Anesthetic management and surgical site infections in total hip or knee replacement: a population-based study.
Epidural or spinal anesthesia involves several mechanisms hypothesized to reduce risk of surgical site infections (SSIs) during this decisive period. This study aims to compare the risk of SSI within 30 days of surgery for patients receiving total hip or knee replacement under general anesthesia versus those under epidural or spinal anesthesia. We used the Longitudinal Health Insurance Database of Taiwan. A total of 3,081 patients who underwent primary total hip or knee replacement from 2002 to 2006 were included in the study. Multivariate logistic regression and propensity score analyses were carried out to explore the relationship between method of surgical anesthesia and SSI occurring within 30 days of surgery. Of the 3,081 sampled patients, 56 patients (1.8%) had 30-day SSIs; 33 (2.8% of all under general anesthesia) of them had general anesthesia, and 23 (1.2% of all under epidural or spinal anesthesia) had epidural or spinal anesthesia (P = 0.002). The odds of SSI for patients receiving total hip or knee replacement under general anesthesia were 2.21 (95% CI = 1.25-3.90, P = 0.007) times higher than those who had the same procedure under epidural or spinal anesthesia, after adjusting for the patient's age, sex, the year of surgery, comorbidities, surgeon's age, and hospital teaching status. Total hip or knee replacement under general anesthesia is associated with higher risk of SSI compared with epidural or spinal anesthesia. Our results support the evolving concept of long-term consequences of anesthesia and emphasize the anesthesiologist's role in preventing SSIs.


A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb-polysyndactyly syndrome.
The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.


Homocitrullination of lysine residues mediated by myeloid-derived suppressor cells in the tumor environment is a target for cancer immunotherapy.
Homocitrullination is the post-translational modification of lysine that is recognized by T cells. This study identified homocitrullinated peptides from aldolase, enolase, cytokeratin and binding immunoglobulin protein and used human leukocyte antigen (HLA) transgenic mice to assess immunogenicity by enzyme-linked immunosorbent spot assay. Vaccine efficacy was assessed in tumor therapy studies using HLA-matched B16 melanoma expressing constitutive or interferon γ (IFNγ)-inducible major histocompatibility complex class II (MHC-II) as represented by most human tumors. To determine the mechanism behind the therapy, immune cell infiltrates were analyzed using flow cytometry and therapy studies in the presence of myeloperoxidase (MPO) inhibitor and T-cell depletion performed. We assessed the T-cell repertoire to homocitrullinated peptides in patients with cancer and healthy donors using flow cytometry. Homocitrulline (Hcit) peptide vaccination stimulated strong CD4 T-cell responses and induced significant antitumor therapy in an established tumor model. The antitumor response was dependent on CD4 T cells and the effect was driven mainly via direct tumor recognition, as responses were only observed if the tumors were induced to express MHC-II. In vitro proliferation assays show that healthy donors and patients with cancer have an oligoclonal CD4 T-cell repertoire recognizing homocitrullinated peptides. Inhibition of cyanate generation, which mediates homocitrullination, by MPO inhibition reduced tumor therapy by the vaccine induced T cells (p=0.0018). Analysis of the tumor microenvironment (TME) suggested that myeloid-derived suppressor cells (MDSCs) were a potential source of MPO. The selected B16 melanoma model showed MDSC infiltration and was appropriate to see if the Hcit vaccine could overcome the immunosuppression associated with MDSCs. The vaccine was very effective (90% survival) as the induced CD4 T cells directly targeted the homocitrullinated tumor and likely reversed the immunosuppressive environment. We propose that MPO, potentially produced by MDSCs, catalyzes the buildup of cyanate in the TME which diffuses into tumor cells causing homocitrullination of cytoplasmic proteins which are degraded and, in the presence of IFNγ, presented by MHC-II for direct CD4 T-cell recognition. Homocitrullinated proteins are a new target for cancer vaccines and may be particularly effective against tumors containing high levels of MPO expressing MDSCs.


Gap junctions in goldfish preoptic ependyma: regional variation in cellular differentiation.
Ependyma adjacent to the goldfish preoptic neurosecretory nucleus was examined with transmission electron microscopy. Ependymal cells adjoining the rostroventral end of the nucleus were spindle-shaped with their long axes perpendicular to the ventricular surface. Gap junctions and desmosomes were common near the apical (ventricular) ends of these cells, and less frequent laterally in the ependymal layer. Ependymal cells in more caudodorsal preoptic regions (adjacent to large neurosecretory cells) were progressively more pleomorphic. The frequent occurrence of apparently internalized gap junctions and of gap junction fragments enclosed within lysosome-like organelles indicated extensive turnover of these junctions, or uncoupling. Ependymal cells in the caudodorsal region formed gap junctions on their lateral and basal (abluminal) surfaces with glial processes containing bundles of intermediate filaments. Subependymally, these processes (presumptive radial glia) were parallel to one another and coupled together by gap junctions. Neurites containing dense core vesicles occasionally invaginated into ependymal cells in the caudal region, but did not appear to form gap junctions. Previous observations indicate continuing maturation and growth of the goldfish preoptic area with neurosecretory cell formation rostroventrally and a rostroventral to caudodorsal gradient of maturation. The present findings suggest a parallel and related gradient in preoptic ependyma. Ependymal cell differentiation possibly involves loss of gap junctions, and radial migration or differentiation into underlying neurons and glia.


Longitudinal monitoring of fetlock lesions in Thoroughbred racehorses using standing 18F-sodium fluoride positron emission tomography.
To assess the repeatability of equine 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) findings, and to evaluate the ability of PET to monitor the progression of areas of increased radiopharmaceutical uptake (IRU) in the fetlocks of Thoroughbred racehorses. 25 racehorses with clinical signs related to fetlock injuries. This study is a prospective, longitudinal clinical study. Twenty-five racehorses (54 fetlocks) underwent three 18F-NaF PET scans 6 weeks apart. The first 18F-NaF PET scan was performed at the start of a 12-week period of rest from racing (lay-up). Areas of IRU in the fetlock joints were quantified using maximal standardized uptake values (SUVmax) and were graded by 2 experienced observers. Statistical comparisons were made between scans to detect changes in IRU grade and SUVmax over time. Standing PET findings were repeatable, with 131/149 (88%) areas of IRU identified on the initial scans seen again at the 6-week follow-up scan. The palmar/plantar condyles were the sites most commonly presenting with IRU, followed by the proximal sesamoid bones. Overall, 65% of fetlocks demonstrated improvement in IRU grade during the 12-week period of rest from racing. Areas of higher IRU grade took longer to resolve than the lower graded areas. Standing PET findings in the racehorse fetlock were repeatable. The SUV-based grading system may be helpful when determining appropriate lay-up duration for Thoroughbred racehorses. PET may be used to monitor areas of the fetlock involved in catastrophic breakdown injuries in Thoroughbred racehorses.


Recent advances in the study of limb development: the emergence and function of the apical ectodermal ridge.
Vertebrate extremities develop from limb buds, which emerge as paired protrusions in the lateral plate mesoderm. Forelimb buds are located anteriorly and hindlimb buds are positioned posteriorly. The morphogenesis of the limb requires coordinated actions of several organizing centers, among which the apical ectodermal ridge (AER) plays crucial roles in limb development. Recent studies have shown how the life of the AER (induction, maturation, maintenance and regression) is regulated. This regulation includes cell type- and process- specific roles of previously identified molecules, such as fibroblast growth factors (FGFs), Wnts and bone morphogenetic proteins (BMPs). The studies have also revealed several new players, such as Arid3b, R-Spondin 2 and Flrt3. These advances have enhanced the understanding of how the AER is regulated from its emergence to its regression. Progress has also been made in understanding AER function in relation to processes critical for limb development: proximal-distal patterning, anterior-posterior patterning, chondrogenesis and apoptosis. By focusing on two major model systems, chick and mouse embryos, we will review recent advances in combination with relevant previous studies in the development and function of the AER.


Novel oxytocin gene expression in the hindbrain is induced by alcohol exposure: transgenic zebrafish enable visualization of sensitive neurons.
Fetal Alcohol Spectrum Disorders (FASD) are a collection of disorders resulting from fetal ethanol exposure, which causes a wide range of physical, neurological and behavioral deficits including heightened susceptibility for alcoholism and addictive disorders. While a number of mechanisms have been proposed for how ethanol exposure disrupts brain development, with selective groups of neurons undergoing reduced proliferation, dysfunction and death, the induction of a new neurotransmitter phenotype by ethanol exposure has not yet been reported. The effects of embryonic and larval ethanol exposure on brain development were visually monitored using transgenic zebrafish expressing cell-specific green fluorescent protein (GFP) marker genes. Specific subsets of GFP-expressing neurons were highly sensitive to ethanol exposure, but only during defined developmental windows. In the med12 mutant, which affects the Mediator co-activator complex component Med12, exposure to lower concentrations of ethanol was sufficient to reduce GFP expression in transgenic embryos. In transgenic embryos and larva containing GFP driven by an oxytocin-like (oxtl) promoter, ethanol exposure dramatically up-regulated GFP expression in a small group of hindbrain neurons, while having no effect on expression in the neuroendocrine preoptic area. Alcohol exposure during limited embryonic periods impedes the development of specific, identifiable groups of neurons, and the med12 mutation sensitizes these neurons to the deleterious effects of ethanol. In contrast, ethanol exposure induces oxtl expression in the hindbrain, a finding with profound implications for understanding alcoholism and other addictive disorders.


The LIM domain only 4 protein is a metabolic responsive inhibitor of protein tyrosine phosphatase 1B that controls hypothalamic leptin signaling.
Protein tyrosine phosphatase 1B (PTP1B) counteracts leptin signaling and is a therapeutic target for obesity and diabetes. Here we found that LIM domain only 4 (LMO4) inhibits PTP1B activity by increasing the oxidized inactive form of PTP1B. Mice with neuronal ablation of LMO4 have elevated PTP1B activity and impaired hypothalamic leptin signaling, and a PTP1B inhibitor normalized PTP1B activity and restored leptin control of circulating insulin levels. LMO4 is palmitoylated at its C-terminal cysteine, and deletion of this residue prevented palmitoylation and retention of LMO4 at the endoplasmic reticulum and abolished its inhibitory effect on PTP1B. Importantly, LMO4 palmitoylation is sensitive to metabolic stress; mice challenged with a brief high-fat diet or acute intracerebroventricular infusion of saturated fatty acid had less palmitoylated LMO4, less oxidized PTP1B, and increased PTP1B activity in the hypothalamus. Thus, unleashed PTP1B activity attributable to loss of LMO4 palmitoylation may account for rapid loss of central leptin signaling after acute exposure to saturated fat.


Impact of sleep disorder treatment on fatigue in multiple sclerosis.
We recently reported that sleep disorders are significantly associated with fatigue in multiple sclerosis (MS). The objective of this paper is to assess the effects of sleep disorder treatment on fatigue and related clinical outcomes in MS. This was a controlled, non-randomized clinical treatment study. Sixty-two MS patients completed standardized questionnaires including the Fatigue Severity Scale (FSS), Multidimensional Fatigue Inventory (MFI), Epworth Sleepiness scale (ESS) and Pittsburgh Sleep Quality Index (PSQI), and underwent polysomnography (PSG). Patients with sleep disorders were offered standard treatment. Fifty-six subjects repeated the questionnaires after ≥ three months, and were assigned to one of three groups: sleep disorders that were treated (SD-Tx, n=21), sleep disorders remaining untreated (SD-NonTx, n=18) and no sleep disorder (NoSD, n=17). FSS and MFI general and mental fatigue scores improved significantly from baseline to follow-up in SD-Tx (p <0.03), but not SD-NonTx or NoSD subjects. ESS and PSQI scores also improved significantly in SD-Tx subjects (p <0.001). Adjusted multivariate analyses confirmed significant effects of sleep disorder treatment on FSS (-0.87, p = 0.005), MFI general fatigue score (p = 0.034), ESS (p = 0.042) and PSQI (p = 0.023). Treatment of sleep disorders can improve fatigue and other clinical outcomes in MS.


Formation of ion gels by polymerization of block copolymer/ionic liquid/oil mesophases.
In this study, we introduce a new method of developing ion gels through polymerization of lyotropic liquid crystal (LLC) templates of monomer (styrene), cross-linker (divinylbenzene), ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate), and amphiphilic block copolymers (Pluronic F127). The polymerization of the oil phase boosts the mechanical properties of the ion-conducting electrolytes. We discuss the effect of tortuosity induced by crystalline domains and LLC structure on the conductivity of ion gels. The ion transport in polymerized LLCs (polyLLCs) can be controlled by changing the composition of the mesophases. Increasing the block copolymer concentration enhances the crystallinity of PEO blocks in the conductive domains, which slows down the dynamics of PEO chain and ion transport. We show that by adjusting the composition of LLC mesophases, the mechanical strength of ion gels can be increased one order of magnitude without compromising the ionic conductivity. The polyLLCs with 45/25/30 wt% (block copolymer/IL/oil) composition has storage modulus and ionic conductivity higher than 1 MPa and 3 mS cm-1 at 70 °C, respectively. The results suggest that LLC templating is a promising method to develop highly conductive ion gels, which provides advantages in terms of variety and processing.


Paracrine signals from mesenchymal cell populations govern the expansion and differentiation of human hepatic stem cells to adult liver fates.
The differentiation of embryonic or determined stem cell populations into adult liver fates under known conditions yields cells with some adult-specific genes but not others, aberrant regulation of one or more genes, and variations in the results from experiment to experiment. We tested the hypothesis that sets of signals produced by freshly isolated, lineage-dependent mesenchymal cell populations would yield greater efficiency and reproducibility in driving the differentiation of human hepatic stem cells (hHpSCs) into adult liver fates. The subpopulations of liver-derived mesenchymal cells, purified by immunoselection technologies, included (1) angioblasts, (2) mature endothelia, (3) hepatic stellate cell precursors, (4) mature stellate cells (pericytes), and (5) myofibroblasts. Freshly immunoselected cells of each of these subpopulations were established in primary cultures under wholly defined (serum-free) conditions that we developed for short-term cultures and were used as feeders with hHpSCs. Feeders of angioblasts yielded self-replication, stellate cell precursors caused lineage restriction to hepatoblasts, mature endothelia produced differentiation into hepatocytes, and mature stellate cells and/or myofibroblasts resulted in differentiation into cholangiocytes. Paracrine signals produced by the different feeders were identified by biochemical, immunohistochemical, and quantitative reverse-transcription polymerase chain reaction analyses, and then those signals were used to replace the feeders in monolayer and three-dimensional cultures to elicit the desired biological responses from hHpSCs. The defined paracrine signals were proved to be able to yield reproducible responses from hHpSCs and to permit differentiation into fully mature and functional parenchymal cells. Paracrine signals from defined mesenchymal cell populations are important for the regulation of stem cell populations into specific adult fates; this finding is important for basic and clinical research as well as industrial investigations.


Assessing the health effects associated with occupational radiation exposure in Korean radiation workers: protocol for a prospective cohort study.
The cancer risk of radiation exposure in the moderate-to-high dose range has been well established. However, the risk remains unclear at low-dose ranges with protracted low-dose rate exposure, which is typical of occupational exposure. Several epidemiological studies of Korean radiation workers have been conducted, but the data were analysed retrospectively in most cases. Moreover, groups with relatively high exposure, such as industrial radiographers, have been neglected. Therefore, we have launched a prospective cohort study of all Korean radiation workers to assess the health effects associated with occupational radiation exposure. Approximately 42 000 Korean radiation workers registered with the Nuclear Safety and Security Commission from 2016 to 2017 are the initial target population of this study. Cohort participants are to be enrolled through a nationwide self-administered questionnaire survey between 24 May 2016 and 30 June 2017. As of 31 March 2017, 22 982 workers are enrolled in the study corresponding to a response rate of 75%. This enrolment will be continued at 5-year intervals to update information on existing study participants and recruit newly hired workers. Survey data will be linked with the national dose registry, the national cancer registry, the national vital statistics registry and national health insurance data via personal identification numbers. Age-specific and sex-specific standardised incidence and mortality ratios will be calculated for overall comparisons of cancer risk. For dose-response assessment, excess relative risk (per Gy) and excess absolute risk (per Gy) will be estimated with adjustments for birth year and potential confounders, such as lifestyle factors and socioeconomic status. This study has received ethical approval from the institutional review board of the Korea Institute of Radiological and Medical Sciences (IRB No. K-1603-002-034). All participants provided written informed consent prior to enrolment. The findings of the study will be disseminated through scientific peer-reviewed journals and be provided to the public, including radiation workers, via the study website (http://www.rhs.kr/) and onsite radiation safety education.


Self-propagated combustion synthesis of few-layered graphene: an optical properties perspective.
This paper describes a labour efficient and cost-effective strategy to prepare few-layered of reduced graphene oxide like (RGOL) sheets from graphite. The self-propagated combustion route enables the bulk production of RGOL sheets. Microscopic and spectroscopic analyses confirmed the formation of few-layer graphene sheets of an average thickness of ∼3 nm and the presence of some oxygen functional groups with a C/O ratio of 8.74. A possible mechanistic pathway for the formation of RGOL sheets is proposed. The optical properties of the RGOL sample were studied in detail by means of Spectroscopic Ellipsometry (SE). The experimental abilities of SE in relating the optical properties with the number of oxygen functionalities present in the samples are explored. The data were analysed by a double-layered optical model along with the Drude-Lorentz oscillatory dispersion relation. The refractive index (n = 2.24), extinction coefficient (k = 2.03), and dielectric functions are obtained using point-by-point analysis and are also checked for Kramers-Kronig (KK) consistency.


Fission yeast Rap1 homolog is a telomere-specific silencing factor and interacts with Taz1p.
Taz1p is the fission yeast orthologue of human TRF2, a telomeric repeat-binding protein. Delta(taz1) mutants are defective in telomeric silencing, telomere length control, and meiotic recombination events. A recent report demonstrated that the human Rap1p homolog (hRap1) is recruited to telomere by interaction with TRF2, arguing that the telomere control mechanism of higher eukaryotes is distinct from that of the budding yeast. Taz1p showed a significant similarity to human TRF2, but not with the budding yeast Rap1p (scRap1p). This suggests that Taz1p and TRF2 share common features in telomere regulation. To assess the roles of Taz1p in telomere-related functions in detail, we attempted to identify a protein(s) that interacts with Taz1p by using two-hybrid screening. Interestingly, the sequence analysis of a positive clone revealed a perfect match with a Rap1 homolog in S. pombe (spRap1), which showed a significant homology with scRap1p and hRap1p. Here we show that the spRap1 deficiency in haploid cells is viable, which results in increased telomere length regulation, disruption of telomere silencing, and aberrant meiosis (like the delta(taz1) mutant). This suggests that spRap1p might be recruited to the telomere by Taz1p and play crucial roles in telomere function. Interestingly, the delta(rap1) mutants in fission yeast are defective only for telomere silencing. Therefore, the role of spRap1p may be distinct from that of scRap1p, which is involved in the silencing at both the telomere and mating type locus. Our data, therefore, suggest that the regulation mechanisms of telomere in fission yeast resemble that of higher eukaryotic cells rather than the budding yeast.


Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders.
There is limited evidence on whether growing mobile phone availability in sub-Saharan Africa can be used to promote high adherence to antiretroviral therapy (ART). This study tested the efficacy of short message service (SMS) reminders on adherence to ART among patients attending a rural clinic in Kenya. A randomized controlled trial of four SMS reminder interventions with 48 weeks of follow-up. Four hundred and thirty-one adult patients who had initiated ART within 3 months were enrolled and randomly assigned to a control group or one of the four intervention groups. Participants in the intervention groups received SMS reminders that were either short or long and sent at a daily or weekly frequency. Adherence was measured using the medication event monitoring system. The primary outcome was whether adherence exceeded 90% during each 12-week period of analysis and the 48-week study period. The secondary outcome was whether there were treatment interruptions lasting at least 48 h. In intention-to-treat analysis, 53% of participants receiving weekly SMS reminders achieved adherence of at least 90% during the 48 weeks of the study, compared with 40% of participants in the control group (P = 0.03). Participants in groups receiving weekly reminders were also significantly less likely to experience treatment interruptions exceeding 48 h during the 48-week follow-up period than participants in the control group (81 vs. 90%, P = 0.03). These results suggest that SMS reminders may be an important tool to achieve optimal treatment response in resource-limited settings.


From deep-sea volcanoes to human pathogens: a conserved quorum-sensing signal in Epsilonproteobacteria.
Chemosynthetic Epsilonproteobacteria from deep-sea hydrothermal vents colonize substrates exposed to steep thermal and redox gradients. In many bacteria, substrate attachment, biofilm formation, expression of virulence genes and host colonization are partly controlled via a cell density-dependent mechanism involving signal molecules, known as quorum sensing. Within the Epsilonproteobacteria, quorum sensing has been investigated only in human pathogens that use the luxS/autoinducer-2 (AI-2) mechanism to control the expression of some of these functions. In this study we showed that luxS is conserved in Epsilonproteobacteria and that pathogenic and mesophilic members of this class inherited this gene from a thermophilic ancestor. Furthermore, we provide evidence that the luxS gene is expressed--and a quorum-sensing signal is produced--during growth of Sulfurovum lithotrophicum and Caminibacter mediatlanticus, two Epsilonproteobacteria from deep-sea hydrothermal vents. Finally, we detected luxS transcripts in Epsilonproteobacteria-dominated biofilm communities collected from deep-sea hydrothermal vents. Taken together, our findings indicate that the epsiloproteobacterial lineage of the LuxS enzyme originated in high-temperature geothermal environments and that, in vent Epsilonproteobacteria, luxS expression is linked to the production of AI-2 signals, which are likely produced in situ at deep-sea vents. We conclude that the luxS gene is part of the ancestral epsilonproteobacterial genome and represents an evolutionary link that connects thermophiles to human pathogens.


Prognostic factors in patients with spinal metastasis: a systematic review and meta-analysis.
Incidence of symptomatic spinal metastasis has increased owing to improvement in treatment of the disease. One of the key factors that influences decision-making is expected patient survival. To our knowledge, no systematic reviews or meta-analysis have been conducted that review independent prognostic factors in spinal metastases. This study aimed to determine independent prognostic factors that affect outcome in patients with metastatic spine disease. This is a systematic literature review and meta-analysis of publications for prognostic factors in spinal metastatic disease. Pooled patient results from cohort and observational studies. Meta-analysis for poor prognostic factors as determined by hazard ratio (HR) and 95% confidential interval (95% CI). We systematically searched relevant publications in PubMed and Embase. The following search terms were used: ("'spinal metastases'" OR "'vertebral metastases'" OR ""spinal metastasis" OR 'vertebral metastases') AND ('"prognostic factors"' OR "'survival'"). Inclusion criteria were prospective and retrospective cohort series that report HR and 95% CI of independent prognostic factors from multivariate analysis. Two reviewers independently assessed all papers. The quality of included papers was assessed by using Newcastle-Ottawa Scale for cohort studies and publication bias was assessed by using funnel plot, Begg test, and Egger test. The prognostic factors that were mentioned in at least three publications were pooled. Meta-analysis was performed using HR and 95% CI as the primary outcomes of interest. Heterogeneity was assessed using the I2 method. A total of 3,959 abstracts (1,382 from PubMed and 2,577 from Embase) were identified through database search and 40 publications were identified through review of cited publications. The reviewers selected a total of 51 studies for qualitative synthesis and 43 studies for meta-analysis. Seventeen poor prognostic factors were identified. These included presence of a neurologic deficit before surgery, non-ambulatory status before radiotherapy (RT), non-ambulatory status before surgery, presence of bone metastases, presence of multiple bone metastases (>2 sites), presence of multiple spinal metastases (>3 sites), development of motor deficit in <7 days before initiating RT, development of motor deficit in <14 days before initiating RT, time interval from cancer diagnosis to RT <15 months, Karnofsky Performance Score (KPS) 10-40, KPS 50-70, KPS<70, Eastern Cooperative Oncology Group (ECOG) grade 3-4, male gender, presence of visceral metastases, moderate growth tumor on Tomita score (TS) classification, and rapid growth tumor on TS classification. Seventeen independent poor prognostic factors were identified in this study. These can be categorized into cancer-specific and nonspecific prognostic factors. A tumor-based prognostic scoring system that combines all specific and general factors may enhance the accuracy of survival prediction in patients with metastatic spine disease.


Altered ribosomes after inhibition of Escherichia coli by rifampicin.
Addition of rifampicin to growing cells of Escherichia coli affected the ribosomes. The polyribosomes first decayed to 70S ribosomes. These later dissociated to particles distinct from ribosomal subunits. The altered ribosomes sedimented more slowly than the corresponding subunits and had lost some protein; their ribosomal RNA was intact, but they were more susceptible to degradation by ribonuclease than normal ribosomes. The addition of rifampicin to preparations of lysed cells caused no detectable changes in the ribosome fraction.


Cognitive Behavioural Therapy for Nightmares for Patients with Persecutory Delusions (Nites): An Assessor-Blind, Pilot Randomized Controlled Trial.
Nightmares are relatively common in patients experiencing psychosis but rarely assessed or treated. Nightmares may maintain persecutory delusions by portraying fears in sensory-rich detail. We tested the potential benefits of imagery-focused cognitive behavioural therapy (CBT) for nightmares on nightmare severity and persecutory delusions. This assessor-blind parallel-group pilot trial randomized 24 participants with nightmares and persecutory delusions to receive CBT for nightmares delivered over 4 weeks in addition to treatment as usual (TAU) or TAU alone. Assessments were at 0, 4 (end of treatment), and 8 weeks (follow-up). Feasibility outcomes assessed therapy uptake, techniques used, satisfaction, and attrition. The primary efficacy outcome assessed nightmare severity at week 4. Analyses were intention to treat, estimating treatment effect with 95% confidence intervals (CIs). All participants offered CBT completed therapy (mean [SD], 4.8 [0.6] sessions) with high satisfaction, and 20 (83%) participants completed all assessments. Compared with TAU, CBT led to large improvements in nightmares (adjusted mean difference = -7.0; 95% CI, -12.6 to -1.3; d = -1.1) and insomnia (6.3; 95% CI, 2.6 to 10.0; d = 1.4) at week 4. Gains were maintained at follow-up. Suicidal ideation was not exacerbated by CBT but remained stable to follow-up, compared with TAU, which reduced at follow-up (6.8; 95% CI, 0.3 to 3.3; d = 0.7). CBT led to reductions in paranoia (-20.8; 95% CI, -43.2 to 1.7; d = -0.6), although CIs were wide. Three serious adverse events were deemed unrelated to participation (CBT = 2, TAU = 1). CBT for nightmares is feasible and may be efficacious for treating nightmares and comorbid insomnia for patients with persecutory delusions. It shows promise on paranoia but potentially not on suicidal ideation.


Diagnostic accuracy of magnification endoscopy with acetic acid enhancement and narrow-band imaging in gastric mucosal neoplasms.
Magnification endoscopy with narrow-band imaging (NBIME) and NBIME with acetic acid enhancement (A-NBIME) visualize the capillary and microstructure patterns of the gastric mucosal surface, respectively. This study aimed to compare the diagnostic accuracy and interobserver agreement for white-light endoscopy (WLE), NBIME, and A-NBIME in the different histologic types of gastric mucosal neoplasm. Consecutive gastric neoplasms (n = 220; 49 adenomas, 144 differentiated adenocarcinomas, and 27 undifferentiated adenocarcinomas) were photographed with WLE, NBIME, and A-NBIME. Macroscopic patterns using WLE, capillary patterns using NBIME, and microstructure patterns using A-NBIME were respectively classified into type M1/M2/M3, type C1/C2/C3/C4, and type S1/S2/S3, as the indicators of adenoma, differentiated adenocarcinoma, and undifferentiated adenocarcinoma (Type C4, unevaluable because of capillary invisibility), according to the previously reported classifications. Endoscopic images were independently reviewed by three experts and three non-experts. Diagnostic accuracy and interobserver diagnostic agreement were compared among the modalities. Kappa values (95 % confidence interval [CI]) for WLE, NBIME, and A-NBIME diagnosis were 0.36 (0.33 - 0.39), 0.58 (0.54 - 0.61), and 0.62 (0.55 - 0.68) for experts and 0.31 (0.29 - 0.33), 0.36 (0.34 - 0.38), and 0.52 (0.48 - 0.56) for non-experts, showing good reproducibility of A-NBIME diagnosis regardless of proficiency. All experts and non-experts diagnosed the histologic types statistically more accurately with A-NBIME than with WLE and NBIME (P < 0.05). Overall the "experts-agreed" diagnostic accuracy (95 %CI) was 75.5 % (70.0 - 81.0) for WLE vs. 74.1 % (67.6 - 80.6) for NBIME vs. 90.5 % (86.7 - 94.1) for A-NBIME (P < 0.05). WLE and NBIME were insufficient to predict the diagnosis of adenomas and undifferentiated adenocarcinomas. A-NBIME showed statistically significantly higher diagnostic accuracy for gastric mucosal neoplasms, with good reproducibility, compared with WLE and NBIME, which provided similar lower accuracy.


A powerful two-stage association test using case-control and case-parents genotype data.
The performance of association tests based on case-control or case-parents substudy alone can be improved by jointly using genetic data from two substudies. However, genetic data from different sources may not be combinable due to population stratification. We propose a two-stage association test based on using combinability tests in stage 1 and association tests in stage 2. The combinability tests are designed for testing that genotype data from different sources have same genotype frequencies and relative risks. The association tests are well known tests in the literature. We propose a method to adjust the significance levels at two stages so that the overall type I error rate of the two-stage test can be controlled at the desired level. The simulation results confirm that the two-stage test has empirical type I error rates approximately equal to the predetermined levels while making substantially fewer false negatives than the usual test based only on case-parents substudy. It is advantageous to combinecase-control and case-parents data into a single analysis.The two-stage test has significant power improvement when the family-based test has weak or moderate power performance and is robust to the effect of population stratification.


Orchestrated transcription of key pathways in Arabidopsis by the circadian clock.
Like most organisms, plants have endogenous biological clocks that coordinate internal events with the external environment. We used high-density oligonucleotide microarrays to examine gene expression in Arabidopsis and found that 6% of the more than 8000 genes on the array exhibited circadian changes in steady-state messenger RNA levels. Clusters of circadian-regulated genes were found in pathways involved in plant responses to light and other key metabolic pathways. Computational analysis of cycling genes allowed the identification of a highly conserved promoter motif that we found to be required for circadian control of gene expression. Our study presents a comprehensive view of the temporal compartmentalization of physiological pathways by the circadian clock in a eukaryote.


A mobile hospice nurse teaching team's experience: training care workers in spiritual and existential care for the dying - a qualitative study.
Nursing home and home care nursing staff must increasingly deal with palliative care challenges, due to cost cutting in specialized health care. Research indicates that a significant number of dying patients long for adequate spiritual and existential care. Several studies show that this is often a source of anxiety for care workers. Teaching care workers to alleviate dying patients' spiritual and existential suffering is therefore important. The aim of this study is to illuminate a pioneering Norwegian mobile hospice nurse teaching team's experience with teaching and training care workers in spiritual and existential care for the dying in nursing homes and home care settings. The team of expert hospice nurses participated in a focus group interview. Data were analyzed using a phenomenological hermeneutical method. The mobile teaching team taught care workers to identify spiritual and existential suffering, initiate existential and spiritual conversations and convey consolation through active presencing and silence. The team members transferred their personal spiritual and existential care knowledge through situated "bedside teaching" and reflective dialogues. "The mobile teaching team perceived that the care workers benefitted from the situated teaching because they observed that care workers became more courageous in addressing dying patients' spiritual and existential suffering. Educational research supports these results. Studies show that efficient workplace teaching schemes allowexpert practitioners to teach staff to integrate several different knowledge forms and skills, applying a holisticknowledge approach. One of the features of workplace learning is that expert nurses are able to guide novices through the complexities of practice. Situated learning is therefore central for becoming proficient. Situated bedside teaching provided by expert mobile hospice nurses may be an efficient way to develop care workers' courage and competency to provide spiritual and existential end-of-life-care. Further research is recommended on the use of mobile expert nurse teaching teams to improve nursing competency in the primary health care sector.


Evidence-based obesity prevention in childhood and adolescence: critique of recent etiological studies, preventive interventions, and policies.
Prevention of obesity in childhood and adolescence remains a worthwhile and realistic goal, but preventive efforts have been beset by a number of problems, which are the subject of this review. The review draws on recent systematic reviews and evidence appraisals and has a United Kingdom (UK) perspective because there is a rich evidence base in the United Kingdom that may be helpful to obesity prevention researchers elsewhere. Recent evidence of a leveling off in child and adolescent obesity prevalence in some Western nations should not encourage the belief that the obesity prevention problem has been solved, although a better understanding of recent secular trends might be helpful for prevention strategy in future. An adequate body of evidence provides behavioral targets of preventive interventions, and there are frameworks for prioritizing these targets logically and models for translating them into generalizable interventions with a wide reach (e.g., school-based prevention interventions such as Planet Health). An improved understanding of the "energy gap" that children and adolescents experience would be helpful to the design of preventive interventions and to their tailoring to particular groups. In the United Kingdom, some recent etiological evidence has been taken as indicative of the need for paradigm shifts in obesity prevention, but this evidence from single studies has not been replicated, and paradigm shifts probably occur only rarely. Ensuring that the evidence base on etiology and prevention influences policy effectively remains one of the greatest challenges for childhood obesity researchers.


Online Peer-to-Peer Communities in the Daily Lives of People With Chronic Illness: A Qualitative Systematic Review.
This qualitative systematic review investigated how individuals with chronic illness experience online peer-to-peer support and how their experiences influence daily life with illness. Selected studies were appraised by quality criteria focused upon research questions and study design, participant selection, methods of data collection, and methods of analysis. Four themes were identified: (a) illness-associated identity work, (b) social support and connectivity, (c) experiential knowledge sharing, and (d) collective voice and mobilization. Findings indicate that online peer-to-peer communities provide a supportive space for daily self-care related to chronic illness. Online communities provided a valued space to strengthen social ties and exchange knowledge that supported offline ties and patient-doctor relationships. Individuals used online communities to exchange experiential knowledge about everyday life with illness. This type of knowledge was perceived as extending far beyond medical care. Online communities were also used to mobilize and raise collective awareness about illness-specific concerns.


Schottky barrier and band edge engineering via the interfacial structure and strain for the Pt/TiO2 heterostructure.
Charge transfer across the Pt/TiO2 interface, which is mainly determined by the interface Schottky barrier height (SBH), is an important process in the (photo)catalytic and electronic applications of the Pt/TiO2 composite. Therefore, systematic investigation of the factors that affect the interface SBH is indispensable for understanding and optimizing its performance. In this work, a systematic study of the effects of the interfacial structure and strain on the SBH of the Pt/TiO2(001) interface has been carried out based on the first-principles calculations. The results of interface adhesion energy show that two different interfacial structures for the Pt/TiO2(001) heterointerface may exist experimentally, namely, O-Pt bonding and Ti-Pt bonding. Moreover, the interfacial structures result in not only different values for the SBH, but also different dependences of the SBH on strain. Detailed investigations show that these versatile modulations of the SBH with the structure and strain are mainly attributed to the strong dependence of the band edges of TiO2 and the interfacial potential alignments on the strain and structure, suggesting that these results are general and may be applicable to other metal/TiO2 heterostructures.


Leveraging Nonhuman Primate Multisensory Neurons and Circuits in Assessing Consciousness Theory.
Both the global neuronal workspace (GNW) and integrated information theory (IIT) posit that highly complex and interconnected networks engender perceptual awareness. GNW specifies that activity recruiting frontoparietal networks will elicit a subjective experience, whereas IIT is more concerned with the functional architecture of networks than with activity within it. Here, we argue that according to IIT mathematics, circuits converging on integrative versus convergent yet non-integrative neurons should support a greater degree of consciousness. We test this hypothesis by analyzing a dataset of neuronal responses collected simultaneously from primary somatosensory cortex (S1) and ventral premotor cortex (vPM) in nonhuman primates presented with auditory, tactile, and audio-tactile stimuli as they are progressively anesthetized with propofol. We first describe the multisensory (audio-tactile) characteristics of S1 and vPM neurons (mean and dispersion tendencies, as well as noise-correlations), and functionally label these neurons as convergent or integrative according to their spiking responses. Then, we characterize how these different pools of neurons behave as a function of consciousness. At odds with the IIT mathematics, results suggest that convergent neurons more readily exhibit properties of consciousness (neural complexity and noise correlation) and are more impacted during the loss of consciousness than integrative neurons. Last, we provide support for the GNW by showing that neural ignition (i.e., same trial coactivation of S1 and vPM) was more frequent in conscious than unconscious states. Overall, we contrast GNW and IIT within the same single-unit activity dataset, and support the GNW.SIGNIFICANCE STATEMENT A number of prominent theories of consciousness exist, and a number of these share strong commonalities, such as the central role they ascribe to integration. Despite the important and far reaching consequences developing a better understanding of consciousness promises to bring, for instance in diagnosing disorders of consciousness (e.g., coma, vegetative-state, locked-in syndrome), these theories are seldom tested via invasive techniques (with high signal-to-noise ratios), and never directly confronted within a single dataset. Here, we first derive concrete and testable predictions from the global neuronal workspace and integrated information theory of consciousness. Then, we put these to the test by functionally labeling specific neurons as either convergent or integrative nodes, and examining the response of these neurons during anesthetic-induced loss of consciousness.


An improved robust stability result for uncertain neural networks with multiple time delays.
This paper proposes a new alternative sufficient condition for the existence, uniqueness and global asymptotic stability of the equilibrium point for the class of delayed neural networks under the parameter uncertainties of the neural system. The existence and uniqueness of the equilibrium point is proved by using the Homomorphic mapping theorem. The asymptotic stability of the equilibrium point is established by employing the Lyapunov stability theorems. The obtained robust stability condition establishes a new relationship between the network parameters of the system. We compare our stability result with the previous corresponding robust stability results derived in the past literature. Some comparative numerical examples together with some simulation results are also given to show the applicability and advantages of our result.


A universal vaccine candidate against Plasmodium vivax malaria confers protective immunity against the three PvCSP alleles.
Malaria is a highly prevalent parasitic disease in regions with tropical and subtropical climates worldwide. Among the species of Plasmodium causing human malaria, P. vivax is the second most prevalent and the most geographically widespread species. A major target of a pre-erythrocytic vaccine is the P. vivax circumsporozoite protein (PvCSP). In previous studies, we fused two recombinant proteins representing three allelic variants of PvCSP (VK210, VK247 and P. vivax-like) to the mumps virus nucleocapsid protein to enhance immune responses against PvCSP. The objective of the present study was to evaluate the protective efficacy of these recombinants in mice challenged with transgenic P. berghei parasites expressing PvCSP allelic variants. Formulations containing Poly (I:C) or Montanide ISA720 as adjuvants elicited high and long-lasting IgG antibody titers specific to each PvCSP allelic variant. Immunized mice were challenged with two existing chimeric P. berghei parasite lines expressing PvCSP-VK210 and PvCSP-VK247. We also developed a novel chimeric line expressing the third allelic variant, PvCSP-P. vivax-like, as a new murine immunization-challenge model. Our formulations conferred partial protection (significant delay in the time to reach 1% parasitemia) against challenge with the three chimeric parasites. Our results provide insights into the development of a vaccine targeting multiple strains of P. vivax.


Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation.
Competing models of mitochondrial energy metabolism in the heart are highly disputed. In addition, the mechanisms of reactive oxygen species (ROS) production and scavenging are not well understood. To deepen our understanding of these processes, a computer model was developed to integrate the biophysical processes of oxidative phosphorylation and ROS generation. The model was calibrated with experimental data obtained from isolated rat heart mitochondria subjected to physiological conditions and workloads. Model simulations show that changes in the quinone pool redox state are responsible for the apparent inorganic phosphate activation of complex III. Model simulations predict that complex III is responsible for more ROS production during physiological working conditions relative to complex I. However, this relationship is reversed under pathological conditions. Finally, model analysis reveals how a highly reduced quinone pool caused by elevated levels of succinate is likely responsible for the burst of ROS seen during reperfusion after ischemia.


Leaf endophyte load influences fungal garden development in leaf-cutting ants.
Previous work has shown that leaf-cutting ants prefer to cut leaf material with relatively low fungal endophyte content. This preference suggests that fungal endophytes exact a cost on the ants or on the development of their colonies. We hypothesized that endophytes may play a role in their host plants' defense against leaf-cutting ants. To measure the long-term cost to the ant colony of fungal endophytes in their forage material, we conducted a 20-week laboratory experiment to measure fungal garden development for colonies that foraged on leaves with low or high endophyte content. Colony mass and the fungal garden dry mass did not differ significantly between the low and high endophyte feeding treatments. There was, however, a marginally significant trend toward greater mass of fungal garden per ant worker in the low relative to the high endophyte treatment. This trend was driven by differences in the fungal garden mass per worker from the earliest samples, when leaf-cutting ants had been foraging on low or high endophyte leaf material for only 2 weeks. At two weeks of foraging, the mean fungal garden mass per worker was 77% greater for colonies foraging on leaves with low relative to high endophyte loads. Our data suggest that the cost of endophyte presence in ant forage material may be greatest to fungal colony development in its earliest stages, when there are few workers available to forage and to clean leaf material. This coincides with a period of high mortality for incipient colonies in the field. We discuss how the endophyte-leaf-cutter ant interaction may parallel constitutive defenses in plants, whereby endophytes reduce the rate of colony development when its risk of mortality is greatest.


Genetic Analysis of Signal Generation by the Rgt2 Glucose Sensor of Saccharomyces cerevisiae.
The yeast S. cerevisiae senses glucose through Snf3 and Rgt2, transmembrane proteins that generate an intracellular signal in response to glucose that leads to inhibition of the Rgt1 transcriptional repressor and consequently to derepression of HXT genes encoding glucose transporters. Snf3 and Rgt2 are thought to be glucose receptors because they are similar to glucose transporters. In contrast to glucose transporters, they have unusually long C-terminal tails that bind to Mth1 and Std1, paralogous proteins that regulate function of the Rgt1 transcription factor. We show that the C-terminal tail of Rgt2 is not responsible for its inability to transport glucose. To gain insight into how the glucose sensors generate an intracellular signal, we identified RGT2 mutations that cause constitutive signal generation. Most of the mutations alter evolutionarily-conserved amino acids in the transmembrane spanning regions of Rgt2 that are predicted to be involved in maintaining an outward-facing conformation or to be in the substrate binding site. Our analysis of these mutations suggests they cause Rgt2 to adopt inward-facing or occluded conformations that generate the glucose signal. These results support the idea that Rgt2 and Snf3 are glucose receptors that signal in response to binding of extracellular glucose and inform the basis of their signaling.


Dissecting tocopherols content in maize (Zea mays L.), using two segregating populations and high-density single nucleotide polymorphism markers.
Tocopherols, which are vitamin E compounds, play an important role in maintaining human health. Compared with other staple foods, maize grains contain high level of tocopherols. Two F(2) populations (K22/CI7 and K22/Dan340, referred to as POP-1 and POP-2, respectively), which share a common parent (K22), were developed and genotyped using a GoldenGate assay containing 1,536 single nucleotide polymorphism (SNP) markers. An integrated genetic linkage map was constructed using 619 SNP markers, spanning a total of 1649.03 cM of the maize genome with an average interval of 2.67 cM. Seventeen quantitative trait loci (QTLs) for all the traits were detected in the first map and 13 in the second. In these two maps, QTLs for different traits were localized to the same genomic regions and some were co-located with candidate genes in the tocopherol biosynthesis pathway. Single QTL was responsible for 3.03% to 52.75% of the phenotypic variation and the QTLs in sum explained 23.4% to 66.52% of the total phenotypic variation. A major QTL (qc5-1/qd5-1) affecting α-tocopherol (αT) was identified on chromosome 5 between the PZA03161.1 and PZA02068.1 in the POP-2. The QTL region was narrowed down from 18.7 Mb to 5.4 Mb by estimating the recombination using high-density markers of the QTL region. This allowed the identification of the candidate gene VTE4 which encodes γ-tocopherol methyltransferase, an enzyme that transforms γ-tocopherol (γT)to αT. These results demonstrate that a few QTLs with major effects and several QTLs with medium to minor effects might contribute to the natural variation of tocopherols in maize grain. The high-density markers will help to fine map and identify the QTLs with major effects even in the preliminary segregating populations. Furthermore, this study provides a simple guide line for the breeders to improve traits that minimize the risk of malnutrition, especially in developing countries.


Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling.
The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer.


Cost of care for patients in cancer clinical trials.
Information on the costs of medical care for patients enrolled in clinical trials is needed by policymakers evaluating ways to facilitate clinical research in a managed care environment. We examined the direct costs of medical care for patients enrolled in cancer clinical trials at a large health maintenance organization (HMO). Costs for 135 patients who entered 22 cancer clinical trials (including 12 breast cancer trials) at Kaiser Permanente in Northern California, from 1994 through 1996 were compared with costs for 135 matched control subjects who were not enrolled in such trials. Cancer registry data and medical charts were used in matching the control subjects to the trial enrollees with respect to cancer site, stage, date of diagnosis, age, sex, and trial eligibility. The direct costs of medical care were compared between trial enrollees and the control subjects for a 1-year period, with data on costs and utilization of services obtained from Kaiser Permanente databases and medical charts. Mean 1-year costs for the enrollees in trials were 10% higher than those for the control subjects ($17 003 per enrollee compared with $15 516 per control subject; two-sided P =.011). The primary component of this difference was a $1376 difference in chemotherapy costs ($4815 per trial enrollee versus $3439 per control subject; two-sided P<.001). Costs for the 11 enrollees in trials that had a bone marrow transplant (BMT) arm were approximately double the costs for their matched control subjects (borderline significance: two-sided P=.054). The $15 041 mean cost for the enrollees in trials without BMT was similar to the $15 186 mean cost for their matched control subjects. Participation in cancer clinical trials at a large HMO did not result in substantial increases in the direct costs of medical care.


Neuroimaging and clinical features in adults with a 22q11.2 deletion at risk of Parkinson's disease.
The recurrent 22q11.2 deletion is a genetic risk factor for early-onset Parkinson's disease. Adults with the associated 22q11.2 deletion syndrome (22q11.2DS) may exhibit phenotypes that could help identify those at highest risk and reveal disease trajectories. We investigated clinical and neuroimaging features relevant to Parkinson's disease in 26 adults: 13 with 22q11.2DS at genetic risk of Parkinson's disease (mean age = 41.5 years, standard deviation = 9.7), 12 healthy age and sex-matched controls, and a 22q11.2DS patient with l-DOPA-responsive early-onset Parkinson's disease. Neuroimaging included transcranial sonography and positron emission tomography using 11C-dihydrotetrabenazine (11C-DTBZ), a radioligand that binds to the presynaptic vesicular monoamine transporter. The 22q11.2DS group without Parkinson's disease demonstrated significant motor and olfactory deficits relative to controls. Eight (61.5%) were clinically classified with parkinsonism. Transcranial sonography showed a significantly larger mean area of substantia nigra echogenicity in the 22q11.2DS risk group compared with controls (P = 0.03). The 22q11.2DS patient with Parkinson's disease showed the expected pattern of severely reduced striatal 11C-DTBZ binding. The 22q11.2DS group without Parkinson's disease however showed significantly elevated striatal 11C-DTBZ binding relative to controls (∼33%; P < 0.01). Results were similar within the 22q11.2DS group for those with (n = 7) and without (n = 6) psychotic illness. These findings suggest that manifestations of parkinsonism and/or evolution to Parkinson's disease in this genetic at-risk population may include a hyperdopaminergic mechanism. Adequately powered longitudinal studies and animal models are needed to evaluate the relevance of the observed clinical and imaging phenotypes to Parkinson's disease and other disorders that are more prevalent in 22q11.2DS, such as schizophrenia.


SMARCD2 subunit of SWI/SNF chromatin-remodeling complexes mediates granulopoiesis through a CEBPɛ dependent mechanism.
Recent studies suggest that individual subunits of chromatin-remodeling complexes produce biologically specific meaning in different cell types through combinatorial assembly. Here we show that granulocyte development requires SMARCD2, a subunit of ATP-dependent SWI/SNF (BAF) chromatin-remodeling complexes. Smarcd2-deficient mice fail to generate functionally mature neutrophils and eosinophils, a phenotype reminiscent of neutrophil-specific granule deficiency (SGD) in humans, for which loss-of-function mutations in CEBPE (encoding CEBPɛ) have been reported. SMARCD2-containing SWI/SNF complexes are necessary for CEBPɛ transcription factor recruitment to the promoter of neutrophilic secondary granule genes and for granulocyte differentiation. The homologous SMARCD1 protein (63% identical at the amino acid level) cannot replace the role of SMARCD2 in granulocyte development. We find that SMARCD2 functional specificity is conferred by its divergent coiled-coil 1 and SWIB domains. Strikingly, both CEBPE and SMARCD2 loss-of-function mutations identified in patients with SGD abolish the interaction with SWI/SNF and thereby secondary granule gene expression, thus providing a molecular basis for this disease.


Projections from the ventral nucleus of the lateral lemniscus to the cochlea in the mouse.
Auditory efferents originate in the central auditory system and project to the cochlea. Although the specific anatomy of the olivocochlear (OC) efferents can vary between species, two types of auditory efferents have been identified based upon the general location of their cell bodies and their distinctly different axon terminations in the organ of Corti. In the mouse, the relatively small somata of the lateral (LOC) efferents reside in the lateral superior olive (LSO), have unmyelinated axons, and terminate around ipsilateral inner hair cells (IHCs), primarily against the afferent processes of type I auditory nerve fibers. In contrast, the larger somata of the medial (MOC) efferents are distributed in the ventral nucleus of the trapezoid body (VNTB), have myelinated axons, and terminate bilaterally against the base of multiple outer hair cells (OHCs). Using in vivo retrograde cell body marking, anterograde axon tracing, immunohistochemistry, and electron microscopy, we have identified a group of efferent neurons in mouse, whose cell bodies reside in the ventral nucleus of the lateral lemniscus (VNLL). By virtue of their location, we call them dorsal efferent (DE) neurons. Labeled DE cells were immuno-negative for tyrosine hydroxylase, glycine, and GABA, but immuno-positive for choline acetyltransferase. Morphologically, DEs resembled LOC efferents by their small somata, unmyelinated axons, and ipsilateral projection to IHCs. These three classes of efferent neurons all project axons directly to the cochlea and exhibit cholinergic staining characteristics. The challenge is to discover the contributions of this new population of neurons to auditory efferent function.


Favorable effects of omega-3 polyunsaturated fatty acids in attentional control and conversion rate to psychosis in 22q11.2 deletion syndrome.
Omega-3-polyunsaturated-fatty-acids were suggested against cognitive dysfunctions and conversion to psychosis. However, a recent multicenter trial found no effect in reducing conversion rates in individuals at risk of developing schizophrenia. Patients' genetic heterogeneity and the timing of treatment might influence omega-3 efficacy. Here, we addressed the impact of omega-3 early treatment in both mice and human subjects with a 22q11.2 genetic hemi-deletion (22q11DS), characterized by cognitive dysfunctions and high penetrance of schizophrenia. We first tested the behavioural and cognitive consequences of adolescent exposure to normal or omega-3-enriched diets in wild-type and 22q11DS (LgDel/+) mice. We then contrasted mouse data with those gathered from sixty-two patients with 22q11DS exposed to a normal diet or supplemented with omega-3 during pre-adolescence/adolescence. Adolescent omega-3 exposure had no effects in wild-type mice. However, this treatment ameliorated distractibility deficits revealed in LgDel/+ mice by the Five Choice Serial Reaction Time Task (5CSRTT). The omega-3 improvement in LgDel/+ mice was selective, as no other generalized cognitive and non-cognitive effects were evident. Similarly, omega-3-exposed 22q11DS patients showed long-lasting improvements on distractibility as revealed by the continuous performance test (CPT). Moreover, omega-3-exposed 22q11DS patients showed less risk of developing an Ultra High Risk status and lower conversion rate to psychosis. Our convergent mouse-human findings represent a first analysis on the effects of omega-3 early treatment in 22q11DS. The beneficial effects in attentional control and transition to psychosis could support the early use of omega-3 supplementation in the 22q11DS population.


The vascular anatomy of the rat superficial epigastric flap by vascular corrosion casting and technical refinement for the study of choke vessels in cadaveric flap models.
Accurate depiction of cutaneous vascular microanatomy is of relevance to plastic surgical flap research, and to descriptive anatomy. Yet current techniques have not permitted full visualization of the subdermal plexus, or potential angiosomal connections. Nor has endothelial visualization been facilitated. Vascular corrosion casting techniques are promising in that regard, and were applied in an extended lateral thoracoabdominal suprafascial adipocutaneous flap in the rat (based on the superficial epigastric bundle). Technical refinements for application to further study of human cadaveric flap models are presented. The intraflap vascular branching pattern of the superficial epigastric artery is described, with filling of the lateral thoracic, intercostals, and iliolumbar angiosomes found when coagulation of vessels at the periphery was delayed until after clearance. The vascular casting protocol presented is an effective and promising tool for the study of macro- and microvascular anatomy.


Studies on the mechanisms of the antisecretory and cytoprotective actions of SCH 28080.
The antisecretory and cytoprotective actions of SCH 28080 (2-methyl-8-(phenylmethoxy)imidazol[ 1,2-a ]pyridine-3-acetonitrile), an antiulcer compound, were characterized. In the isolated guinea-pig gastric mucosa, SCH 28080 at 5 X 10(-8) M abolished the acid secretory responses to histamine and methacholine but at 5 X 10(-7) M also inhibited the responses to dibutyryl cyclic AMP plus theophylline. The data suggest that the antisecretory effect of SCH 28080 involves a direct action on the parietal cells distal to the primary events mediating the cholinergic and H2 histaminergic secretory mechanisms. In the histamine-stimulated dogs, a prolonged suppression of acid secretion was accompanied by only a transient fall in the ratio of mucosal plasma flow to acid output after i.v. dosing of SCH 28080, 1 mg/kg, indicating that the antisecretory action of SCH 28080 was not secondary to changes in gastric blood flow. Mechanisms mediating the cytoprotective effects of SCH 28080 were investigated. SCH 28080 (10 mg/kg p.o.) increased total mucus as determined by measurements of N-acetylneuraminic acid in rat stomach. In the isolated guinea-pig gastric mucosa, bicarbonate secretion was augmented in a dose-dependent (10(-6)-10(-4) M) manner. Concomitant stimulation of the gastric mucus and bicarbonate by SCH 28080 may lead to strengthening of the gastric mucosal barrier and account for its gastric cytoprotective activity against injuring agents. In conclusion, the antisecretory and cytoprotective activities of SCH 28080 are due to a direct action on the parietal cells and a stimulatory effect on mucus and bicarbonate secretion by the mucosal epithelial cells, respectively.


Combined experimental and computational NMR study of crystalline and amorphous zeolitic imidazolate frameworks.
Zeolitic imidazolate frameworks (ZIFs) have attracted great interest in recent years due to their high chemical and thermal stability with promising applications in gas storage and separations. We investigate the structures of three different crystalline ZIFs - ZIF-4, ZIF-8, ZIF-zni - and their amorphous counterparts using high field (13)C and (15)N CP MAS NMR. The high field (20 T) allows for the observation of all crystallographically independent carbon and nitrogen atoms in the crystalline ZIFs. Combining our experimental results with density functional theory calculations enabled the assignment of all chemical shifts. The crystalline spectra reveal the potential of high field NMR to distinguish between two ZIF polymorphs, ZIF-4 and ZIF-zni, with identical [Zn(C3H3N2)2] chemical compositions. (13)C and (15)N CP MAS NMR data obtained for the amorphous ZIFs clearly showed signal broadening upon amorphization, confirming the retention of chemical composition and the structural similarity of amorphous ZIF-4 and ZIF-zni. In the case of amorphous ZIF-8, we present evidence for the partial de-coordination of the 2-methyl imidazole linker.


Polarization phase-shifting interferometric technique for complete evaluation of birefringence.
A full-field technique for simultaneous measurement of the magnitude of birefringence and its orientation is presented. This is achieved using a monolithic birefringence sensitive interferometer where the interference fringes carry the information of both the birefringence phase and the orientation of the fast axis of an optically transmissive anisotropic material placed at the output of the interferometer. The interferometer consists of a suitably polarization-masked cube beam splitter, orientated as in the Gates interferometer, which serves to generate a pair of orthogonally polarized and collinearly propagating light beams. Experimental results are obtained through an algorithm incorporating eight polarization phase-shifted interferograms.


Method and Instrumented Fixture for Femoral Fracture Testing in a Sideways Fall-on-the-Hip Position.
Mechanical testing of femora brings valuable insights into understanding the contribution of clinically-measureable variables such as bone mineral density distribution and geometry on the femoral mechanical properties. Currently, there is no standard protocol for mechanical testing of such geometrically complex bones to measure strength, and stiffness. To address this gap we have developed a protocol to test cadaveric femora to fracture and to measure their biomechanical parameters. This protocol describes a set of adaptable fixtures to accommodate the various load magnitudes and directions accounting for possible bone orientations in a fall on the hip configuration, test speed, bone size, and left leg-right leg variations. The femora were prepared for testing by cleaning, cutting, scanning, and potting the distal end and greater trochanter contact surfaces in poly(methyl methacrylate) (PMMA) as presented in a different protocol. The prepared specimens were placed in the testing fixture in a position mimicking a sideways fall on the hip and loaded to fracture. During testing, two load cells measured vertical forces applied to the femoral head and greater trochanter, a six-axis load cell measured forces and moments at the distal femoral shaft, and a displacement sensor measured differential displacement between the femoral head and trochanter contact supports. High speed video cameras were used to synchronously record the sequence of fracture events during testing. The reduction of this data allowed us to characterize the strength, stiffness, and fracture energy for nearly 200 osteoporotic, osteopenic, and normal cadaveric femora for further development of engineering-based diagnostic tools for osteoporosis research.


Experimental spectral measurements of heavy K-edge filtered beams for x-ray computed mammotomography.
A dual modality computed mammotomography (CmT) and single photon emission computed tomography (SPECT) system for dedicated 3D breast imaging is in development. Using heavy K-edge filtration, the CmT component narrows the energy spectrum of the cone-shaped x-ray beam incident on the patient's pendant, uncompressed breast. This quasi-monochromatic beam is expected to improve discrimination of tissue with similar attenuation coefficients while restraining absorbed dose to below that of dual view mammography. Previous simulation studies showed the optimal energy that maximizes dose efficiency for a 50/50% adipose/glandular breast is between 30 and 40 keV. This study experimentally validates these results using pre-breast and post-breast spectral measurements made under tungsten tube voltages between 40 and 100 kVp using filter materials with K-edge values ranging from 15 to 70 keV. Different filter material thicknesses are used, approximately equivalent to the 200th and 500th attenuating value layer (VL) thickness. Cerium (K = 40.4 keV) filtered post-breast spectra for 8-18 cm breasts are measured for a range of breast compositions. Figures of merit include mean beam energy, spectral full-width at tenth-maximum, beam hardening and dose for the range of breast sizes. Measurements corroborate simulation results, indicating that for a given dose, a 200th VL of cerium filtration may have optimal performance in the dedicated mammotomography paradigm.


Macroscopic Portal Vein Thrombosis in HCC Patients.
Macroscopic portal vein invasion (PVT) by hepatocellular carcinoma (HCC) in the liver is one of the most important negative prognostic factors for HCC patients. The characteristics of a large cohort of such patients were examined. We found that the percent of patients with PVT significantly increased with increasing maximum tumor diameter (MTD), from 13.7% with tumors of MTD <5cm to 56.4% with tumors of MTD >10cm. There were similar numbers of HCC patients with very large tumors with and without PVT. Thus, MTD alone was insufficient to explain the presence of PVT, as were high AFP levels, since less than 50% of high AFP patients had PVT. However, the percent of patients with PVT was also found to significantly increase with increasing blood alpha-fetoprotein (AFP) levels and tumor multifocality. A logistic regression model that included these 3 factors together showed an odds ratio of 17.9 for the combination of MTD>5.0cm plus tumor multifocality plus elevated AFP, compared to low levels of these 3 parameters. The presence or absence of macroscopic PVT may therefore represent different HCC aggressiveness phenotypes, as judged by a significant increase in tumor multifocality and AFP levels in the PVT positive patients. Factors in addition to MTD and AFP must also contribute to PVT development.


Neoplasia and the Heart: Pathological Review of Effects With Clinical and Radiological Correlation.
The intersection of oncological and cardiovascular diseases is an increasingly recognized phenomenon. This recognition has led to the emergence of cardio-oncology as a true subspecialty. This field is not simply limited to primary cardiac tumors or complications of chemotherapeutic medications. Rather, it also encompasses metastatic cardiovascular complications and secondary cardiovascular effects of the underlying neoplasia. This review will broadly cover primary and metastatic cardiac neoplasms, as well as secondary cardiovascular effects of extracardiac neoplasia (e.g., amyloidosis, carcinoid valvulopathy, and chemotherapeutic cardiotoxicities).


Temporally distinct and ligand-specific recruitment of nuclear receptor-interacting peptides and cofactors to subnuclear domains containing the estrogen receptor.
Ligand binding to estrogen receptor (ER) is presumed to regulate the type and timing of ER interactions with different cofactors. Using fluorescence microscopy in living cells, we characterized the recruitment of five different green fluorescent protein (GFP)-labeled ER-interacting peptides to the distinct subnuclear compartment occupied by blue fluorescent protein (BFP)-labeled ER alpha. Different ligands promoted the recruitment of different peptides. One peptide was recruited in response to estradiol (E2), tamoxifen, raloxifene, or ICI 182,780 incubation whereas other peptides were recruited specifically by E2 or tamoxifen. Peptides containing different sequences surrounding the ER-interacting motif LXXLL were recruited with different time courses after E2 addition. Complex temporal kinetics also were observed for recruitment of the full-length, ER cofactor glucocorticoid receptor-interacting protein 1 (GRIP1); rapid, E2-dependent recruitment of GRIP1 was blocked by mutation of the GRIP1 LXXLL motifs to LXXAA whereas slower E2 recruitment persisted for the GRIP1 LXXAA mutant. This suggested the presence of multiple, temporally distinct GRIP 1 recruitment mechanisms. E2 recruitment of GRIP1 and LXXLL peptides was blocked by coincubation with excess ICI 182,780. In contrast, preformed E2/ER/GRIP1 and E2/ER/LXXLL complexes were resistant to subsequent ICI 182,780 addition whereas ICI 182,780 dispersed preformed complexes containing the GRIP1 LXXAA mutant. This suggested that E2-induced LXXLL binding altered subsequent ligand/ER interactions. Thus, alternative, ligand-selective recruitment and dissociation mechanisms with distinct temporal sequences are available for ER alpha action in vivo.


Global reactivation of epigenetically silenced genes in prostate cancer.
Transcriptional silencing associated with aberrant promoter hypermethylation is a common mechanism of inactivation of tumor suppressor genes in cancer cells. To globally profile the genes silenced by hypermethylation in prostate cancer, we screened a whole genome expression microarray for genes reactivated in the LNCaP, DU-145, PC-3, and MDA2b prostate tumor cell lines after treatment with the demethylating drug 5-aza-2-deoxycytidine and the histone deacetylation-inhibiting drug trichostatin A. A total of 2,997 genes showed at least 2-fold upregulation of expression after drug treatment in at least one prostate tumor cell line. For validation, we examined the first 45 genes, ranked by upregulation of expression, which had a typical CpG island and were known to be expressed in the normal cell counterpart. Two important findings were, first, that several genes known to be frequently hypermethylated in prostate cancer were apparent, and, second, that validation studies revealed eight novel genes hypermethylated in the prostate tumor cell lines, four of which were unmethylated in normal prostate cells and hypermethylated in primary prostate tumors (SLC15A3, 66%; KRT7, 54%; TACSTD2, 17%; GADD45b, 3%). Thus, we established the utility of our screen for genes hypermethylated in prostate cancer cells. One of the novel genes was TACSTD2/TROP2, a marker of human prostate basal cells with stem cell characteristics. TACSTD2 was unmethylated in prostatic intraepithelial neoplasia and may have utility in emerging methylation-based prostate cancer tests. Further study of the hypermethylome will provide insight into the biology of the disease and facilitate translational studies in prostate cancer.


Carnosic Acid Alleviates BDL-Induced Liver Fibrosis through miR-29b-3p-Mediated Inhibition of the High-Mobility Group Box 1/Toll-Like Receptor 4 Signaling Pathway in Rats.
Fibrosis reflects a progression to liver cancer or cirrhosis of the liver. Recent studies have shown that high-mobility group box-1 (HMGB1) plays a major role in hepatic injury and fibrosis. Carnosic acid (CA), a compound extracted from rosemary, has been reported to alleviate alcoholic and non-alcoholic fatty liver injury. CA can also alleviate renal fibrosis. We hypothesized that CA might exert anti-liver fibrosis properties through an HMGB1-related pathway, and the results of the present study showed that CA treatment significantly protected against hepatic fibrosis in a bile duct ligation (BDL) rat model. CA reduced the liver expression of α-smooth muscle actin (α-SMA) and collagen 1 (Col-1). Importantly, we found that CA ameliorated the increase in HMGB1 and Toll-like receptor 4 (TLR4) caused by BDL, and inhibited NF-κB p65 nuclear translocation in fibrotic livers. In vitro, CA inhibited LX2 cell activation by inhibiting HMGB1/TLR4 signaling pathway. Furthermore, miR-29b-3p decreased HMGB1 expression, and a dual-luciferase assay validated these results. Moreover, CA down-regulated HMGB1 and inhibited LX2 cell activation, and these effects were significantly counteracted by antago-miR-29b-3p, indicating that the CA-mediated inhibition of HMGB1 expression might be miR-29b-3p dependent. Collectively, the results demonstrate that a miR-29b-3p/HMGB1/TLR4/NF-κB signaling pathway, which can be modulated by CA, is important in liver fibrosis, and indicate that CA might be a prospective therapeutic drug for liver fibrosis.


[Clinicoepidemiological analysis of genetic testing in 1,000 cases of hereditary neurological disorders].
A total of 1,000 neurological patients were examined for genetic testings at the Department of Neurology, Okayama University, from 1992 to 2010. To investigate the role and significance of genetic testings in neurological diagnostic consultation, we divided the analysis period into two, the former period (1992 to 2000) and the latter period (2001 to 2010). The number of genetic testings was 669 cases in the former period, and 331 cases in the latter period. However, the positive rate of genetic testings was 25.3% in the former period, and 48.1% in the latter period. The reason of this remarkable rise of the positive rate in the latter period was mainly attributable to our feedback inquiry to the doctors from 2001, noticing them the total number of test in a year, positive rate with or without family history, and an encouragement to examine more clinical details of their patients. The genetic testing plays an essential role in clinical neurology. It is important that the application of genetic testing to each case should be considered more carefully and properly.


ATLANTIC-DIP: raised maternal body mass index (BMI) adversely affects maternal and fetal outcomes in glucose-tolerant women according to International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria.
Raised maternal body mass index (BMI) in association with hyperglycemia is associated with adverse pregnancy outcome. The contribution of raised BMI as an independent risk factor for adverse pregnancy outcome is of growing concern and increasing prevalence. The aim of this study was to investigate the effects of raised maternal BMI on pregnancy outcome in glucose-tolerant women using the International Association of Diabetes and Pregnancy Study Groups criteria. We studied a cohort of glucose-tolerant, pregnant women (n = 3656) who were attending antenatal obstetric clinics and were recruited to a universal screening program for gestational diabetes under the ATLANTIC-DIP partnership. We conducted a prospective observational study of pregnancy outcome. Maternal outcomes include glucose, delivery mode, pregnancy-induced hypertension, preeclampsia, antepartum hemorrhage, and postpartum hemorrhage. Fetal outcomes included birthweight, congenital malformation, fetal death, neonatal jaundice, hypoglycemia, and respiratory distress. Increasing maternal BMI was associated with adverse pregnancy outcomes: higher cesarean section rates, preeclampsia, pregnancy-induced hypertension, increased birth weight, and congenital malformation. The association of glucose with adverse pregnancy outcome was weak and did not interact with raised BMI. A BMI threshold of 28 kg/m(2) was associated with a significant rise in adverse pregnancy outcome. Raised maternal BMI, within the overweight range, is associated with adverse pregnancy outcomes. These adverse effects of BMI occur independently of maternal glucose. It is apparent that pregnancy unmasks an underlying unhealthy metabolic milieu in obese and overweight women.


Estrogen-dependent Leydig cell protein recognized by monoclonal antibody to MCF-7 cell line.
A protein (27,000 molecular weight) was previously found in rat Leydig cells after treatment with estradiol (E2) and human chorionic gonadotropin (hCG) in vitro. The effect of hCG occurred through increased E2 production. This hormone-regulated rat testicular protein was compared to an estrogen-regulated protein of similar physical characteristics isolated from a human mammary cancer cell line (MCF-7) and present in normal human estrogen target organs. The Leydig cells from rat and human tissue showed specific immunofluorescence and immunoperoxidase staining in the cytoplasm upon incubation with a monoclonal antibody (C11) to the estrogen-regulated protein from MCF-7 cells. Leydig cells after exposure to E2 or hCG showed the highest fluorescence intensity; this intensity was reduced by treatment with Tamoxifen. No reaction was associated with other testicular cells. The estrogen-regulated protein from human cell lines is therefore immunologically similar to that from the rat Leydig cell. The monoclonal antibody should be useful for further characterization of the Leydig cell protein.


Innate antifungal immunity of human eosinophils mediated by a beta 2 integrin, CD11b.
Eosinophils produce and release various proinflammatory mediators and also show immunomodulatory and tissue remodeling functions; thus, eosinophils may be involved in the pathophysiology of asthma and other eosinophilic disorders as well as host defense. Several major questions still remain. For example, how do human eosinophils become activated in diseased tissues or at the site of an immune response? What types of host immunity might potentially involve eosinophils? Herein, we found that human eosinophils react vigorously to a common environmental fungus, Alternaria alternata, which is implicated in the development and/or exacerbation of human asthma. Eosinophils release their cytotoxic granule proteins, such as eosinophil-derived neurotoxin and major basic protein, into the extracellular milieu and onto the surface of fungal organisms and kill the fungus in a contact-dependent manner. Eosinophils use their versatile beta(2) integrin molecule, CD11b, to adhere to a major cell wall component, beta-glucan, but eosinophils do not express other common fungal receptors, such as dectin-1 and lactosylceramide. The I-domain of CD11b is distinctively involved in the eosinophils' interaction with beta-glucan. Eosinophils do not react with another fungal cell wall component, chitin. Because human eosinophils respond to and kill certain fungal organisms, our findings identify a previously unrecognized innate immune function for eosinophils. This immune response by eosinophils may benefit the host, but, in turn, it may also play a role in the development and/or exacerbation of eosinophil-related allergic human diseases, such as asthma.


The roles of c-Jun NH2-terminal kinases (JNKs) in obesity and insulin resistance.
Obesity is currently at epidemic levels worldwide and is associated with a wide range of diseases such as type 2 diabetes, cardiovascular disease, fatty liver disease and certain forms of cancer. Obesity-induced chronic inflammation is central to the disrupted metabolic homeostasis which underlies many of these conditions. While research over the past decade has identified many of the cells and signalling molecules that contribute to obesity-induced inflammation, perhaps the best characterised are the stress-activated c-Jun NH2 -terminal kinases (JNKs). JNKs are activated in obesity in numerous metabolically important cells and tissues such as adipose tissue, macrophages, liver, skeletal muscle and regions of the brain and pituitary. Elegant in vivo mouse studies using Cre-LoxP-mediated recombination of the JNK1 and JNK2 genes have revealed the remarkably diverse roles that JNKs play in the development of obesity-induced inflammation, impaired glucose homeostasis and hepatic steatosis. While JNK activation in classical metabolically active tissues such as skeletal muscle and adipose tissue only appears to play a minor role on the induction of the above-mentioned pathologies, recent studies have clearly established the important roles JNK signalling fulfils in macrophages, the liver and cells of the anterior pituitary. Collectively, these studies place JNKs as important mediators of obesity and obesity-associated disruptions to metabolic homeostasis.


Impact of chronic gastrointestinal symptoms in diabetes mellitus on health-related quality of life.
Morbidity from GI symptoms in diabetes is considered to be high, but no studies have quantified the impact of GI symptoms in diabetes on health-related quality of life. We hypothesized that diabetics reporting increased GI symptoms would experience more impaired quality of life. Subjects from the community with diabetes (n = 892) and outpatients with diabetes (n = 209) were recruited for this study. Subjects were divided into type 1 (diabetes diagnosed at age <30 yr and requiring insulin) and type 2. A validated questionnaire measuring GI symptoms and diabetes status and the Short Form-36 were completed. The results were compared with Australian normal data. GI symptom groups measured were frequent abdominal pain, bowel-related abdominal pain, reflux, dyspepsia, constipation, diarrhea, and fecal incontinence. There was a clinically significant decrease in quality-of-life scores in diabetics compared with population norms across all subscales. The impact on quality of life in diabetes was predominantly observed in type 2 diabetics. The quality-of-life scores in all subscales decreased markedly with increasing numbers of distinct GI symptom groups, and this was similar in community and outpatient diabetics. For all the Short Form-36 subscales, GI symptom groups were significantly (all p < 0.0001) associated with poorer quality of life in diabetes, independent of age, gender, smoking, alcohol use, and type of diabetes. GI symptoms impact negatively on health-related quality of life in diabetes mellitus.


Marjolin ulcers: secondary carcinomas in chronic wounds.
Marjolin ulcers are malignant tumors arising in chronic wounds. Strictly defined, they include carcinomas that transform from the chronic open wounds of pressure sores or burn scars. They behave aggressively and have a propensity for local recurrence and lymph node metastases. A retrospective study was done at a single institution identifying six individuals who had chronic wound ulcers that underwent malignant transformation into a carcinoma. Sinus tract degeneration in osteomyelitis was not included. The average latency time between ulcer formation and documentation of a malignancy was 30 years. All wounds were about the pelvis or flank. Major oncologic surgical procedures were done in an attempt to eradicate the cancer. High-grade tumors had positive lymph node metastases, portending a grave prognosis. All four individuals with nodal metastases eventually died of systemic disease. Early recognition and proper staging offers the best chance for cure.


Desert ant navigation: how miniature brains solve complex tasks.
This essay presents and discusses the state of the art in studies of desert ant (Cataglyphis) navigation. In dealing with behavioural performances, neural mechanisms, and ecological functions these studies ultimately aim at an evolutionary understanding of the insect's navigational toolkit: its skylight (polarization) compass, its path integrator, its view-dependent ways of recognizing places and following landmark routes, and its strategies of flexibly interlinking these modes of navigation to generate amazingly rich behavioural outputs. The general message is that Cataglyphis uses path integration as an egocentric guideline to acquire continually updated spatial information about places and routes. Hence, it relies on procedural knowledge, and largely context-dependent retrieval of such knowledge, rather than on all-embracing geocentred representations of space.


From migration to nomadism: movement variability in a northern ungulate across its latitudinal range.
Understanding the causes and consequences of animal movements is of fundamental biological interest because any alteration in movement can have direct and indirect effects on ecosystem structure and function. It is also crucial for assisting spatial wildlife management under variable environmental change scenarios. Recent research has highlighted the need of quantifying individual variability in movement behavior and how it is generated by interactions between individual requirements and environmental conditions, to understand the emergence of population-level patterns. Using a multi-annual movement data set of 213 individual moose (Alces alces) across a latitudinal gradient (from 56 degrees to 67 degrees N) that spans over 1100 km of varying environmental conditions, we analyze the differences in individual and population-level movements. We tested the effect of climate, risk, and human presence in the landscape on moose movements. The variation in these factors explained the existence of multiple movements (migration, nomadism, dispersal, sedentary) among individuals and seven populations. Population differences were primarily related to latitudinal variation in snow depth and road density. Individuals showed both fixed and flexible behaviors across years, and were less likely to migrate with age in interaction with snow and roads. For the predominant movement strategy, migration, the distance, timing, and duration at all latitudes varied between years. Males traveled longer distances and began migrating later in spring than females. Our study provides strong quantitative evidence for the dynamics of animal movements in response to changes in environmental conditions along with varying risk from human influence across the landscape. For moose, given its wide distributional range, changes in the distribution and migratory behavior are expected under future warming scenarios.


One-step patterning of hybrid xerogel materials for the fabrication of disposable solid-state light emitters.
The one-step room-temperature micropatterning of a fluorophore-doped xerogel material on silicon oxide substrates is reported. The organo-alkoxysilane precursors and organic fluorescent dyes, as well as the polymerization experimental conditions, were tailored in order to obtain a highly homogeneous transparent material suitable for photonic applications. A thorough structural characterization was carried out by Fourier transform infrared (FT-IR) spectroscopy, (29)Si nuclear magnetic resonance ((29)Si NMR), thermogravimetric analysis (TGA), N(2) adsorption Brunauer-Emmett-Teller (BET) porosimetry, and confocal microscopy. These studies revealed a stable nonporous highly cross-linked polymer network containing evenly dispersed fluorescent molecules. Xerogel microstructures having thicknesses between 4 and 80 μm and height-to-width ratios between 0.04 and 4, as well as showing different geometries, from well arrays to waveguides, were patterned in a single step by micromolding in capillaries (MIMIC) soft lithographic technique. The reliability of the replication process was tested by bright-field optical microscopy and scanning electron microscopy (SEM) that show the close fidelity of the microstructures to the applied mold. The optical performance of the developed material was demonstrated by fabricating waveguides and evaluating their corresponding spectral response, obtaining absorption bands, at the expected excitation wavelengths of the corresponding fluorescent dyes and gain due to photonic re-emission (fluorescence) at their corresponding dye emission wavelengths. The hybrid xerogel material and the application of the simple fabrication technology presented herein can be directly applied to the development of cost-effective photonic components, as could be light emitters, to be readily integrated in single-use lab-on-chip devices and other polymeric microsystems.


Abomasal infusion of arginine stimulates SCD and C/EBPß gene expression, and decreases CPT1ß gene expression in bovine adipose tissue independent of conjugated linoleic acid.
Based on previous research with bovine peadipocytes, we hypothesized that infusion of arginine into the abomasum of Angus steers stimulates stearoyl-CoA desaturase (SCD) gene expression in bovine subcutaneous (s.c.) adipose tissue, and that this would be attenuated by conjugated linoleic acid (CLA). Growing Angus steers were infused abomasally with L-arginine 50 g/day; n = 13; provided as L-arginine HCl) or L-alanine (isonitrogenous control, 100 g/day; n = 11) for 14 days. For the subsequent 14 days, half of the steers in each amino acid group were infused with CLA (100 g/day). Body weight gain and average daily gain were unaffected (P > 0.15) by infusion of arginine or CLA into the abomasum. The plasma concentrations of cis-9, trans-11 and trans-10, cis-12 CLA were increased CLA infusion (P = 0.001) and infusion of arginine increased plasma arginine (P = 0.01). Compared with day 0, fatty acid synthase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase enzyme activities in s.c. adipose tissue increased by day 14 in steers infused with either alanine or arginine (all P < 0.01). NADP-MDH activity was higher (P = 0.01) in steers infused with arginine than in steers infused with arginine plus CLA by day 28, but lipid synthesis in vitro from glucose and acetate was unaffected by infusion of either arginine or CLA (P > 0.40). By day 28, C/EBPβ and SCD gene expression was higher, and CPT1β gene expression was lower, in s.c. adipose tissue of steers infused with arginine than in steers infused with alanine (±CLA) (P = 0.05). CLA decreased adipose tissue oleic acid (18:1n-9) in alanine- or arginine-infused steers (P = 0.05), although CLA had no effect on SCD gene expression. The data indicate that supplemental arginine promotes adipogenic gene expression and may promote lipid accumulation in bovine adipose tissue. L-Arginine may beneficially improve beef quality for human consumption.