middle income countries.


Conservation and management of seahorses and other Syngnathidae.
This article analyses the pressures on seahorses and explores conservation responses. It focuses on seahorses (Hippocampus spp.) but also considers pipefishes and seadragons, especially where they can fill gaps in seahorse knowledge. The charisma of many syngnathids can make them good flagship species for threats and solutions in marine conservation. The article combines a synthesis of published literature with new data on the trade in seahorses for traditional medicine, aquarium display and curiosities. Most traded seahorses come from trawl by-catch, although seahorses are also targeted. The total extraction is large, tens of millions of animals annually, and unsustainable. A first review of the effect of habitat change on syngnathids raises many questions, while suggesting that some species may cope better than others. The combination of pressures means that many species of syngnathid are now included in the IUCN Red List of Threatened Species or national equivalents. In addition, seahorse exports from 175 countries are limited to sustainable levels under the Convention on International Trade in Endangered Species (CITES) of Wild Fauna and Flora. Possible conservation measures include marine protected areas, fisheries management, select aquaculture ventures, trade regulation, improved governance (particularly) and consumer engagement.


Cytokeratin 12 in human ocular surface epithelia is the antigen reactive with a commercial anti-Galpha q antibody.
In our initial attempt to identify differentiation markers for ocular surface epithelia, we observed a unique staining pattern by a commercial anti-Galphaq antibody. We further isolate and characterize the protein reactive with this anti-Galphaq antibody in human ocular surface epithelia. Human donor corneoscleral buttons were sectioned and stained with a battery of commercial antibodies against Galpha proteins. Western blot analysis of cell lysates of corneal epithelial cells and HEK 293 cells transfected with Galphaq cDNA was used to determine the identity of the protein reactive with the anti-Galphaq antibody (E-17). Comparisons were made with another anti-Galphaq antibody (G4415) and an anti-cytokeratin 12C (J7) antibody. The isolated proteins reactive with E17 and J7 were then analyzed with two dimensional isoelectric focusing. Polypeptide sequences were identified using matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) after in-gel protein digestion. The E-17 anti-Galphaq antibody preferentially stained the entire corneal epithelia and the suprabasal layers of the limbus with complete absence of staining in the basal limbus and conjunctiva. Western blot analysis of corneal epithelial cells showed that E-17 antibody identified a protein with a molecular weight of 55 kDa. However, the antibody did not react with the purported antigen, Galphaq protein (42 kDa) produced by Galphaq cDNA. Another anti-Galphaq antibody (G4415) did not react with the 55 kDa protein but did react with the 42 kDa Galphaq protein. Further comparison of the E-17 antibody with the J7 antibody revealed that both recognized the 55 kDa band in one and two dimensional analysis. MALDI-TOF MS analysis confirmed that the 55 kDa protein of interest was actually cytokeratin 12 (CK12), rather than Galphaq protein. The commercial E-17 anti-Galphaq antibody did not react with Galphaq protein, its purported antigen. Instead, it recognized a 55 kDa protein, which was characterized to be cytokeratin 12 by isoelectric focusing and peptide fingerprinting with mass spectrometry. Based on its reactivity with CK12, this commercial E-17 can be used as a differentiation marker to study ocular surface epithelia.


Beneficial effects of intracoronary thrombolysis up to eighteen hours after onset of pain in evolving myocardial infarction.
Coronary arteriography and intracoronary streptokinase (STK) infusion were performed on 89 patients with evolving acute myocardial infarction (AMI). Ventricular function was followed in these patients during their hospitalization by gated radionuclide ventriculography. In 35 of these patients thallium imaging was performed on admission and 4 hours after reperfusion. An additional 30 patients with AMI who either met exclusion criteria for the STK protocol or refused study served as a control group. In patients admitted 0 to 6, 6 to 12, or 12 to 18 hours after onset of pain, there was no difference in change in left ventricular ejection fraction (LVEF) from admission to discharge, in percent of patients with total occlusion demonstrating reperfusion, or in percent of patients demonstrating a significant increase in LVEF. The average increase in LVEF from admission to discharge in patients reperfused ws 8% (40% +/- 14% to 48% +/- 13%, p less than 0.001). No change in LVEF was demonstrated in the control population or in patients in whom coronary reperfusion was unsuccessful. Reperfusion produced an increase in thallium uptake in the infarct-related myocardium that was accompanied by an improvement in regional function. Failure of reperfusion produced no change in either thallium uptake or regional function.


Clinical and radiological results 6 years after treatment of traumatic thoracolumbar burst fractures with pedicle screw instrumentation and balloon assisted endplate reduction.
When used to fixate traumatic thoracolumbar burst fractures, pedicle screw constructs may fail in the presence of severe vertebral body comminution as the intervertebral disc can creep through the fractured endplates leading to insufficient anterior column support. Balloon-assisted endplate reduction (BAER) and subsequent calcium phosphate cement augmentation may prevent this event by restoring the disc space boundaries. The results of the first studies using BAER after pedicle screw fixation are encouraging, showing good fracture reduction, few complications, and minimal loss of correction at 2 years of follow-up. To present the clinical and radiological outcome of 20 patients treated for traumatic thoracolumbar burst fractures with pedicle screws and BAER after a minimum of 6 years follow-up. Prospective trial. Twenty consecutive neurologically intact adult patients with traumatic thoracolumbar burst fractures were included. Radiological parameters (wedge/Cobb angle on plain radiographs and mid-sagittal anterior/central vertebral body height on magnetic resonance imaging scans) and patient reported parameters (EQ-5D and Oswestry Disability Index) were used. All patients had previously undergone pedicle screw fixation and BAER with calcium phosphate cement augmentation. The posterior instrumentation was removed approximately 1.5 years after index surgery. Radiographs were obtained preoperatively, postoperatively, after removal of the pedicle screws, and at final follow-up (minimum 6 years post-trauma). Magnetic resonance imaging scans were obtained preoperatively, 1 month after index surgery, and 1 month after pedicle screw removal. Health questionnaires were filled out during the last outpatient visit. The pedicle screw instrumentation was removed uneventfully in all patients and posterolateral fusion was observed in every case. The mean wedge and Cobb angle converged to almost identical values (5.3° and 5.8°, respectively) and the mid-sagittal anterior and central endplates were reduced to approximately 90% and 80% of the estimated preinjury vertebral body height, respectively; this reduction was sustained at follow-up. Patient-reported outcomes showed favorable results in 79% of the patients. One patient required (posterior) reoperation due to adjacent osteoporotic vertebral body collapse after pedicle screw removal. Balloon-assisted endplate reduction is a safe and low-demanding adjunct to pedicle screw fixation for the treatment of traumatic thoracolumbar burst fractures. It may help achieve minimal residual deformity and reduce the number of secondary (anterior) procedures. Despite these positive findings, one in five patients experienced daily discomfort and disability.


C-reactive protein (CRP) induces chemokine secretion via CD11b/ICAM-1 interaction in human adherent monocytes.
Several studies support C-reactive protein (CRP) as a systemic cardiovascular risk factor. The recent detection of CRP in arterial intima suggests a dual activity in atherosclerosis as a circulating and tissue mediator on vascular and immune cells. In the present paper, we focused on the inflammatory effects of CRP on human monocytes, which were isolated by Ficoll-Percoll gradients and cultured in adherence to polystyrene, endothelial cell monolayer, or in suspension. Chemokine levels, adhesion molecule, and chemokine receptor expression were detected by ELISA, flow cytometry, and real-time RT-PCR. Migration assays were performed in a Boyden chamber. Stimulation with CRP induced release of CCL2, CCL3, and CCL4 in adherent monocytes through the binding to CD32a, CD32b, and CD64, whereas no effect was observed in suspension culture. This was associated with CRP-induced up-regulation of adhesion molecules membrane-activated complex 1 (Mac-1) and ICAM-1 on adherent monocytes. Blockade of Mac-1/ICAM-1 interaction inhibited the CRP-induced chemokine secretion. In addition, CRP reduced mRNA and surface expression of corresponding chemokine receptors CCR1, CCR2, and CCR5 in adherent monocytes. This effect was a result of chemokine secretion, as coincubation with neutralizing anti-CCL2, anti-CCL3, and anti-CCL4 antibodies reversed the effect of CRP. Accordingly, a reduced migration of CRP-treated monocytes to CCL2 and CCL3 was observed. In conclusion, our data suggest an in vitro model to study CRP activities in adherent and suspension human monocytes. CRP-mediated induction of adhesion molecules and a decrease of chemokine receptors on adherent monocytes might contribute to the retention of monocytes within atherosclerotic lesions and recruitment of other circulating cells.


The N-glycan structures of the antigenic variants of chlorovirus PBCV-1 major capsid protein help to identify the virus-encoded glycosyltransferases.
The chlorovirus Paramecium bursaria chlorella virus 1 (PBCV-1) is a large dsDNA virus that infects the microalga Chlorella variabilis NC64A. Unlike most other viruses, PBCV-1 encodes most, if not all, of the machinery required to glycosylate its major capsid protein (MCP). The structures of the four N-linked glycans from the PBCV-1 MCP consist of nonasaccharides, and similar glycans are not found elsewhere in the three domains of life. Here, we identified the roles of three virus-encoded glycosyltransferases (GTs) that have four distinct GT activities in glycan synthesis. Two of the three GTs were previously annotated as GTs, but the third GT was identified in this study. We determined the GT functions by comparing the WT glycan structures from PBCV-1 with those from a set of PBCV-1 spontaneous GT gene mutants resulting in antigenic variants having truncated glycan structures. According to our working model, the virus gene a064r encodes a GT with three domains: domain 1 has a β-l-rhamnosyltransferase activity, domain 2 has an α-l-rhamnosyltransferase activity, and domain 3 is a methyltransferase that decorates two positions in the terminal α-l-rhamnose (Rha) unit. The a075l gene encodes a β-xylosyltransferase that attaches the distal d-xylose (Xyl) unit to the l-fucose (Fuc) that is part of the conserved N-glycan core region. Last, gene a071r encodes a GT that is involved in the attachment of a semiconserved element, α-d-Rha, to the same l-Fuc in the core region. Our results uncover GT activities that assemble four of the nine residues of the PBCV-1 MCP N-glycans.


Entropy-mediated patterning of surfactant-coated nanoparticles and surfaces.
We perform atomistic and mesoscale simulations to explain the origin of experimentally observed stripelike patterns formed by immiscible ligands coadsorbed on the surfaces of gold and silver nanoparticles. We show that when the conformational entropy gained via this morphology is sufficient, microphase-separated stripelike patterns form. When the entropic gain is not sufficient, we instead predict bulk phase-separated Janus particles. We also show corroborating experimental results that confirm our simulational predictions that stripes form on flat surfaces as well as on curved nanoparticle surfaces.


Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease.
Peripheral infections in mammals are characterised by local, systemic and CNS effects. The latter give rise to sickness behaviour. Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) are thought to be important mediators of this neuro-immune signalling (Cartmell et al., 1999). There is anecdotal evidence suggesting that peripheral infections in patients with Alzheimer's disease have more severe behavioural consequences than those in otherwise healthy elderly subjects, and it is well known that brain microglia are activated in the elderly and in Alzheimer's disease (McGeer et al., 1987). Using ME7-induced murine prion disease as a model of chronic neurodegeneration that displays chronic microglial activation, and the intra-peritoneal injection of bacterial lipopolysaccharide to mimic a peripheral infection, we have shown that the temperature and activity responses of animals with pre-clinical prion disease were exaggerated compared with controls, and that this was associated with a significant increase in brain levels of IL-1beta. We hypothesise that prior priming of microglia by the degenerative process, followed by further activation through signalling from the periphery, resulted in increased brain IL-1beta synthesis and the consequent acute sickness behavioural responses. These findings demonstrate an interaction between peripheral infection and pre-existing CNS inflammation and suggest that further stimulation of an already primed microglial population by a peripheral infection may drive disease progression in chronic inflammatory conditions such as Alzheimer's disease and prion disease.


Grid cells on steeply sloping terrain: evidence for planar rather than volumetric encoding.
Neural encoding of navigable space involves a network of structures centered on the hippocampus, whose neurons -place cells - encode current location. Input to the place cells includes afferents from the entorhinal cortex, which contains grid cells. These are neurons expressing spatially localized activity patches, or firing fields, that are evenly spaced across the floor in a hexagonal close-packed array called a grid. It is thought that grids function to enable the calculation of distances. The question arises as to whether this odometry process operates in three dimensions, and so we queried whether grids permeate three-dimensional (3D) space - that is, form a lattice - or whether they simply follow the environment surface. If grids form a 3D lattice then this lattice would ordinarily be aligned horizontally (to explain the usual hexagonal pattern observed). A tilted floor would transect several layers of this putative lattice, resulting in interruption of the hexagonal pattern. We model this prediction with simulated grid lattices, and show that the firing of a grid cell on a 40°-tilted surface should cover proportionally less of the surface, with smaller field size, fewer fields, and reduced hexagonal symmetry. However, recording of real grid cells as animals foraged on a 40°-tilted surface found that firing of grid cells was almost indistinguishable, in pattern or rate, from that on the horizontal surface, with if anything increased coverage and field number, and preserved field size. It thus appears unlikely that the sloping surface transected a lattice. However, grid cells on the slope displayed slightly degraded firing patterns, with reduced coherence and slightly reduced symmetry. These findings collectively suggest that the grid cell component of the metric representation of space is not fixed in absolute 3D space but is influenced both by the surface the animal is on and by the relationship of this surface to the horizontal, supporting the hypothesis that the neural map of space is "multi-planar" rather than fully volumetric.


Expression of the fgr protooncogene product as a function of myelomonocytic cell maturation.
The fgr protooncogene is a member of the src family of protein tyrosine kinases. Recent studies have shown that normal myelomonocytic cells and tissue macrophages are the major sites of fgr mRNA expression. In the present study, we have identified the fgr protooncogene protein product in HL60 cells and have examined its expression as a function of HL60 cell maturation. Whether induced toward monocytic or granulocytic lineages, p55c-fgr accumulated in HL60 cells during maturation. In differentiated cells, the protein was active as a protein tyrosine kinase and was localized to peripheral cell membranes. Demonstration that a myristyl group was covalently bound to the protein probably accounted for its subcellular distribution. These findings establish developmental regulation of p55c-fgr in a lineage that represents its natural site of expression.


Enhancing biodegradation and energy generation via roughened surface graphite electrode in microbial desalination cell.
The microbial desalination cell (MDC) is known as a newly developed technology for water and wastewater treatment. In this study, desalination rate, organic matter removal and energy production in the reactors with and without desalination function were compared. Herein, a new design of plain graphite called roughened surface graphite (RSG) was used as the anode electrode in both microbial fuel cell (MFC) and MDC reactors for the first time. Among the three type of anode electrodes investigated in this study, RSG electrode produced the highest power density and salt removal rate of 10.81 W/m3 and 77.6%, respectively. Such a power density was 2.33 times higher than the MFC reactor due to the junction potential effect. In addition, adding the desalination function to the MFC reactor enhanced columbic efficiency from 21.8 to 31.4%. These results provided a proof-of-concept that the use of MDC instead of MFC would improve wastewater treatment efficiency and power generation, with an added benefit of water desalination. Furthermore, RSG can successfully be employed in an MDC or MFC, enhancing the bio-electricity generation and salt removal.


Facile Synthesis of Three-Dimensional Sandwiched MnO2@GCs@MnO2 Hybrid Nanostructured Electrode for Electrochemical Capacitors.
Designable control over the morphology and structure of active materials is highly desirable for achieving high-performance devices. Here, we develop a facile microwave-assisted synthesis to decorate MnO2 nanocrystals on three-dimensional (3D) graphite-like capsules (GCs) to obtain sandwich nanostructures (3D MnO2@GCs@MnO2) as electrode materials for electrochemical capacitors (ECs). A templated growth of the 3D GCs was carried out via catalytic chemical vapor deposition and MnO2 was decorated on the exterior and interior surfaces of the GC walls through microwave irradiation to build an engineered architecture with robust structural and morphological stability. The unique sandwiched architecture has a large interfacial surface area, and allows for rapid electrolyte diffusion through its hollow/open framework and fast electronic motion via the carbon backbone. Furthermore, the tough and rigid nature of GCs provides the necessary structural stability, and the strong synergy between MnO2 and GCs leads to high electrochemical activity in both neutral (265.1 F/g at 0.5 A/g) and alkaline (390 F/g at 0.5 A/g) electrolytes. The developed hybrid exhibits stable capacitance up to 6000 cycles in 1 M Na2SO4. The hybrid is a potential candidate for future ECs and the present study opens up an effective avenue to design hybrid materials for various applications.


Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms.
There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the β-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.


A curriculum model for an integrated senior year clinical experience.
Transformations in the delivery of health care from hospital to community have brought about many changes in nursing practice. These, in turn, have necessitated alterations in the education of nursing students, the curricula, and clinical experiences. Confident that nursing is an independent practice, exclusive of the health care setting, our faculty decided to direct our teaching efforts to reflect changes in health care delivery. We restructured our baccalaureate nursing program's senior level clinical education experience to prepare students to meet the needs of the clients we serve--the community--and the demands of professional nursing education. In doing so, we have supported Ryan's definition of community, which includes "all settings where consumers seek health care" (1, p. 140). In response to the recommendation by the pew health professions commission for new models of content integration "between education and the highly managed and integrated systems of care" (2, p. 51), a decision was made to merge three senior level clinical courses--pediatrics, public health, and nursing leadership and management--into one integrated experience. This process required an examination of collective values and beliefs with respect to course content and learning experiences. The challenge was to examine "sacred cows" and eliminate redundancies and replication of learning activities.


A Business Analytics Framework for Primary Care.
In this paper, we present a Business Analytics (BA) framework, which addresses the challenge of analysing primary care outcomes for both patients and clinicians from multiple data sources in an accurate manner. A review of the process monitoring literature has been conducted in the context of healthcare management and decision making and its findings have informed the formulation of a BA conceptual framework for process monitoring and decision support in primary care. Furthermore, a real case study is conducted to demonstrate the application of the BA framework to implement a BA dashboard tool within one of the largest primary care providers in England. Findings: The main contributions of the presented work are the development of a conceptual BA framework and a BA dashboard tool to support management and decision making in primary care. This was evaluated through a case study of the implementation of the BA dashboard tool in London's largest primary care provider. This BA tool provides real-time information to enable simpler decision-making processes and to inform business transformation in a number of areas. The resulting increased efficiency has led to significant cost savings and improved delivery of patient care.


Abnormalities in thyroid function tests in patients admitted to medical service.
Serum thyroid hormone, thyrotropin (TSH) and thyroxine-binding globulin (TBG) concentrations, free thyroxine index values, and free thyroxine concentrations were measured at the time of admission in all 77 patients hospitalized on a medical service on four separate days. Serum thyroxine (T4) concentrations and serum free T4 index values were decreased in 19.5% and 11.7%, respectively, and increased in 3.9% and 11.7%, respectively; serum free T4 concentrations were decreased in 6.8% and increased in 5.4%. Six patients (7.8%) had increased serum TSH concentrations. Serum triiodothyronine (T3) concentrations were decreased in 26.0% and reverse triiodothyronine (rT3) concentrations were increased in 29.9%. None had manifestations of thyroid disease. These results indicate that available thyroid function tests may give misleading results in patients with nonthyroid illness and suggest that caution be exercised in diagnosing thyroid disease in hospitalized patients.


Discover context-specific combinatorial transcription factor interactions by integrating diverse ChIP-Seq data sets.
Combinatorial interactions among transcription factors (TFs) are critical for integrating diverse intrinsic and extrinsic signals, fine-tuning regulatory output and increasing the robustness and plasticity of regulatory systems. Current knowledge about combinatorial regulation is rather limited due to the lack of suitable experimental technologies and bioinformatics tools. The rapid accumulation of ChIP-Seq data has provided genome-wide occupancy maps for a large number of TFs and chromatin modification marks for identifying enhancers without knowing individual TF binding sites. Integration of the two data types has not been researched extensively, resulting in underused data and missed opportunities. We describe a novel method for discovering frequent combinatorial occupancy patterns by multiple TFs at enhancers. Our method is based on probabilistic item set mining and takes into account uncertainty in both types of ChIP-Seq data. By joint analysis of 108 TFs in four human cell types, we found that cell-type-specific interactions among TFs are abundant and that the majority of enhancers have flexible architecture. We show that several families of transposable elements disproportionally overlap with enhancers with combinatorial patterns, suggesting that these transposable element families play an important role in the evolution of combinatorial regulation.


Effects of lung inflation on nasal airway resistance in the anesthetized rat.
Nasal airway resistance was assessed in halothane-anesthetized rats by measuring the transnasal pressure at constant airflow through both nasal cavities. Low inflation pressures (2.5-5 cmH2O) decreased nasal airway resistance, whereas higher inflation pressures (10-20 cmH2O) caused a biphasic response: an initial increase in resistance followed by a decrease in resistance. The nasal responses to all levels of inflation were completely abolished by hexamethonium, guanethidine, or bretylium pretreatment or cervical sympathectomy and greatly lessened by cervical vagotomy or phenoxybenzamine pretreatment. Atropine and propranolol pretreatments had no effect on the responses. These findings indicate that the nasal airway resistance is related to the level of inflation through pulmonary reflexes with afferents along the vagi and efferents via the alpha-adrenergic nervous system.


Temporary loss of perivascular aquaporin-4 in neocortex after transient middle cerebral artery occlusion in mice.
The aquaporin-4 (AQP4) pool in the perivascular astrocyte membranes has been shown to be critically involved in the formation and dissolution of brain edema. Cerebral edema is a major cause of morbidity and mortality in stroke. It is therefore essential to know whether the perivascular pool of AQP4 is up- or down-regulated after an ischemic insult, because such changes would determine the time course of edema formation. Here we demonstrate by quantitative immunogold cytochemistry that the ischemic striatum and neocortex show distinct patterns of AQP4 expression in the reperfusion phase after 90 min of middle cerebral artery occlusion. The striatal core displays a loss of perivascular AQP4 at 24 hr of reperfusion with no sign of subsequent recovery. The most affected part of the cortex also exhibits loss of perivascular AQP4. This loss is of magnitude similar to that of the striatal core, but it shows a partial recovery toward 72 hr of reperfusion. By freeze fracture we show that the loss of perivascular AQP4 is associated with the disappearance of the square lattices of particles that normally are distinct features of the perivascular astrocyte membrane. The cortical border zone differs from the central part of the ischemic lesion by showing no loss of perivascular AQP4 at 24 hr of reperfusion but rather a slight increase. These data indicate that the size of the AQP4 pool that controls the exchange of fluid between brain and blood during edema formation and dissolution is subject to large and region-specific changes in the reperfusion phase.


Nonbone marrow-derived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia.
Circulating progenitor cells home to sites of postnatal neovascularization and differentiate into endothelial cells but questions remain regarding the source of these cells. Indeed, a recent study suggests that nonbone marrow-derived cells may be even more important than bone marrow-derived cells in the setting of transplant arteriosclerosis. Thus, we aimed to thoroughly investigate the contribution of nonbone marrow-derived progenitor cells for neovascularization. We exclusively identified nonbone marrow-derived progenitor cells by combining a parabiosis model with reverse bone marrow transplantation followed by hindlimb ischemia. In this model, nonbone marrow-derived circulating progenitor cells attributed for 74+/-13% of the circulating progenitor cells that incorporated into the ischemic hindlimb. Increasing evidence suggests that organs such as small intestine and liver contain a considerable number of tissue resident progenitor cells and, thus, represent putative sources for nonbone marrow-derived progenitors. To track organ-derived progenitors, we transplanted sex-mismatched small intestine or liver, respectively, into rats followed by induction of hindlimb ischemia. These experiments show that organ-derived progenitor cells are contributing to postnatal vasculogenesis (intestine: 4.7+/-3.7%; liver: 6.3+/-2.2%). Based on the subsequent observation that liver-derived nonhematopoietic c-kit(+)CD45(-) progenitors are mobilized on induction of hindlimb ischemia, we prospectively isolated and intravenously infused these progenitors from murine livers. The isolated cells demonstrated a marked capacity for enhancing neovascularization and restoring blood flow to the ischemic hindlimb (no cells: 26.4+/-4.8% of normal blood flow; c-kit(+)CD45(-) cells: 67.0+/-8.0% of normal flow; P<0.01). In conclusion, we find that nonbone marrow-derived c-kit(+)CD45(-) progenitors contribute to postnatal neovascularization to an extent that is similar to that of bone marrow-derived progenitor cells. Intestine and liver represent a rich source for mobilized tissue-residing progenitor cells.


Layer-by-layer thin film of reduced graphene oxide and gold nanoparticles as an effective sample plate in laser-induced desorption/ionization mass spectrometry.
This work demonstrated a simple platform for rapid and effective surface-assisted laser desorption/ionization time-of-flight mass spectrometry (SALDI-TOF MS) measurements based on the layer structure of reduced graphene oxide (rGO) and gold nanoparticles. A multi-layer thin film was fabricated by alternate layer-by-layer depositions of rGO and gold nanoparticles (LBL rGO/AuNP). The flat and clean two-dimensional film was served as the sample plate and also functioned as the matrix in SALDI-TOF MS. By simply one-step deposition of analytes onto the LBL rGO/AuNP sample plate, the MS measurements of various homogeneous samples were ready to execute. The optimization of MS signal was reached by the variation of the layer numbers of rGO and gold nanoparticles. Also, the small molecules including amino acids, carbohydrates and peptides were successfully analyzed in SALDI-TOF MS using the LBL rGO/AuNP sample plate. The results showed that the signal intensity, S N(-1) ratio and reproducibility of SALDI-TOF spectra have been significantly improved in comparison to the uses of gold nanoparticles or α-cyano-4-hydroxy-cinnamic acid (CHCA) as the assisted matrixes. Taking the advantages of the unique properties of rGO and gold nanoparticles, the ready-to-use MS sample plate, which could absorb and dissipate laser energy to analytes quite efficiently and homogeneously, has shown great commercial potentials for MS applications.


Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer's disease.
The factors driving clinical heterogeneity in Alzheimer's disease are not well understood. This study assessed the relationship between amyloid deposition, glucose metabolism and clinical phenotype in Alzheimer's disease, and investigated how these relate to the involvement of functional networks. The study included 17 patients with early-onset Alzheimer's disease (age at onset <65 years), 12 patients with logopenic variant primary progressive aphasia and 13 patients with posterior cortical atrophy [whole Alzheimer's disease group: age = 61.5 years (standard deviation 6.5 years), 55% male]. Thirty healthy control subjects [age = 70.8 (3.3) years, 47% male] were also included. Subjects underwent positron emission tomography with (11)C-labelled Pittsburgh compound B and (18)F-labelled fluorodeoxyglucose. All patients met National Institute on Ageing-Alzheimer's Association criteria for probable Alzheimer's disease and showed evidence of amyloid deposition on (11)C-labelled Pittsburgh compound B positron emission tomography. We hypothesized that hypometabolism patterns would differ across variants, reflecting involvement of specific functional networks, whereas amyloid patterns would be diffuse and similar across variants. We tested these hypotheses using three complimentary approaches: (i) mass-univariate voxel-wise group comparison of (18)F-labelled fluorodeoxyglucose and (11)C-labelled Pittsburgh compound B; (ii) generation of covariance maps across all subjects with Alzheimer's disease from seed regions of interest specifically atrophied in each variant, and comparison of these maps to functional network templates; and (iii) extraction of (11)C-labelled Pittsburgh compound B and (18)F-labelled fluorodeoxyglucose values from functional network templates. Alzheimer's disease clinical groups showed syndrome-specific (18)F-labelled fluorodeoxyglucose patterns, with greater parieto-occipital involvement in posterior cortical atrophy, and asymmetric involvement of left temporoparietal regions in logopenic variant primary progressive aphasia. In contrast, all Alzheimer's disease variants showed diffuse patterns of (11)C-labelled Pittsburgh compound B binding, with posterior cortical atrophy additionally showing elevated uptake in occipital cortex compared with early-onset Alzheimer's disease. The seed region of interest covariance analysis revealed distinct (18)F-labelled fluorodeoxyglucose correlation patterns that greatly overlapped with the right executive-control network for the early-onset Alzheimer's disease region of interest, the left language network for the logopenic variant primary progressive aphasia region of interest, and the higher visual network for the posterior cortical atrophy region of interest. In contrast, (11)C-labelled Pittsburgh compound B covariance maps for each region of interest were diffuse. Finally, (18)F-labelled fluorodeoxyglucose was similarly reduced in all Alzheimer's disease variants in the dorsal and left ventral default mode network, whereas significant differences were found in the right ventral default mode, right executive-control (both lower in early-onset Alzheimer's disease and posterior cortical atrophy than logopenic variant primary progressive aphasia) and higher-order visual network (lower in posterior cortical atrophy than in early-onset Alzheimer's disease and logopenic variant primary progressive aphasia), with a trend towards lower (18)F-labelled fluorodeoxyglucose also found in the left language network in logopenic variant primary progressive aphasia. There were no differences in (11)C-labelled Pittsburgh compound B binding between syndromes in any of the networks. Our data suggest that Alzheimer's disease syndromes are associated with degeneration of specific functional networks, and that fibrillar amyloid-β deposition explains at most a small amount of the clinico-anatomic heterogeneity in Alzheimer's disease.


Natural Product Potential of the Genus Nocardiopsis.
Actinomycetes are a relevant source of novel bioactive compounds. One of the pharmaceutically and biotechnologically important genera that attract natural products research is the genus Nocardiopsis, mainly for its ability to produce a wide variety of secondary metabolites accounting for its wide range of biological activities. This review covers the literature from January 2015 until February 2018 making a complete survey of all the compounds that were isolated from the genus Nocardiopsis, their biological activities, and natural sources, whenever applicable.


Cytosolic Ca2+ oscillations in REF52 fibroblasts: Ca(2+)-stimulated IP3 production or voltage-dependent Ca2+ channels as key positive feedback elements.
Oscillations in cytosolic free calcium concentrations ([Ca2+]i) can be elicited in REF52 fibroblasts by three different modes of stimulation. We have previously demonstrated that [Ca2+]i oscillations result when these cells are simultaneously depolarized and stimulated with a hormone linked to phosphoinositide breakdown. Further evidence is now presented that such oscillations are linked to fluctuations in the concentration of IP3 and the Ca2+ content of an IP3-sensitive Ca2+ store. [Ca2+]i oscillations can also be generated in REF52 cells either by direct stimulation of G-proteins with GTP gamma S or AlF4- or by destabilizing the membrane potential and opening voltage-dependent calcium channels. This report compares the different types of oscillations and their mechanisms.


Meningeal carcinomatosis from solid tumors: clinical analysis of 42 cases.
From January 1984 to June 1990, we observed 42 patients with meningeal carcinomatosis, 20 men and 22 women, aged 21 to 80 years (median age, 53 years). The two most common primary malignancies were lung cancer (50%) and breast cancer (31%). Sixty-four per cent was adenocarcinoma. On the first lumbar puncture, 86% had malignant cells in the cerebrospinal fluid. The findings of brain computed tomography were hydrocephalus (62%), contrast enhancement in the cerebral sulci or basal cisterns (31%), concomitant parenchymal metastases (15%) and normal scan (18%). In five out of seven cases, myelography showed irregular filling defects over the spinal cord or cauda equina. Treatment results were evaluated in 24 patients. Eight received radiation therapy (RT) alone, and 16 had combined therapy with RT plus intrathecal methotrexate (IT MTX). Of the patients who received RT alone, only one patient with lung carcinoma was stabilized clinically. Of the cases receiving combined therapy, seven improved clinically. Six of these were patients with breast carcinoma who received IT MTX via Ommaya reservoir. The latter had a median survival of 23 weeks. The follow-up period of the entire group of patients ranged from one day to 50 weeks. The median survival was four weeks. Based on this study, combined therapy with RT and IT MTX is indicated for breast carcinoma with meningeal carcinomatosis, but the therapeutic effects are uncertain for lung carcinoma and other malignancies.


A Systems Approach Implicates a Brain Mitochondrial Oxidative Homeostasis Co-expression Network in Genetic Vulnerability to Alcohol Withdrawal.
Genetic factors significantly affect vulnerability to alcohol dependence (alcoholism). We previously identified quantitative trait loci on distal mouse chromosome 1 with large effects on predisposition to alcohol physiological dependence and associated withdrawal following both chronic and acute alcohol exposure in mice (Alcdp1 and Alcw1, respectively). We fine-mapped these loci to a 1.1-1.7 Mb interval syntenic with human 1q23.2-23.3. Alcw1/Alcdp1 interval genes show remarkable genetic variation among mice derived from the C57BL/6J and DBA/2J strains, the two most widely studied genetic animal models for alcohol-related traits. Here, we report the creation of a novel recombinant Alcw1/Alcdp1 congenic model (R2) in which the Alcw1/Alcdp1 interval from a donor C57BL/6J strain is introgressed onto a uniform, inbred DBA/2J genetic background. As expected, R2 mice demonstrate significantly less severe alcohol withdrawal compared to wild-type littermates. Additionally, comparing R2 and background strain animals, as well as reciprocal congenic (R8) and appropriate background strain animals, we assessed Alcw1/Alcdp1 dependent brain gene expression using microarray and quantitative PCR analyses. To our knowledge this includes the first Weighted Gene Co-expression Network Analysis using reciprocal congenic models. Importantly, this allows detection of co-expression patterns limited to one or common to both genetic backgrounds with high or low predisposition to alcohol withdrawal severity. The gene expression patterns (modules) in common contain genes related to oxidative phosphorylation, building upon human and animal model studies that implicate involvement of oxidative phosphorylation in alcohol use disorders (AUDs). Finally, we demonstrate that administration of N-acetylcysteine, an FDA-approved antioxidant, significantly reduces symptoms of alcohol withdrawal (convulsions) in mice, thus validating a phenotypic role for this network. Taken together, these studies support the importance of mitochondrial oxidative homeostasis in alcohol withdrawal and identify this network as a valuable therapeutic target in human AUDs.


Evaluating driver drowsiness countermeasures.
Driver drowsiness contributes to a substantial number of fatal and nonfatal crashes, with recent estimates attributing up to 21% of fatal crashes to drowsiness. This article describes recent NHTSA research on in-vehicle drowsiness countermeasures. Recent advances in technology and state detection algorithms have shown success in detecting drowsiness using a variety of data sources, including camera-based eye tracking, steering wheel position, yaw rate, and vehicle lane position. However, detection is just the first step in reducing drowsy driving crashes. Countermeasures are also needed to provide feedback to the driver, modify driver behavior, and prevent crashes. The goal of this study was to evaluate the effectiveness of in-vehicle drowsiness countermeasures in reducing drowsy lane departures. The tested countermeasures included different warning modalities in either a discrete or staged interface. Data were collected from 72 young adult drivers (age 21-32) in the high-fidelity full-motion National Advanced Driving Simulator. Drivers completed a 45-min simulated nighttime drive at 2 time points, late night and early morning, where drowsiness was manipulated by continuous hours awake. Forty-eight drivers were exposed to one of 6 countermeasures that varied along 2 dimensions, type and modality. The countermeasures relied on a steering-based drowsiness detection algorithm developed in prior NHTSA research. Twenty-four drivers received no countermeasure and were used as a baseline comparison. System effectiveness was measured by lane departures and standard deviation in lateral position (SDLP). There was a reduction in drowsy lane departure frequency and lane position variability for drivers with countermeasures compared to the baseline no-countermeasure group. Importantly, the data suggest that multistage alerts, which provide an indication of increasing urgency, were more effective in reducing drowsy lane departures than single-stage discrete alerts, particularly during early morning drives when drivers were drowsier. The results indicate that simple in-vehicle countermeasures, such as an auditory-visual coffee cup icon, can reduce the frequency of drowsy lane departures in the context of relatively short drives. An important next step is to evaluate the impact of drowsiness countermeasures in the context of longer, multiple-hour drives. In these cases, it may not be possible to keep drivers awake via feedback warnings and it is important to understand whether countermeasures prompt drivers to stop to rest. The next phase of this research project will examine the role of drowsiness countermeasures over longer drives using a protocol that replicates the motivational conditions of drowsy driving.


A structural variation reference for medical and population genetics.
Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.


Testing systems for assessment of negative symptoms in schizophrenia.
To compare methods of measuring negative symptoms, eight rating scales were employed to retrospectively assess and subtype 187 patients with schizophrenia from the Chestnut Lodge Follow-up Study. These included Andreasen's Schedule for Assessment of Negative Symptoms, Carpenter's Criteria for the Deficit Syndrome, Kay and Opler's Positive and Negative Symptom Scale, the scales developed by Krawiecka et al and Crow's modification of them, the Negative Symptom Scale developed by Lewine et al, Pogue-Geile and Harrow's Negative Symptom Scale, and Abrams and Taylor's Emotional Blunting Scale. The overlap and concordance, temporal stability, and predictive validity of these instruments are described. When rated from detailed medical records, the reliability of all scales was fair to good. Despite their inclusion of different items, there were high positive correlations between the scales when used to rate negative symptoms dimensionally. When used to classify individual patients as having the negative or deficit syndrome, however, concordance among criteria was low. Using the broadest criteria (Pogue-Geile and Harrow), 75 (40%) patients were diagnosed as having negative syndrome; the narrowest criteria (Andreasen and Olsen) yielded 11 (6%) diagnoses of negative syndrome. Narrower definitions tended to be subsets of broader ones. Carpenter's Criteria for the Deficit Syndrome focus on primary enduring negative symptoms and show the greatest temporal stability. Broader criteria, which diagnose the deficit or negative syndrome independent of severity of positive symptoms, had the greatest predictive validity.


Rice cytochrome P450 MAX1 homologs catalyze distinct steps in strigolactone biosynthesis.
Strigolactones (SLs) are a class of phytohormones and rhizosphere signaling compounds with high structural diversity. Three enzymes, carotenoid isomerase DWARF27 and carotenoid cleavage dioxygenases CCD7 and CCD8, were previously shown to convert all-trans-β-carotene to carlactone (CL), the SL precursor. However, how CL is metabolized to SLs has remained elusive. Here, by reconstituting the SL biosynthetic pathway in Nicotiana benthamiana, we show that a rice homolog of Arabidopsis More Axillary Growth 1 (MAX1), encodes a cytochrome P450 CYP711 subfamily member that acts as a CL oxidase to stereoselectively convert CL into ent-2'-epi-5-deoxystrigol (B-C lactone ring formation), the presumed precursor of rice SLs. A protein encoded by a second rice MAX1 homolog then catalyzes the conversion of ent-2'-epi-5-deoxystrigol to orobanchol. We therefore report that two members of CYP711 enzymes can catalyze two distinct steps in SL biosynthesis, identifying the first enzymes involved in B-C ring closure and a subsequent structural diversification step of SLs.


Proteomic investigation of interhyphal interactions between strains of Agaricus bisporus.
Hyphae of filamentous fungi undergo polar extension, bifurcation and hyphal fusion to form reticulating networks of mycelia. Hyphal fusion or anastomosis, a ubiquitous process among filamentous fungi, is a vital strategy for how fungi expand over their substrate and interact with or recognise self- and non-self hyphae of neighbouring mycelia in their environment. Morphological and genetic characterisation of anastomosis has been studied in many model fungal species, but little is known of the direct proteomic response of two interacting fungal isolates. Agaricus bisporus, the most widely cultivated edible mushroom crop worldwide, was used as an in vitro model to profile the proteomes of interacting cultures. The globally cultivated strain (A15) was paired with two distinct strains; a commercial hybrid strain and a wild isolate strain. Each co-culture presented a different interaction ranging from complete vegetative compatibility (self), lack of interactions, and antagonistic interactions. These incompatible strains are the focus of research into disease-resistance in commercial crops as the spread of intracellular pathogens, namely mycoviruses, is limited by the lack of interhyphal anastomosis. Unique proteomic responses were detected between all co-cultures. An array of cell wall modifying enzymes, plus fungal growth and morphogenesis proteins were found in significantly (P < 0.05) altered abundances. Nitrogen metabolism dominated in the intracellular proteome, with evidence of nitrogen starvation between competing, non-compatible cultures. Changes in key enzymes of A. bisporus morphogenesis were observed, particularly via increased abundance of glucanosyltransferase in competing interactions and certain chitinases in vegetative compatible interactions only. Carbohydrate-active enzyme arsenals are expanded in antagonistic interactions in A. bisporus. Pathways involved in carbohydrate metabolism and genetic information processing were higher in interacting cultures, most notably during self-recognition. New insights into the differential response of interacting strains of A. bisporus will enhance our understanding of potential barriers to viral transmission through vegetative incompatibility. Our results suggest that a differential proteomic response occurs between A. bisporus at strain-level and findings from this work may guide future proteomic investigation of fungal anastomosis.


The incidence and risk of developing a second primary esophageal cancer in patients with oral and pharyngeal carcinoma: a population-based study in Taiwan over a 25 year period.
The incidence of oral and pharyngeal (including oral cavity, oropharynx and hypopharynx) carcinoma increases rapidly in Asia and South Pacific because of betel quid chewing. Thus far, large-scale epidemiological studies are not available yet to stratify these patients by their risks of developing a second primary cancer in the digestive tract including esophagus, stomach, colon, and rectum. A population-based study was conducted using the database from the Taiwan National Cancer Registry for the period 1979-2003. We quantified standardized incidence ratios (SIRs) and cumulative incidence of second primary cancers among 33,787 patients with initial diagnoses of oral and pharyngeal carcinoma. Among these four digestive tract organs, the esophagus was the only site of second cancer with excess risk in patients with oral and pharyngeal carcinoma. The incidence and risk of developing a second primary esophageal cancer differed by the site of the primary index tumor, most frequently seen in hypopharyngeal cancer (71/4,218 = 1.68%, SIR = 22.76, 95% CI 17.77-28.70), followed by oropharyngeal cancer (30/3,403 = 0.88%, SIR = 14.29, 95% CI 9.64-20.39) and the least in oral cavity cancer (99/26,166 = 0.38%, SIR = 5.57, 95% CI 4.53-6.78). In addition, the risk was extraordinarily high for patients with a follow-up interval <or= 1 year and those with first primary cancer diagnosed at age <or=50. These patients may justify more close surveillance. The present study represents the first population-based study in Asia attempting to stratify the patients of oral and pharyngeal carcinoma by their risk of developing a second esophageal cancer. It helps identify patients at high risk and tailor the application of intense follow-up surveillance to the estimated risk in each individual case.


Autoimmune Hepatitis: a Review of Established and Evolving Treatments.
Autoimmune hepatitis (AIH) is a necroinflammatory liver disease commonly presenting with a fluctuating course of activity, presence of circulating autoantibodies, hyperglobulinemia of IgG, and/or response to immunosuppressive drugs. However, the disease displays a considerable heterogeneity. No single clinical or biochemical test may establish diagnosis of AIH. Thus, diagnosis still requires extensive clinical evaluation and experience. Prednisolone and azathioprine are considered standard treatment leading to remission in most patients. However, this standard treatment may not be effective in some patients or not be feasible due to one of these drugs. Over the past two decades additional immunosuppressant drugs for the treatment of AIH have been evaluated and have significantly extended the therapeutic spectrum. Among those novel drugs are mycophenolate mofetil, tacrolimus, everolimus, 6-mercaptopurine, infliximab, rituximab and several others. In this review we summarize the current standard of therapy but also efforts of providing novel therapeutic strategies to AIH patients.


Image speckle contrast reduction resulting from integrative synthetic aperture imaging.
Reduction of image speckle noise with the use of an integrative synthetic aperture imaging technique is studied. It is found that the Fourier inversion of the mutual intensity estimate [Appl. Opt. 30, 206-213 (1991)] yields an image intensity that corresponds exactly to the illumination of the object with partially coherent light from source optics imaging a delta-function incoherent source. An expression for the signal-to-noise ratio at an image point is derived for a large rough object with delta-function correlated amplitude reflection. A synthetic aperture system receiver of sufficiently small diameter yields image speckle with a signal-to-noise ratio (SNR) equal to 1. When the receiver and the transmitter diameters are equal, the SNR is 2 for linearly polarized speckle. The SNR continues to increase with receiver size and is linear in the diameter for large receiver-to-transmitter diameter ratios.


Father-child transmission of school adjustment: a prospective intergenerational study.
The intergenerational transmission of school adjustment was explored in a sample of 213 children and their fathers. The fathers were participants in a longitudinal study that began when they were in the 4th grade, and their children have been assessed at the ages of 21 months and 3, 5, and 7 years. Two components of school adjustment were measured: academic achievement and peer relations. Results show that the fathers' academic achievement and peer relations were directly related to the same factors in their offspring even when the fathers' educational attainment, and both the fathers' and the children's general cognitive abilities were included in the models. When potential mechanisms of intergenerational transmission were examined, father's age at the birth of the child, income, and educational expectations for the child were links in the transmission of academic achievement from one generation to the next. For peer relations across generations, income, inconsistent parenting, and educational expectations were links in transmission. Implications of these findings are considered, including the possibility that interventions to improve school adjustment in one generation might have significant and long-reaching effects for the next.


Cross-fostering eggs reveals that female collared flycatchers adjust clutch sex ratios according to parental ability to invest in offspring.
Across animal taxa, reproductive success is generally more variable and more strongly dependent upon body condition for males than for females; in such cases, parents able to produce offspring in above-average condition are predicted to produce sons, whereas parents unable to produce offspring in good condition should produce daughters. We tested this hypothesis in the collared flycatcher (Ficedula albicollis) by cross-fostering eggs among nests and using the condition of foster young that parents raised to fledging as a functional measure of their ability to produce fit offspring. As predicted, females raising heavier-than-average foster fledglings with their social mate initially produced male-biased primary sex ratios, whereas those raising lighter-than-average foster fledglings produced female-biased primary sex ratios. Females also produced male-biased clutches when mated to males with large secondary sexual characters (wing patches), and tended to produce male-biased clutches earlier within breeding seasons relative to females breeding later. However, females did not adjust the sex of individuals within their clutches; sex was distributed randomly with respect to egg size, laying order and paternity. Future research investigating the proximate mechanisms linking ecological contexts and the quality of offspring parents are able to produce with primary sex-ratio variation could provide fundamental insight into the evolution of context-dependent sex-ratio adjustment.


Medical practice in the ancient Asclepeion in Kos island.
Asclepius was called "a great doctor for every disease". Asclepius was born in Trikala, Thessaly, in the middle of Greece, where the first Asclepeion was established. Patients coming to the Asclepeia were first taking cleaning baths and then entered the main Asclepeion, where they were examined by priests-therapists and were accommodated in certain areas-rooms of the Asclepeion. Inscriptions found in marble plaques describe treatment of some diseases and the sum of money paid for every treatment. These were the first medical records and fees in ancient Greece. Patients were considered as a unique psychosomatic entity. Patients followed many instructions in order to relax and rest, submitted daily baths, exercises, massages, entertainment attending theatrical or poetic or athletic races, reading special books, promenades, special diets or were kept fasting and were instructed to take many kinds of medicine per os, suppositories, ointments, eye drops etc. The main diseases treated in the Asclepeia were: chronic neuropsychological disorders, skin diseases and chronic lung diseases. Other diseases gynaecological, ophthalmic and surgical were also treated. Today, like in the ancient Asclepeia, the psychology of patients is important and certain preparatory drugs are administered before the actual main treatment of surgery or of some psychic disorders. In Aalborg, Denmark, a large prototype medical university hospital, is scheduled to be built in an area of 350acres within the next 15 years. The psychosomatic dogma and principals of a "green building" will be well respected. The Asclepeion of the island of Kos, where as we know Hippocrates was born, was built on the 5th century B.C. and functioned till the 4th century A.D. and had three floors. The Asclepeion had many dedications, of which many parts of the human body in marble: an ear, a damaged penis and two breasts. Surgical tools were also found and are now exhibited in the Dion Museum. After the 4th century A.D. the Asclepeion was destructed and/or destroyed by religious groups, more earthquakes, conflagrations, the Saint John's Knights of Jerusalem and the Turks. Recent excavations in the area in order to find and restore the old Asclepeion started in 1902. Now Asclepeion is partly restored. In conclusion, it is suggested that Hippocratic medicine, as practiced in the Asclepeion of the island of Kos, using psychosomatic means of treatment in a green natural environment was effective for many diseases at that time but also inspired modern medicine and as an example a large university institution is now under constructions based on the above ideals.


Analysis of the Effect of Intestinal Ischemia and Reperfusion on the Rat Neutrophils Proteome.
Intestinal ischemia and reperfusion injury is a model system of possible consequences of severe trauma and surgery, which might result into tissue dysfunction and organ failure. Neutrophils contribute to the injuries preceded by ischemia and reperfusion. However, the mechanisms by which intestinal ischemia and reperfusion stimulate and activate circulating neutrophils is still not clear. In this work, we used proteomics approach to explore the underlying regulated mechanisms in Wistar rat neutrophils after ischemia and reperfusion. We isolated neutrophils from three different biological groups; control, sham laparotomy, and intestinal ischemia/reperfusion. In the workflow, we included iTRAQ-labeling quantification and peptide fractionation using HILIC prior to LC-MS/MS analysis. From proteomic analysis, we identified 2,045 proteins in total that were grouped into five different clusters based on their regulation trend between the experimental groups. A total of 417 proteins were found as significantly regulated in at least one of the analyzed conditions. Interestingly, the enzyme prediction analysis revealed that ischemia/reperfusion significantly reduced the relative abundance of most of the antioxidant and pro-survival molecules to cause more tissue damage and ROS production whereas some of the significantly up regulated enzymes were involved in cytoskeletal rearrangement, adhesion and migration. Clusters based KEGG pathways analysis revealed high motility, phagocytosis, directional migration, and activation of the cytoskeletal machinery in neutrophils after ischemia and reperfusion. Increased ROS production and decreased phagocytosis were experimentally validated by microscopy assays. Taken together, our findings provide a characterization of the rat neutrophil response to intestinal ischemia and reperfusion and the possible mechanisms involved in the tissue injury by neutrophils after intestinal ischemia and reperfusion.