Immune-regulation of the apolipoprotein A-I/C-III/A-IV gene cluster in experimental inflammation.
Apolipoprotein A-IV is a member of the apo A-I/C-III/A-IV gene cluster. In order to investigate its hypothetical coordinated regulation, an acute phase was induced in pigs by turpentine oil injection. The hepatic expression of the gene cluster as well as the plasma levels of apolipoproteins were monitored at different time periods. Furthermore, the involvement of the inflammatory mediators' interleukins 1 and 6 and tumor necrosis factor in the regulation of this gene cluster was tested in cultured pig hepatocytes, incubated with those mediators and apo A-I/C-III/A-IV gene cluster expression at the mRNA level was measured. In response to turpentine oil-induced inflammation, a decreased hepatic apo A-IV mRNA expression was observed (independent of apo A-I and apo C-III mRNA) not correlating with the plasma protein levels. The distribution of plasma apo A-IV experienced a shift from HDL to larger particles. In contrast, the changes in apo A-I and apo C-III mRNA were reflected in their corresponding plasma levels. Addition of cytokines to cultured pig hepatocytes also decreased apo A-IV and apo A-I mRNA levels. All these results show that the down-regulation of apolipoprotein A-I and A-IV messages in the liver may be mediated by interleukin 6 and TNF-alpha. The well-known HDL decrease found in many different acute-phase responses also appears in the pig due to the decreased expression of apolipoprotein A-I and the enlargement of the apolipoprotein A-IV-containing HDL.


Effects of Percutaneous Transluminal Angioplasty of Superficial Femoral Artery on Photoplethysmographic Pulse Transit Times.
We analyze the changes in upper and lower limb pulse transit times (PTT) caused by peripheral artery disease (PAD) and its treatment with percutaneous transluminal angioplasty (PTA) of the superficial femoral artery. PTTs were extracted from the photoplethysmograms (PPG) recorded from an index finger and 2nd toes. PTTs were defined between the R-peaks of the ECG and different reference points of the PPG: foot and peak points, maxima of 1st and 2nd derivative, and by means of intersecting tangents method. Also the PTTs between the toe and finger pulses were analyzed. Our sample consists of 24 subjects examined before and after the PTA and in 1-month follow-up visit. Also 28 older than 65 years controls having normal ankle-to-brachial pressure index (ABI) and no history in cardiovascular diseases as well as 21 younger subjects were examined. The differences between the groups and pre- and post-treatment phases were analyzed by means of non-parametric statistical tests. The changes in the PTTs of upper limb and non-treated lower limb were negligible. The agreement with the reference values, ABI and toe pressures, was studied by kappa-analysis, resulting in kappa-values of 0.33-0.91. Differences in PTTs were found between pre-treatment state of the treated limb, post-treatment state and the follow-up visit, as well as between the pre-treatment state and controls. If patients' age and systolic blood pressure were taken into consideration, the method of lower limb PTT calculation from the peak point turns out feasible in finding the markers of PAD and monitoring post-treatment vascular remodellation.


The evolutionary rate of nonpathogenic simian immunodeficiency virus (SIVagm) is in agreement with a rapid and continuous replication in vivo.
African green monkeys (AGMs) are divided into four species (Cercopithecus aethiops, C. pygerythrus, C. sabaeus, C. tantalus), each harboring a species-specific simian immunodeficiency virus (SIVagm). Little is known about the host and/or viral factors that are responsible for the apathogenicity of SIVagm infections in their natural hosts. In order to analyze the specific selective pressures exerted by the host on the virus in vivo, we compared the genetic evolution of SIVagm.tan in its natural host (C. tantalus) and in a foreign host species (Erythrocebus patas), in which we could obtain a reproducible and persistent infection by SIVagm.tan. As in AGMs, patas monkeys do not develop any disease following SIVagm infection. Our longitudinal study in env (V3-C3-V4-C4-V5) of SIVagm.tan from three AGMs and three patas monkeys revealed a high ratio of synonymous to nonsynonymous mutation frequencies (1.5-6.2). These data indicate that the selective pressures for stability exerted by AGMs and patas monkeys on SIVagm override positive selection for change reported in pathogenic HIV-1 infections. The rapid accumulation of mutations observed in AGMs and patas monkeys (0.4-7.2 x 10(-2) nucleotide substitutions per site per year) suggests a continuous replication of SIVagm viruses in vivo. We thus propose that nonpathogenic SIVagm infections are the result of a long-term selection of SIVagm variants whose dissemination can be controlled in the host, rather than being explained by a low ability of the virus to replicate in vivo.


Characterisation and Molecular Analysis of an Unusual Chimeric Methicillin Resistant Staphylococcus Aureus Strain and its Bacteriophages.
In the context of microarray-based epidemiological typing of the clonal organism Staphylococcus aureus/MRSA, a strain was identified that did not belong to known clonal complexes. The molecular analysis by microarray-based typing yielded signals suggesting that it was a mosaic or hybrid strain of two lineages. To verify this result, the isolate was sequenced with both, short-read Illumina and long-read Nanopore technologies and analysed in detail. This supported the hypothesis that the genome of this strain, ST6610-MRSA-IVg comprised of segments originating from two different clonal complexes (CC). While the backbone of the strain's genome, i.e., roughly 2 megabases, belongs to CC8, a continuous insert of 894 kb (approx. 30% of the genome) originated from CC140. Beside core genomic markers in the normal succession and orientation, this insert also included the mecA gene, coding for PbP2a and causing methicillin resistance, localised on an SCCmec IVg element. This particular SCCmec type was also previously observed in CC140 MRSA from African countries. A second conspicuous observation was the presence of the trimethoprim resistance gene dfrG within on a prophage that occupied an attachment site normally used by Panton-Valentine Leucocidin phages. This observation could indicate a role of large-scale chromosomal recombination in the evolution of S. aureus as well as a role of phages in the dissemination of antibiotic resistance genes.


Prevalence and associated factors of alexithymia among Chinese adolescents in Hong Kong.
Alexithymia ("no words for feelings") is a personality construct characterized by an inability to identify, describe, and verbalize one's feelings, constricted imagination, and an externally oriented way of thinking. Alexithymia is commonly measured with self-report instruments. Data, in particular from Asian countries, regarding the epidemiology of alexithymia in adolescents are relatively limited. The objectives of this study were to examine the prevalence and explore the relationship between alexithymia, family emotional expressiveness, parental acceptance-rejection, and depression. A total of 1606 Chinese adolescents aged between 10 and 17 years old were recruited from 11 schools across the three major geographical regions of Hong Kong. A self-report questionnaire was administered. About 36% of adolescents were classified as alexithymic in the whole sample (males: 34.3%, females: 40.0%) and no gender differences were found. Adolescents with lower family emotional expressiveness and depression were more likely to report alexithymia. The alexithymia rate among Chinese adolescents was higher than in most of the existing studies. The association of alexithymia with diminished family emotional expressiveness underscores the relevance of targeting adolescents with low family emotional expressiveness, and depressive symptoms to increase their capacity to identify and communicate emotions in order to improve their psychological well-being.


Evaluation of analgesic effect of local administration of morphine after iliac crest bone graft harvesting: A double blind study.
Pain is a complex process influenced by both physiological and psychological factors. In spite of an armamentarium of analgesic drugs and techniques available to combat post-operative pain, appropriate selection, and effective management for relief of post-operative pain still poses unique challenges. The discovery of peripheral opioid receptors has led to growing interest in the use of locally applied opioids (intra-articular, intra-pleural, intra-peritoneal, and perineural) for managing acute pain. As bone graft harvesting is associated with significant post-operative pain and there is a paucity of literature on the use of peripheral opioids at the iliac crest bone harvesting site, the present study was planned to evaluate the analgesic efficacy of local administration of morphine after iliac crest bone graft harvesting. A total of 60 patients, 20-50 years of age scheduled to undergo elective surgery for delayed and non-union fracture both bone leg with bone grafting under general anaesthesia (GA) were randomly assigned to one of the four groups of 15 patients each: group 1: 2.5 ml normal saline (NS) +2.5 ml NS infiltrated into the harvest site at 2 sites + 1 ml NS intramuscularly (i/m); Group 2: 2.5 ml NS + 2.5 ml NS infiltrated into the harvest site at 2 sites + 5 mg morphine in 1 ml i/m.; Group 3: 2.5 mg (2.5 ml) morphine + 2.5 mg (2.5 ml) morphine infiltrated into the harvest site at 2 sites + 1 ml NS i/m; Group 4: 0.5 mg naloxone (2.5 ml) +5 mg (2.5 ml) morphine infiltrated into the harvest site at 2 sites + 1 ml NS i/m. Pain from the bone graft site and operative site was assessed for 24 h post-operatively. The patients who had received morphine infiltration (Group 3) had significantly less pain scores at the graft site at 4, 6, and 10 post-operative hours. They also had significantly less morphine consumption and overall better pain relief as compared to the other groups. Morphine administered peripherally provided better analgesia as compared to that given systemically and this effect was noticeable after 4 h post-operatively.


Self-related awareness and emotion regulation.
The regulation of emotions is an ongoing internal process and often a challenge. Current related neural models concern the intended control of reactions towards external events, mediated by prefrontal cortex regions upon basal emotion processing as in the amygdala. Cognitive strategies to regulate emotions in the context of affective disorders or stress reduction, increasingly applied in clinical practice, are also related to mindfulness techniques. We questioned their effects on neural emotion processing and investigated brain activity during purely internal mental self-referential processes of making current emotions and self-related cognitions aware. Thirty healthy subjects performed a task comprising periods of cognitive self-reflection, of introspection for actual own emotions and feelings, and of a neutral condition, while they were scanned with functional magnetic resonance imaging. Brain activations of twenty-seven subjects during emotion-introspection and self-reflection, and also a conjunction of both, were compared with the neutral condition. The conditions of self-reflection and emotion-introspection showed distinguishable activations in medial and ventrolateral prefrontal areas, in parietal regions and in the amygdala. Notably, amygdala activity decreased during emotion-introspection and increased compared to 'neutral' during self-reflection. The results indicate that already the self-referential mental state of making the actual emotional state aware is capable of attenuating emotional arousal. This extends current theories of emotion regulation and has implications for the application of mindfulness techniques as a component of psychotherapeutic strategies in affective disorders and also for possible everyday emotion regulation.


Sox2 is required for olfactory pit formation and olfactory neurogenesis through BMP restriction and Hes5 upregulation.
The transcription factor Sox2 is necessary to maintain pluripotency of embryonic stem cells, and to regulate neural development. Neurogenesis in the vertebrate olfactory epithelium persists from embryonic stages through adulthood. The role Sox2 plays for the development of the olfactory epithelium and neurogenesis within has, however, not been determined. Here, by analysing Sox2 conditional knockout mouse embryos and chick embryos deprived of Sox2 in the olfactory epithelium using CRISPR-Cas9, we show that Sox2 activity is crucial for the induction of the neural progenitor gene Hes5 and for subsequent differentiation of the neuronal lineage. Our results also suggest that Sox2 activity promotes the neurogenic domain in the nasal epithelium by restricting Bmp4 expression. The Sox2-deficient olfactory epithelium displays diminished cell cycle progression and proliferation, a dramatic increase in apoptosis and finally olfactory pit atrophy. Moreover, chromatin immunoprecipitation data show that Sox2 directly binds to the Hes5 promoter in both the PNS and CNS. Taken together, our results indicate that Sox2 is essential to establish, maintain and expand the neuronal progenitor pool by suppressing Bmp4 and upregulating Hes5 expression.


FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma.
Extraventricular neurocytoma (EVN) is a rare primary brain tumor occurring in brain parenchyma outside the ventricular system. Histopathological characteristics resemble those of central neurocytoma but exhibit a wider morphologic spectrum. Accurate diagnosis of these histologically heterogeneous tumors is often challenging because of the overlapping morphological features and the lack of defining molecular markers. Here, we explored the molecular landscape of 40 tumors diagnosed histologically as EVN by investigating copy number profiles and DNA methylation array data. DNA methylation profiles were compared with those of relevant differential diagnoses of EVN and with a broader spectrum of diverse brain tumor entities. Based on this, our tumor cohort segregated into different groups. While a large fraction (n = 22) formed a separate epigenetic group clearly distinct from established DNA methylation profiles of other entities, a subset (n = 14) of histologically diagnosed EVN grouped with clusters of other defined entities. Three cases formed a small group close to but separated from the epigenetically distinct EVN cases, and one sample clustered with non-neoplastic brain tissue. Four additional samples originally diagnosed otherwise were found to molecularly resemble EVN. Thus, our results highlight a distinct DNA methylation pattern for the majority of tumors diagnosed as EVN, but also indicate that approximately one third of morphological diagnoses of EVN epigenetically correspond to other brain tumor entities. Copy number analysis and confirmation through RNA sequencing revealed FGFR1-TACC1 fusion as a distinctive, recurrent feature within the EVN methylation group (60%), in addition to a small number of other FGFR rearrangements (13%). In conclusion, our data demonstrate a specific epigenetic signature of EVN suitable for characterization of these tumors as a molecularly distinct entity, and reveal a high frequency of potentially druggable FGFR pathway activation in this tumor group.


Anthracene-BODIPY cassettes: syntheses and energy transfer.
Compounds based on the 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY) framework are excellent fluorescent markers. When BODIPY dyes of this type are conjugated to functionalities that absorb at relatively short wavelengths, those functionalities can, in some molecules, transmit the absorbed energy to the BODIPY which then fluoresces. In such cases the BODIPY fragment acts as an acceptor while the other group serves as a donor. Energy transfer efficiencies in such donor-acceptor cassette systems must vary with the relative orientation of the two components, and with the structure of the linkers that attach them. This study was designed to probe these issues for the special case in which the linkers between the donor and acceptor fragments are conjugated. To do this, the cassettes 3-10 were prepared. Electrochemical studies were performed to provide insight into the degree of donor-acceptor conjugation in these systems. X-ray Crystallographic studies on single crystals of compounds 7 and 9 revealed the favored conformations of the donor and acceptor fragments in the solid state. Absorption, fluorescence, and time-resolved fluorescence spectra of the compounds were recorded, and quantum yields for the cassettes excited at the donor lambda(max) were measured. Fluorescence steady-state anisotropy data were determined for cassettes 3 and 9 to provide information about the mutual direction of the transition dipole moments.


Prediction of sublayer depth in turbid media using spatially offset Raman spectroscopy.
We demonstrate experimentally the feasibility of monitoring the depth of optically thick layers within turbid media using spatially offset Raman spectroscopy (SORS) in combination with multivariate analysis. The method uses the deep penetration capability of SORS to characterize significantly thicker (by at least a factor of 2) layers than possible with conventional Raman spectroscopy. Typical relative accuracies were between 5 and 10%. The incorporation of depth information into a SORS experiment as an additional dimension allows pure spectra of each individual layer to be resolved using three-dimensional multivariate techniques (parallel factor analysis, PARAFAC) to accuracies comparable with the results of a two-dimensional analysis.


Familial factors and suicide: an adoption study in a Swedish National Cohort.
Parental characteristics influence the risk of offspring suicide. In this study we wanted to separate the hereditary from the environmental influence of such factors by comparing their effects in the adopted versus non-adopted. A register study was conducted in a national cohort of 2,471,496 individuals born between 1946 and 1968, including 27,600 national adoptees, followed-up for suicide during 1987-2001. Cox regression was used to calculate hazard ratios (HR) for suicide of socio-economic indicators of the childhood household and biological parents' suicide, alcohol abuse and psychiatric morbidity separately in the adopted and non-adopted. Differences in effects were tested in interaction analyses. Suicide and indicators of severe psychiatric disorder in the biological parents had similar effects on offspring suicide in the non-adopted and adopted (HR 1.5-2.3). Biological parents' alcohol abuse was a risk factor for suicide in the non-adopted group only (HR 1.8 v. 0.8, interaction effect: p=0.03). The effects of childhood household socio-economic factors on suicide were similar in adopted and non-adopted individuals, with growing up in a single parent household [HR 1.5 (95% confidence interval 1.4-1.5)] as the most important socio-economic risk factor for the non-adopted. The main familial effects of parental suicide and psychiatric morbidity on offspring suicide are not mediated by the post-natal environment or imitation, in contrast to effects of parental alcohol abuse that are primarily mediated by the post-natal environment. Social drift over generations because of psychiatric disorders does not seem likely to explain the association of socio-economic living conditions in childhood to suicide.


A case of intrahepatic clear cell cholangiocarcinoma.
Intrahepatic clear cell cholangiocarcinoma is very rare - only 8 cases have been reported. A 56-year-old Japanese man with chronic hepatitis B infection was diagnosed with a 2.2 cm hepatocellular carcinoma on imaging, and hepatic segmentectomy was performed. Histopathologically, the tumor cells had copious clear cytoplasm and formed glandular structures or solid nests. These pathological findings suggested the tumor was a clear cell variant of intrahepatic cholangiocarcinoma. Particular stains and radiological images suggested that the cause of the clear cell change had been glycogen, not mucin nor lipid. On immunohistochemical staining, cytokeratin (CK) 7 and CK19 were positive, whereas CK20 was negative. Vimentin was detected on the cell membranes, and CD56 was focally positive. The patient was given adjuvant chemotherapy and is currently free from the tumor 7 mo postoperatively. Careful follow-up with adequate postoperative supplementary chemotherapy is necessary because the characteristics of this type of tumor are unknown.


UNR facilitates the interaction of MLE with the lncRNA roX2 during Drosophila dosage compensation.
Dosage compensation is a regulatory process that balances the expression of X-chromosomal genes between males (XY) and females (XX). In Drosophila, this requires non-coding RNAs and RNA-binding proteins (RBPs) whose specific functions remain elusive. Here we show that the Drosophila RBP UNR promotes the targeting of the activating male-specific-lethal complex to the X-chromosome by facilitating the interaction of two crucial subunits: the RNA helicase MLE and the long non-coding RNA roX2.


Emerging biomarkers and intervention targets for immune-modulation of atherosclerosis - a review of the experimental evidence.
The role of inflammation in atherosclerosis and plaque vulnerability is well recognized. However, it is only during recent years it has become evident that this inflammation is modulated by immune responses against plaque antigens such as oxidized LDL. Interestingly, both protective and pathogenic immune responses exist and experimental data from animal studies suggest that modulation of these immune responses represents a promising new target for treatment of cardiovascular disease. It has been proposed that during early stages of the disease, autoimmune responses against plaque antigens are controlled by regulatory T cells that inhibit the activity of auto-reactive Th1 effector T cells by release of anti-inflammatory cytokines such as IL-10 and TGF-β. As the disease progresses this control is gradually lost and immune responses towards plaque antigens switch towards activation of Th1 effector T cells and release of pro-inflammatory cytokines such as interferon-γ, TNF-α and IL-1β. Several novel immune-modulatory therapies that promote or mimic tolerogenic immune responses against plaque antigens have demonstrated athero-protective effects in experimental models and a first generation of such immune-modulatory therapies are now in early or about to enter into clinical testing. A challenge in the clinical development of these therapies is that our knowledge of the role of the immune system in atherosclerosis largely rests on data from animal models of the disease. It is therefore critical that more attention is given to the characterization and evaluation of immune biomarkers for cardiovascular risk.


Aptamer-conjugated gold nanorod for photothermal ablation of epidermal growth factor receptor-overexpressed epithelial cancer.
Biomarker-specific photothermal nanoparticles that can efficiently sense markers that are overexpressed in distinguished adenocarcinomas have attracted much interest in an aspect of efficacy increase of cancer treatment. We demonstrated a promising prospect of a smart photothermal therapy agent employing anti-epidermal growth factor receptor aptamer (AptEGFR)-conjugated polyethylene glycol (PEG) layted gold nanorods (AptEGFR-PGNRs). The cetyltrimethylammonium bromide bilayer on GNRs was replaced with heterobifunctional PEG (COOH-PEG-SH) not only to serve as a biocompatible stabilizer and but also to conjugate AptEGFR. Subsequently, to direct photothermal therapy agent toward epithelial cancer cells, the carboxylated PEGylated GNRs (PGNRs) were further functionalized with AptEGFR using carbodiimide chemistry. Then, to assess the potential as biomarker-specific photothermal therapy agent of synthesized AptEGFR-PGNRs, the optical properties, biocompatibility, colloidal stability, binding affinity, and epicellial cancer cell killing efficacy in vitro/in vivo under near-infrared laser irradiation were investigated. As a result, AptEGFR-PGNRs exhibit excellent tumor targeting ability and feasibility of effective photothermal ablation cancer therapy.


Acute appendicitis in the elderly: risk factors for perforation.
Acute appendicitis is the most common surgical emergency and becomes serious when it perforates. Perforation is more frequent in the elderly patients. The aim of this study was to identify the risk factors of perforation in elderly patients who presented with acute appendicitis. The medical records of 214 patients over the age of 60 years who had a pathologically confirmed diagnosis of acute appendicitis over a period of 10 years (2003-2013) were retrospectively reviewed. Patients were grouped into those with perforated and those with nonperforated appendicitis. Comparison was made between both groups in regard to demography, clinical presentation, and time delay to surgery, diagnosis, hospital stay and postoperative complications. Clinical assessment, Ultrasonography and Computerized tomography, in that order, were used for diagnosis. The incidence of perforation was also compared with a previous report from the same region 10 years earlier. During the study period, a total of 214 patients over the age of 60 years had acute appendicitis, 103 males and 111 females. Appendix was found perforated in 87 (41%) patients, 46 (53%) males and 41 (47%) females. Of all patients, 31% were diagnosed by clinical assessment alone, 40% needed US and 29% CT scan. Of all the risk factors studied, the patient's pre-hospital time delay was the most important risk factor for perforation. Perforation rate was not dependent on the presence of comorbid diseases or in-hospital time delay. Post operative complications occurred in 44 (21%) patients and they were three times more common in the perforated group, 33 (75%) patients in the perforated and 11 (25%) in the nonperforated group. There were 6 deaths (3%), 4 in the perforated and 2 in the nonperforated group. Acute appendicitis in elderly patients is a serious disease that requires early diagnosis and treatment. Appendiceal Perforation increases both mortality and morbidity. All elderly patients presented to the hospital with abdominal pain should be admitted and investigated. The early use of CT scan can cut short the way to the appropriate treatment.


Neuroprotective effect of fermented papaya preparation by activation of Nrf2 pathway in astrocytes.
Nuclear factor erythroid 2-related factor (Nrf2) in astrocyte plays important roles in brain homeostasis. Fermented papaya preparation (FPP) has anti-oxidative, anti-inflammatory, immunoregulatory properties. The present study investigated the effects of FPP on activation of Nrf2 and release of Nrf2-regulated neuroprotective antioxidants and detoxifying molecules. Primary cultured astrocytes from rat embryos were treated with FPP for 6 or 24 hours. The expression levels of nuclear Nrf2 and cytoplasmic Nrf2-regulated molecules were determined by western blot analysis and immunohistochemistry. Glutathione levels were measured in cells and medium. Dopaminergic neurons were exposed 6-hydroxydopamine (6-OHDA) with/without pre-treatment with FPP astrocytes. Mice were treated orally with FPP for 2 weeks. FPP increased nuclear translocation of Nrf2 in striatal astrocytes, induced up-regulation of NAD(P)H quinine oxidoreductase-1, glutathione-S transferase and hemeoxygenase-1, and increased glutathione level and the percentage of metallothionein-expressing astrocytes. Moreover, FPP suppressed 6-OHDA-induced dopaminergic neuronal loss in not only neuron-astrocyte mixed culture, but also neuron-rich cultures pre-treated with glial conditioned medium. Two-week oral treatment of mice with FPP resulted in Nrf2 activation and increase in glutathione level in striatum. The results indicated that FPP enhances the anti-oxidative capacity through activation of Nrf2 in astrocytes, suggesting it may provide neuroprotection in oxidative stress-related neurodegenerative diseases.


Delay Period Activity of the Substantia Nigra during Proactive Control of Response Selection as Determined by a Novel fMRI Localization Method.
The ability to proactively control motor responses, particularly to overcome overlearned or automatic actions, is an essential prerequisite for adaptive, goal-oriented behavior. The substantia nigra (SN), an element of the BG, has figured prominently in current models of response selection. However, because of its small size and proximity to functionally distinct subcortical structures, it has been challenging to test the SN's involvement in response selection using conventional in vivo functional neuroimaging approaches. We developed a new fMRI localization method for directly distinguishing, on echo-planar images, the SN BOLD signal from that of neighboring structures, including the subthalamic nucleus (STN). Using this method, we tested the hypothesis that the SN supports the proactive control of response selection. We acquired high-resolution EPI volumes at 3 T from 16 healthy participants while they completed the Preparing to Overcome Prepotency task of proactive control. There was significantly elevated delay period signal selectively during high- compared with low-control trials in the SN. The STN did not show delay period activity in either condition. SN delay period signal was significantly inversely associated with task performance RTs across participants. These results suggest that our method offers a novel means for measuring SN BOLD responses, provides unique evidence of SN involvement in cognitive control in humans, and suggests a novel mechanism for proactive response selection.


KRIT1 regulates the homeostasis of intracellular reactive oxygen species.
KRIT1 is a gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhage. Comprehensive analysis of the KRIT1 gene in CCM patients has suggested that KRIT1 functions need to be severely impaired for pathogenesis. However, the molecular and cellular functions of KRIT1 as well as CCM pathogenesis mechanisms are still research challenges. We found that KRIT1 plays an important role in molecular mechanisms involved in the maintenance of the intracellular Reactive Oxygen Species (ROS) homeostasis to prevent oxidative cellular damage. In particular, we demonstrate that KRIT1 loss/down-regulation is associated with a significant increase in intracellular ROS levels. Conversely, ROS levels in KRIT1(-/-) cells are significantly and dose-dependently reduced after restoration of KRIT1 expression. Moreover, we show that the modulation of intracellular ROS levels by KRIT1 loss/restoration is strictly correlated with the modulation of the expression of the antioxidant protein SOD2 as well as of the transcriptional factor FoxO1, a master regulator of cell responses to oxidative stress and a modulator of SOD2 levels. Furthermore, we show that the KRIT1-dependent maintenance of low ROS levels facilitates the downregulation of cyclin D1 expression required for cell transition from proliferative growth to quiescence. Finally, we demonstrate that the enhanced ROS levels in KRIT1(-/-) cells are associated with an increased cell susceptibility to oxidative DNA damage and a marked induction of the DNA damage sensor and repair gene Gadd45alpha, as well as with a decline of mitochondrial energy metabolism. Taken together, our results point to a new model where KRIT1 limits the accumulation of intracellular oxidants and prevents oxidative stress-mediated cellular dysfunction and DNA damage by enhancing the cell capacity to scavenge intracellular ROS through an antioxidant pathway involving FoxO1 and SOD2, thus providing novel and useful insights into the understanding of KRIT1 molecular and cellular functions.


Associations of Sedentary Time with Fat Distribution in a High-Risk Population.
The effect of sedentary behavior on regional fat deposition, independent of physical activity, remains equivocal. We examined the cross-sectional associations between objectively measured sedentary time and markers of regional fat distribution (heart, liver, visceral, subcutaneous, and total body fat) in a population at a high risk of type 2 diabetes mellitus (T2DM). Participants were recruited from primary care to two diabetes prevention programs. Sedentary time (<25 counts per 15 s) was measured using ActiGraph GT3X accelerometers. Heart, liver, visceral, subcutaneous, and total body fat were quantified using magnetic resonance images. Fat volumes were calculated by multiplying the cross-sectional areas of the fat-containing pixels by the slice thickness. The liver fat percentage was measured using a representative region of interest created in the right lobe of the liver, avoiding the main portal veins. Linear regression models examined the association of sedentary time with markers of regional fat deposition. Sixty-six participants (age, 47.9 ± 16.2 yr; male, 50.0%) were included. After adjustment for several covariates, including glycemia, whole-body fat, and moderate-to-vigorous physical activity, each 30 min of sedentary time was associated with 15.7 cm higher heart fat (P = 0.008), 1.2% higher liver fat (P = 0.026), and 183.7 cm higher visceral fat (P = 0.039). This study provides new evidence suggesting that objectively measured sedentary behavior may have an independent association with heart, liver, and visceral fat in individuals at a high risk of T2DM.


Social competence among urban minority youth entering middle school: relationships with alcohol use and antisocial behaviors.
Social competence is increasingly multidimensional during adolescence as young people encounter a variety of new social situations and can respond with a broad range of appropriate behaviors. However, research on social competence has focused more on children than adolescents. The present study examined the relationships between components of social competence (e.g., assertiveness and social confidence) and adolescent problem behaviors including alcohol use and antisocial behaviors (e.g., aggression and delinquency). A survey was administered to 6th grade students (N=2411) entering 20 New York City public and parochial middle schools and again a year later in the 7th grade. Findings indicated that verbal aggression was reported most frequently among students (93%), followed by physical aggression (69%), delinquent behaviors (53%), and alcohol use (16%). Structural equation modeling indicated that while assertiveness was protective in terms of adolescent problem behaviors, social confidence--the level of confidence that students had in initiating social interactions including dating--was associated with greater alcohol use and antisocial behavior both cross-sectionally and longitudinally. Additional analyses revealed that social confidence related to the initiation of dating (e.g., asking someone out for a date or having a conversation with a member of the opposite sex) was most strongly correlated with each problem behavior outcome. These findings suggest that social confidence, particularly as it relates to precocious dating behavior during early adolescence, is a risk factor for the early initiation of alcohol use and antisocial behavior.


A mechanistic investigation of the photoinduced, copper-mediated cross-coupling of an aryl thiol with an aryl halide.
Photoinduced, copper-catalyzed cross-coupling can offer a complementary approach to thermal (non-photoinduced) methods for generating C-X (X = C, N, O, S, etc.) bonds. In this report, we describe the first detailed mechanistic investigation of one of the processes that we have developed, specifically, the (stoichiometric) coupling of a copper-thiolate with an aryl iodide. In particular, we focus on the chemistry of a discrete [CuI(SAr)2]- complex (Ar = 2,6-dimethylphenyl), applying a range of techniques, including ESI-MS, cyclic voltammetry, transient luminescence spectroscopy, optical spectroscopy, DFT calculations, Stern-Volmer analysis, EPR spectroscopy, actinometry, and reactivity studies. The available data are consistent with the viability of a pathway in which photoexcited [CuI(SAr)2]-* serves as an electron donor to an aryl iodide to afford an aryl radical, which then reacts in cage with the newly generated copper(II)-thiolate to furnish the cross-coupling product in a non-chain process.


Realized niche and microhabitat selection of the eastern green lizard (Lacerta viridis) at the core and periphery of its distribution range.
The available range of habitats and suitable abiotic conditions like temperature and radiation tends to be narrower toward the periphery of the distribution range of species. Peripheral populations of generalist species could then be more specialized and have a smaller and differentiated realized niche (habitat niche in our study) compared to populations at the core. Likewise, patterns of microhabitat selection can differ between periphery and core. In our study, we compared niche size and microhabitat selection among core (Bulgaria) and northern peripheral (Germany, Czech Republic) populations of Lacerta viridis and estimated niche differentiation among regions. We collected data on vegetation structure and abiotic parameters at the microhabitat scale in each region. In order to compare niche size among regions and estimate niche differentiation, we built multidimensional niche hypervolumes. We applied generalized linear mixed models and model averaging, accounting for spatial autocorrelation when necessary, to analyze microhabitat differences among regions and microhabitat selection in each region. Peripheral populations were more specialized, having a smaller niche than core ones, and their niche differed from that in the core (Sørensen overlap in all comparisons <0.3). Microhabitats at the periphery had lower radiation and soil compaction and less structured vegetation. Microhabitat selection at the core depended solely on abiotic parameters, while at the periphery it was defined by only vegetation structure (Czech Republic) or a combination of both, vegetation structure, and abiotic factors (Germany). Thus, peripheral populations seem to compensate for overall harsher climatic conditions by responding to different parameters of the microhabitat compared to core populations. We suggest specific conservation measures for L. virids in each studied region and point out the general implications of a higher specialization degree of peripheral populations in relation to climate change and habitat fragmentation.


Identification of small molecule synthetic inhibitors of DNA polymerase beta by NMR chemical shift mapping.
DNA polymerase beta (beta-pol) plays a central role in repair of damaged DNA bases by base excision repair (BER) pathways. A predominant phenotype of beta-pol null mouse fibroblasts is hypersensitivity to the DNA-methylating agent methyl methanesulfonate. Residues in the 8-kDa domain of beta-pol that seem to interact with a known natural product beta-pol inhibitor, koetjapic acid, were identified by NMR chemical shift mapping. The data implicate the binding pocket as the hydrophobic cleft between helix-2 and helix-4, which provides the DNA binding and deoxyribose phosphate lyase activities of the enzyme. Nine structurally related synthetic compounds, containing aromatic or other hydrophobic groups in combination with two carboxylate groups, were then tested. They were found to bind to the same or a very similar region on the surface of the enzyme. The ability of these compounds to potentiate methyl methanesulfonate cytotoxicity, an indicator of cellular BER capacity, in wild-type and beta-pol null mouse fibroblasts, was next ascertained. The most active and beta-pol-specific of these agents, pamoic acid, was further characterized and found to be an inhibitor of the deoxyribose phosphate lyase and DNA polymerase activities of purified beta-pol on a BER substrate. Our results illustrate that NMR-based mapping techniques can be used in the design of small molecule enzyme inhibitors including those with potential use in a clinical setting.


2009 ISSLS Prize Winner: Does discography cause accelerated progression of degeneration changes in the lumbar disc: a ten-year matched cohort study.
Prospective, match-cohort study of disc degeneration progression over 10 years with and without baseline discography. Objectives. To compare progression of common degenerative findings between lumbar discs injected 10 years earlier with those same disc levels in matched subjects not exposed to discography. Summary of Background Data. Experimental disc puncture in animal and in vivo studies have demonstrated accelerated disc degeneration. Whether intradiscal diagnostic or treatment procedures used in clinical practice causes any damage to the punctured discs over time is currently unknown. Seventy-five subjects without serious low back pain illness underwent a protocol MRI and an L3/4, L4/5, and L5/S1 discography examination in 1997. A matched group was enrolled at the same time and underwent the same protocol MRI examination. Subjects were followed for 10 years. At 7 to 10 years after baseline assessment, eligible discography and controlled subjects underwent another protocol MRI examination. MRI graders, blind to group designation, scored both groups for qualitative findings (Pfirrmann grade, herniations, endplate changes, and high intensity zone). Loss of disc height and loss of disc signal were measured by quantitative methods. Well matched cohorts, including 50 discography subjects and 52 control subjects, were contacted and met eligibility criteria for follow-up evaluation. In all graded or measured parameters, discs that had been exposed to puncture and injection had greater progression of degenerative findings compared to control (noninjected) discs: progression of disc degeneration, 54 discs (35%) in the discography group compared to 21 (14%) in the control group (P = 0.03); 55 new disc herniations in the discography group compared to 22 in the control group (P = 0.0003). New disc herniations were disproportionately found on the side of the anular puncture (P = 0.0006). The quantitative measures of disc height and disc signal also showed significantly greater loss of disc height (P = 0.05) and signal intensity (P = 0.001) in the discography disc compared to the control disc. Modern discography techniques using small gauge needle and limited pressurization resulted in accelerated disc degeneration, disc herniation, loss of disc height and signal and the development of reactive endplate changes compared to match-controls. Careful consideration of risk and benefit should be used in recommending procedures involving disc injection.


Classification of follicular thyroid tumors by molecular signature: results of gene profiling.
Thyroid nodules are common, with a lifetime risk of developing a clinically significant thyroid nodule of 10% or higher. Preoperative diagnosis was greatly enhanced by the introduction of fine needle aspiration in the 1970s, but there has been little advancement since that time. Discrimination between benign and malignant follicular neoplasms is currently not possible by fine needle aspiration and can even be difficult after full pathologic review. The purpose of these studies is to identify genes expressed in follicular adenomas and carcinomas of the thyroid that will permit molecular differentiation of these neoplasms. Gene expression patterns of 17 thyroid follicular tumors were analyzed by oligonucleotide array analysis. Gene profiles for follicular adenomas and carcinomas were identified, and the two groups were compared for differences in expression levels. The differentially expressed genes were used to perform a hierarchical clustering analysis training set. Five follicular tumors with diagnosis undisclosed to the investigators and 2 minimally invasive carcinomas were entered into the cluster analysis as a test set to determine whether diagnosis by gene profile correlated with that obtained by pathologic evaluation. Thyroid follicular adenomas and carcinomas showed strikingly distinct gene expression patterns. The expression patterns of 105 genes were found to be significantly different between follicular adenoma and carcinoma. Many uncharacterized genes contributed to the distinction between tumor types. For five follicular tumors for which the final diagnosis was undisclosed, the clustering algorithm gave the correct diagnosis in all 5 cases. Gene profiling is a useful tool to predict the molecular diagnosis of follicular thyroid tumors. Genes were identified that reliably differentiate follicular thyroid carcinoma from adenoma. This study provides insight into genes that may be important in the molecular pathogenesis of follicular thyroid tumors, as well candidates for preoperative diagnosis of follicular thyroid carcinoma.


Can the dissociative PTSD subtype be identified across two distinct trauma samples meeting caseness for PTSD?
For over a century, the occurrence of dissociative symptoms in connection to traumatic exposure has been acknowledged in the scientific literature. Recently, the importance of dissociation has also been recognized in the long-term traumatic response within the DSM-5 nomenclature. Several studies have confirmed the existence of the dissociative posttraumatic stress disorder (PTSD) subtype. However, there is a lack of studies investigating latent profiles of PTSD solely in victims with PTSD. This study investigates the possible presence of PTSD subtypes using latent class analysis (LCA) across two distinct trauma samples meeting caseness for DSM-5 PTSD based on self-reports (N = 787). Moreover, we assessed if a number of risk factors resulted in an increased probability of membership in a dissociative compared with a non-dissociative PTSD class. The results of LCA revealed a two-class solution with two highly symptomatic classes: a dissociative class and a non-dissociative class across both samples. Increased emotion-focused coping increased the probability of individuals being grouped into the dissociative class across both samples. Social support reduced the probability of individuals being grouped into the dissociative class but only in the victims of motor vehicle accidents (MVAs) suffering from whiplash. The results are discussed in light of their clinical implications and suggest that the dissociative subtype can be identified in victims of incest and victims of MVA suffering from whiplash meeting caseness for DSM-5 PTSD.


Sources of Caregiving Burden in Middle-Aged and Older Latino Caregivers.
We aimed to identify sources of caregiver burden in middle-aged and older Latino caregivers of people with Alzheimer disease and related dementia (ADRD). Participants were recruited through an agreement with the Rush Alzheimer's Disease Center Clinic Data Repository. We conducted semistructured interviews with 16 middle-aged and older Latinos who were the primary caregiver for a family member diagnosed with ADRD. The interview guide consisted of questions and probes to capture participants' perceptions of family caregiving. Direct content analysis was performed. Participants were aged 50 to 75 years (n = 16) and a majority female (n = 12). The sources of burden identified were (1) caregiver responsibilities, (2) caregiving-related health decline, (3) lack of support, (4) financial status, (5) vigilance, and (6) concerns about the future. The influence of gender roles seemed to play a role in caregivers' perceptions of sources of burden, especially on caregiver responsibilities and perceptions of lack of support. Latinos cultural values such as familismo and marianismo likely reinforced gender disparities in family caregiving.


Schistosomes in the Persian Gulf: novel molecular data, host associations, and life-cycle elucidations.
Avian schistosomes, comprise a diverse and widespread group of trematodes known for their surprising ability to switch into new hosts and habitats. Despite the considerable research attention on avian schistosomes as causatives of the human cercarial dermatitis, less it is known about the diversity, geographical range and host associations of the marine representatives. Our molecular analyses inferred from cox1 and 28S DNA sequence data revealed presence of two schistosome species, Ornithobilharzia canaliculata (Rudolphi, 1819) Odhner, 1912 and a putative new species of Austrobilharzia Johnston, 1917. Molecular elucidation of the life-cycle of O. canaliculata was achieved for the first time via matching novel and published sequence data from adult and larval stages. This is the first record of Ornithobilharzia from the Persian Gulf and globally the first record of this genus in a potamidid snail host. Our study provides: (i) new host and distribution records for major etiological agents of cercarial dermatitis and contributes important information on host-parasite relationships; (ii) highlights the importance of the molecular systematics in the assessment of schistosome diversity; and (iii) calls for further surveys to reach a better understanding of the schistosome diversity and patterns of relationships among them, host associations, transmission strategies and distribution coverage.


Modeling biochemical transformation processes and information processing with Narrator.
Software tools that model and simulate the dynamics of biological processes and systems are becoming increasingly important. Some of these tools offer sophisticated graphical user interfaces (GUIs), which greatly enhance their acceptance by users. Such GUIs are based on symbolic or graphical notations used to describe, interact and communicate the developed models. Typically, these graphical notations are geared towards conventional biochemical pathway diagrams. They permit the user to represent the transport and transformation of chemical species and to define inhibitory and stimulatory dependencies. A critical weakness of existing tools is their lack of supporting an integrative representation of transport, transformation as well as biological information processing. Narrator is a software tool facilitating the development and simulation of biological systems as Co-dependence models. The Co-dependence Methodology complements the representation of species transport and transformation together with an explicit mechanism to express biological information processing. Thus, Co-dependence models explicitly capture, for instance, signal processing structures and the influence of exogenous factors or events affecting certain parts of a biological system or process. This combined set of features provides the system biologist with a powerful tool to describe and explore the dynamics of life phenomena. Narrator's GUI is based on an expressive graphical notation which forms an integral part of the Co-dependence Methodology. Behind the user-friendly GUI, Narrator hides a flexible feature which makes it relatively easy to map models defined via the graphical notation to mathematical formalisms and languages such as ordinary differential equations, the Systems Biology Markup Language or Gillespie's direct method. This powerful feature facilitates reuse, interoperability and conceptual model development. Narrator is a flexible and intuitive systems biology tool. It is specifically intended for users aiming to construct and simulate dynamic models of biology without recourse to extensive mathematical detail. Its design facilitates mappings to different formal languages and frameworks. The combined set of features makes Narrator unique among tools of its kind. Narrator is implemented as Java software program and available as open-source from http://www.narrator-tool.org.


Thermotropic properties of organic nanocrystals embedded in ultrasmall crystallization chambers.
Crystallization of organic compounds in nanometer-scale channels of controlled pore glass (CPG) and porous polystyrene (p-PS), the latter prepared by etching of the polylactide (PLA) component of shear-aligned PS-PLA diblock copolymers, produces crystals with dimensions that reflect the size constraints imposed by the channels. The nanoscopic dimensions of the organic crystals embedded in the channels result in a substantial melting point depression compared with the bulk, as demonstrated here for 2,2,3,3,4,4-hexafluoro-1,5-pentanediol (HFPD) and (R)-(+)-3-methyladipic acid (R-MAA). The melting points decreased with decreasing channel diameter, consistent with the increasing surface-area-to-volume ratio of the crystals. Furthermore, at these length scales the latent heat of melting decreased with decreasing crystal size. The melting point depression for both HFPD and R-MAA was greater in p-PS than in CPG, which can only be explained by interactions of the nanocrystals and their corresponding melts with the channel walls. Collectively, these discoveries reveal that simplified descriptions used in previous investigations of embedded crystals, which were limited to porous glass matrixes and ignored the influence of the channel walls, do not capture all the factors affecting the thermotropic properties of the embedded nanocrystals.


Shape and crystallographic orientation of nanodiamonds for quantum sensing.
Nanodiamonds with dimensions down to a few tens of nanometers containing nitrogen-vacancy (NV) color centers have revealed their potential as powerful and versatile quantum sensors with a unique combination of spatial resolution and sensitivity. The NV centers allow transducing physical properties, such as strain, temperature, and electric or magnetic field, to an optical transition that can be detected in the single photon range. For example, this makes it possible to sense a single electron spin or a few nuclear spins by detecting their magnetic resonance. The location and orientation of these defects with respect to the diamond surface play a crucial role in interpreting the data and predicting their sensitivities. Despite its relevance, the geometry of these nanodiamonds has never been thoroughly investigated. Without accurate data, spherical models have been applied to interpret or predict results in the past. With the use of High Resolution Transmission Electron Microscopy (HR-TEM), Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM), we investigated nanodiamonds with an average hydrodynamic diameter of 25 nm (the most common type for quantum sensing) and found a flake-like geometry, with 23.2 nm and 4.5 nm being the average lateral and vertical dimensions. We have also found evidence for a preferred crystallographic orientation of the main facet in the (110) direction. Furthermore, we discuss the consequences of this difference in geometry on diamond-based applications. Shape not only influences the creation efficiency of nitrogen-vacancy centers and their quantum coherence properties (and thus sensing performance), but also the optical properties of the nanodiamonds, their interaction with living cells, and their surface chemistry.


Can neonatal pelvic osteotomies permanently change pelvic shape in patients with exstrophy? Understanding late rediastasis.
Pelvic osteotomies are frequently used as part of the surgical management of bladder exstrophy. The outcomes are often measured on the basis of the residual symphyseal diastasis. The aims of this study were to evaluate and validate a more reliable radiographic measure of ischiopubic rotation, to utilize this measure in analyzing pelves from patients with exstrophy and controls, and to propose a model for rediastasis in a pelvis with exstrophy. Pelvic radiographs of 164 normal children two months to eighteen years of age were used to determine the changes in interpubic and interischial distances and in the interischial/interpubic (IS/IP) ratio with age. Twenty-one pelvic CT (computed tomography) studies of normal children, two to sixteen years of age, were also used to study the change in the ischiopubic divergence angle. The same parameters were measured on radiographs or CT or magnetic resonance imaging studies of seventy-three patients with classic bladder exstrophy who were followed for two to nineteen years after exstrophy closure with or without pelvic osteotomies. In normal children, the interpubic distance and the ischiopubic divergence angle had a narrow range and were constant with age, whereas the interischial distance and the IS/IP ratio increased progressively and were strongly correlated with age. In the patients with exstrophy, the interpubic distance was positively correlated with the interischial distance, whereas the IS/IP ratio was lower than that in normal controls and was not correlated with age. The IS/IP ratio is a useful measure of ischiopubic rotation and can be used to characterize pelvic growth, including the phenomenon of rediastasis in patients with exstrophy. Pelvic rediastasis is a progressive increase in interpubic distance resulting from growth without loss of rotational correction, as shown by the constancy of the IS/IP ratio with age in these patients. A better rotational position at the time of osteotomy may lead to a better pelvic shape at maturity. Symphyseal rediastasis following neonatal pelvic osteotomies in patients with exstrophy is not due to loss of correction and progressive derotation of the hemipelves but is a consequence of the normal three-dimensional growth of the pelvis. The best correction of the pelvic deformity should always be the aim even in neonatal pelvic osteotomies because this will permanently change the pelvic shape.


EM∩IM: software for relating ion mobility mass spectrometry and electron microscopy data.
We present EM∩IM, software that allows the calculation of collision cross-sections from electron density maps obtained for example by means of transmission electron microscopy. This allows the assessment of structures other than those described by atomic coordinates with ion mobility mass spectrometry data, and provides a new means for contouring and validating electron density maps. EM∩IM thereby facilitates the use of data obtained in the gas phase within structural biology studies employing diverse experimental methodologies.


Timing of omitted events: an analysis of temporal control of inhibitory behavior.
This paper reviews research designed to investigate the temporal control of inhibitory responding using rats as subjects. One area of investigation has focused on the role of temporal variables in conditioned inhibition produced using Pavlov's [Pavlov, I.P., 1927. Conditioned Reflexes. Oxford University Press, London, 430 pp.] procedure. These studies have found that evidence of conditioned inhibition obtained by negative summation testing is strongest when the conditioned inhibitor signals the omission of the unconditioned stimulus (US) at the same temporal location as a transfer excitor signals presentation of the US [e.g., Barnet, R.C., Miller, R.R., 1996. Temporal encoding as a determinant of inhibitory control. Learn. Motiv. 27, 73-91]. Similarly, retardation of acquisition of behavioral control by a previously inhibitory conditioned stimulus (CS) is maximal when the inhibitory CS is paired with the US at the same temporal location as the inhibitor had previously signaled US omission [Burger, D., Denniston, J.C., Miller, R.R., 2001. Temporal coding in condition inhibition: retardation tests. Anim. Learn. Behav. 29, 281-290]. Other lines of research designed to assess the associative structure of temporal control of inhibition [e.g., Denniston, J.C., Blaisdell, A.P., Miller, R.R., 2004. Temporal control in conditioned inhibition: analysis of associative structure of inhibition. J. Exp. Psychol. Anim. Behav. Process. 30, 190-202] are reviewed, as is the assessment of temporal control of inhibition produced through extinction [Denniston, J.C., Miller, R.R., 2003. The role of temporal variables in inhibition produced through extinction. Learn. Behav. 31, 35-48]. These collective observations are discussed in terms of the temporal coding hypothesis [Matzel, L.D., Held, F.P., Miller, R.R., 1988. Reexamination of simultaneous and backward conditioning: Implications for contiguity theory. Learn. Motiv. 19, 317-344].


Treatment of acute femoral neck fractures with total hip arthroplasty.
Between 1973 and 1983, 27 patients with acute femoral neck fractures were treated at the UCLA Medical Center with total hip arthroplasty. These cases were selected on the basis of age, high activity level, and degenerative changes in the acetabular cartilage. The average age was 72 years. There were 19 women and eight men. The average follow-up period was 3.8 years with a range of one to ten years. Methods used included analysis of clinical data, roentgenograms, final pain ratings, walking ratings, and activity levels using the UCLA rating system. Pain relief and overall functional results were better than that of most series of acute femoral neck fractures treated with hemiarthroplasty and similar to that of total hip arthroplasty series. The complication rate was slightly less than both authors' elective total hip series, and considerably less than most hemiarthroplasty series. Complications included a superficial wound infection, a urinary tract infection, and a perforated colon diverticulum. Four patients died within one year from causes unrelated to the hip arthroplasty. There were no deep infections, dislocations, or reoperations. Total hip arthroplasty in selective cases of acute femoral neck fractures can give more consistent pain relief and better functional results than hemiarthroplasty, without an increase in complications.


Speckle reduction of retinal optical coherence tomography based on contourlet shrinkage.
Speckle reduction of retinal optical coherence tomography (OCT) images helps the diagnosis of ocular diseases. In this Letter, we present a speckle reduction method based on shrinkage in the contourlet domain for retinal OCT images. The algorithm overcomes the disadvantages of the wavelet shrinkage method, which lacks directionality and anisotropy. The trade-off between speckle reduction and edge preservation is controlled by a single adjustable parameter, which determines the threshold in the contourlet domain. Results show substantial reduction of speckle noise and enhanced visualization of layer structures as demonstrated in the image of the central fovea region of the human retina. It is expected to be utilized in a wide range of biomedical imaging applications.


A wearable strain sensor based on a carbonized nano-sponge/silicone composite for human motion detection.
Melamine sponge, also known as nano-sponge, is widely used as an abrasive cleaner in our daily life. In this work, the fabrication of a wearable strain sensor for human motion detection is first demonstrated with a commercially available nano-sponge as a starting material. The key resistance sensitive material in the wearable strain sensor is obtained by the encapsulation of a carbonized nano-sponge (CNS) with silicone resin. The as-fabricated CNS/silicone sensor is highly sensitive to strain with a maximum gauge factor of 18.42. In addition, the CNS/silicone sensor exhibits a fast and reliable response to various cyclic loading within a strain range of 0-15% and a loading frequency range of 0.01-1 Hz. Finally, the CNS/silicone sensor as a wearable device for human motion detection including joint motion, eye blinking, blood pulse and breathing is demonstrated by attaching the sensor to the corresponding parts of the human body. In consideration of the simple fabrication technique, low material cost and excellent strain sensing performance, the CNS/silicone sensor is believed to have great potential in the next-generation of wearable devices for human motion detection.


Characterization of neutralizing epitopes in antigenic site B of recently circulating influenza A(H3N2) viruses.
Influenza A(H3N2) viruses are associated with outbreaks worldwide and can cause disease with severe complications. The impact can be reduced by vaccination, which induces neutralizing antibodies that mainly target the haemagglutinin glycoprotein (HA). In this study we generated neutralizing mouse monoclonal antibodies (mAbs) against A/Victoria/361/2011 and identified their epitopes by generating and sequencing escape viruses. The epitopes are located in antigenic site B, which is near the receptor-binding site and is immunodominant in humans. Amino acid (aa) substitutions at positions 156, 158, 159, 189, 190 and 193 in antigenic site B led to reduced ability of mAbs to block receptor-binding. The majority of A(H3N2) viruses that have been circulating since 2014 are antigenically distinct from previous A(H3N2) viruses. The neutralization-sensitive epitopes in antigenic site B of currently circulating viruses were examined with these mAbs. We found that clade 3C.2a viruses, possessing an additional potential glycosylation site at HA1 position N158, were poorly recognized by some of the mAbs, but other residues, notably at position 159, also affected antibody binding. Through a mass spectrometric (MS) analysis of HA, the glycosylated sites of HA1 were established and we determined that residue 158 of HA1 was glycosylated and so modified a neutralization-sensitive epitope. Understanding and monitoring individual epitopes is likely to improve vaccine strain selection.


Antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage increases the risk for deep venous thrombosis: A case-control study.
Aneurysm re-rupture is associated with significant morbidity and mortality in aneurysmal subarachnoid hemorrhage (aSAH). While antifibrinolytics reduce aneurysm re-rupture rates, they have been associated with hydrocephalus, delayed cerebral ischemia, and venous thrombosis. We performed a case-control study in patients enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study to evaluate the impact of short course (<48 h) ɛ-aminocaproic acid (EACA) on deep venous thrombosis (DVT) rates. A case-control study design was utilized to evaluate the effect of EACA on DVT formation. All cases and controls were obtained from the CARAS study, a prospective, blinded study assessing the association of polymorphisms in the renin angiotensin system and aSAH. One hundred and twenty-eight eligible patients were enrolled in CARAS. Overall, 48 (37.5%) patients were screened for DVT, 57 (44.5%) patients were treated with short course (<48 h) EACA, and 8 (6.3%) patients suffered a re-rupture (4 treated with EACA). Ten patients (7.8%) were diagnosed with DVT as evidenced by Doppler US and represent the cases. Twenty controls without evidence of a DVT matched for age, sex, race, tobacco history, Hunt-Hess score, Fisher grade, body mass index, and length of stay were identified from the remaining pool of 118 patients. EACA was found to significantly increase the risk of DVT formation in patients with aSAH (OR 8.49, CI 1.27-77.1). Short course (<48 h) administration of EACA in patients with aneurysmal subarachnoid hemorrhage is associated with an 8.5 times greater risk of DVT formation.


Superposition of nanostructures on microrough titanium-aluminum-vanadium alloy surfaces results in an altered integrin expression profile in osteoblasts.
Recent studies of new surface modifications that superimpose well-defined nanostructures on microrough implants, thereby mimicking the hierarchical complexity of native bone, report synergistically enhanced osteoblast maturation and local factor production at the protein level compared to growth on surfaces that are smooth, nanorough, or microrough. Whether the complex micro/nanorough surfaces enhance the osteogenic response by triggering similar patterns of integrin receptors and their associated signaling pathways as with well-established microrough surfaces, is not well understood. Human osteoblasts (hOBs) were cultured until confluent for gene expression studies on tissue culture polystyrene (TCPS) or on titanium alloy (Ti6Al4V) disks with different surface topographies: smooth, nanorough, microrough, and micro/nanorough surfaces. mRNA expression of osteogenesis-related markers such as osteocalcin (BGLAP) and bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2), BMP4, noggin (NOG) and gremlin 1 (GREM1) were all higher on microrough and micro/nanorough surfaces, with few differences between them, compared to smooth and nanorough groups. Interestingly, expression of integrins α1 and α2, which interact primarily with collagens and laminin and have been commonly associated with osteoblast differentiation on microrough Ti and Ti6Al4V, were expressed at lower levels on micro/nanorough surfaces compared to microrough ones. Conversely, the αv subunit, which binds ligands such as vitronectin, osteopontin, and bone sialoprotein among others, had higher expression on micro/nanorough surfaces concomitantly with regulation of the β3 mRNA levels on nanomodified surfaces. These results suggest that the maturation of osteoblasts on micro/nanorough surfaces may be occurring through different integrin engagement than those established for microrough-only surfaces.


Biochemical characterization of protein complexes from the Helicobacter pylori protein interaction map: strategies for complex formation and evidence for novel interactions within type IV secretion systems.
We have investigated a large set of interactions from the Helicobacter pylori protein interaction map previously identified by high-throughput yeast two-hybrid (htY2H)-based methods. This study had two aims: i) to validate htY2H as a source of protein-protein interaction complexes for high-throughput biochemical and structural studies of the H. pylori interactome; and ii) to validate biochemically interactions shown by htY2H to involve components of the H. pylori type IV secretion systems. Thus, 17 interactions involving 31 proteins and protein fragments were studied, and a general strategy was designed to produce protein-interacting partners for biochemical and structural characterization. We show that htY2H is a valid source of protein-protein complexes for high-throughput proteome-scale characterization of the H. pylori interactome, because 76% of the interactions tested were confirmed biochemically. Of the interactions involving type IV secretion proteins, three could be confirmed. One interaction is between two components of the type IV secretion apparatus, ComB10 and ComB4, which are VirB10 and VirB4 homologs, respectively. Another interaction is between a type IV component (HP0525, a VirB11 homolog) and a non-type IV secretion protein (HP01451), indicating that proteins other than the core VirB (1-11)-VirD4 proteins may play a role in type IV secretion. Finally, a third interaction was biochemically confirmed between CagA, a virulence factor secreted by the type IV secretion system encoded by the Cag pathogenicity island, and a non-type IV secretion protein, HP0496.


Wavelength independent Faraday isolator.
A wavelength independent Faraday isolator has been built using an optically active rotator to compensate the dispersion of a 45 degrees Faraday rotator. Its isolation is better than 30 dB from 735 to 870 nm. Over this wavelength range the measured transmission in the forward direction is better than 80%. Dispersion, temperature, angular tolerance, and other factors affecting the isolation and forward transmission are discussed.


The impact of obesity on health care costs among persons with schizophrenia.
Obesity is the second leading cause of preventable death in the United States and is twice as common among individuals with schizophrenia as the general population. Data from the Clinical Antipsychotic Trials of Intervention Effectiveness, a multisite trial of antipsychotic pharmacotherapy in 1460 patients with schizophrenia, were used to examine the relationships between body mass index (BMI) and medical costs. ANCOVA analyses found significant increases in both psychiatric and nonpsychiatric medication costs associated with increasing BMI and a significant, but smaller, difference in costs of outpatient medical-surgical service utilization: US$41 per month for morbidly obese patients compared to US$26 per month for patients of normal weight (F=2.4, P=.04). In multivariable logistic regression analyses, morbid obesity was associated with significantly increased odds of any outpatient medical-surgical service costs. When compared to observations of BMI>35, BMI observations within the normal range (18.5-24.9) were half as likely to be associated with any outpatient medical-surgical costs (OR=0.53; 95% CI=0.45, 0.63). In this large sample of persons with schizophrenia, obesity was associated with increased outpatient general medical service and medication costs even after controlling for demographic characteristics and medical comorbidity, but the absolute dollar amount was small.


Voltage- and time-dependent properties of the recombinant rat vanilloid receptor (rVR1).
Whole-cell voltage-clamp techniques were used to investigate the capsaicin-, voltage- and time-dependent properties of the rat vanilloid receptor (rVR1) stably expressed in human embryonic kidney (HEK) 293 cells. At a holding potential of -70 mV, application of capsaicin (0.03-30 microM) to HEK 293 cells expressing the rVR1 receptor led to the appearance of inward currents (EC50, 497 nM; Hill coefficient, nH, 2.85) which were reversibly antagonized by 10 microM capsazepine. Current-voltage relationships, determined using depolarizing or hyperpolarizing voltage ramps, had reversal potentials close to 0 mV, exhibited substantial outward rectification and possessed a region of negative slope conductance at holding potentials negative to around -70 mV. Further experiments indicated that the outward rectification and the region of negative slope conductance did not result from external block of the channel by either Ba2+, Ca2+ or Mg2+. During our characterization of rVR1, it became apparent that the rectification behaviour of this receptor was not entirely instantaneous as might be expected for a ligand-gated ion channel, but rather displayed clear time-dependent components. We characterized the kinetics of these novel gating properties in a series of additional voltage-step experiments. The time-dependent changes in rVR1-mediated conductance due to membrane depolarization or repolarization occurred with bi-exponential kinetics. On depolarization to +70 mV the time-dependent increase in outward current developed with mean time constants of 6.7 +/- 0.7 and 51.8 +/- 18.4 ms, with the faster time constant playing a dominant role (64.4 +/- 3.8 %). Similar kinetics also described the decay of 'tail currents' observed on repolarization. Furthermore, these time-dependent changes appeared to be unaffected by the removal of extracellular divalent cations and were not significantly voltage dependent. Our data reveal that rVR1 exhibits substantial time- and voltage-dependent gating properties that may have significance for the physiology of sensory transduction of nociceptive signals.


Genetic contributions to Trail Making Test performance in UK Biobank.
The Trail Making Test (TMT) is a widely used test of executive function and has been thought to be strongly associated with general cognitive function. We examined the genetic architecture of the TMT and its shared genetic aetiology with other tests of cognitive function in 23 821 participants from UK Biobank. The single-nucleotide polymorphism-based heritability estimates for trail-making measures were 7.9% (part A), 22.4% (part B) and 17.6% (part B-part A). Significant genetic correlations were identified between trail-making measures and verbal-numerical reasoning (rg>0.6), general cognitive function (rg>0.6), processing speed (rg>0.7) and memory (rg>0.3). Polygenic profile analysis indicated considerable shared genetic aetiology between trail making, general cognitive function, processing speed and memory (standardized β between 0.03 and 0.08). These results suggest that trail making is both phenotypically and genetically strongly associated with general cognitive function and processing speed.


Action naming is impaired in Parkinson disease patients.
In order to explore the possible contribution of the motor system to the representation of verbs, we studied the relative preservation of the capacity of Parkinson disease patients to name matched sets of object and action pictures. The performance of this group of participants was compared with that of a group of healthy seniors, and a group of Alzheimer disease patients. Generalized linear mixed-effects analyses showed that, whereas the two control groups had similar accuracy scores in response to objects and actions, Parkinson disease patients presented a significant impairment in their capacity to name actions compared to objects. The results of this study support the idea that verb representations are grounded in neural networks to which brain areas involved in motor control contribute.


Network collaboration of organisations for homeless individuals in the Montreal region.
We know little about the intensity and determinants of interorganisational collaboration within the homeless network. This study describes the characteristics and relationships (along with the variables predicting their degree of interorganisational collaboration) of 68 organisations of such a network in Montreal (Quebec, Canada). Data were collected primarily through a self-administered questionnaire. Descriptive analyses were conducted followed by social network and multivariate analyses. The Montreal homeless network has a high density (50.5%) and a decentralised structure and maintains a mostly informal collaboration with the public and cross-sectorial sectors. The network density showed more frequent contacts among four types of organisations which could point to the existence of cliques. Four variables predicted interorganisational collaboration: organisation type, number of services offered, volume of referrals and satisfaction with the relationships with public organisations. The Montreal homeless network seems adequate to address non-complex homelessness problems. Considering, however, that most homeless individuals present chronic and complex profiles, it appears necessary to have a more formal and better integrated network of homeless organisations, particularly in the health and social service sectors, in order to improve services.


CtBP-independent repression in the Drosophila embryo.
There are three mechanisms of transcriptional repression in eukaryotes. The first is quenching, whereby repressors and activators co-occupy closely linked sites and then the repressor inhibits adjacent activators. The second is direct repression, in which repressors block the function of the core transcription complex. The third is competition, in which repressors compete with activators for a common DNA-binding site. Previous studies have shown that the Drosophila melanogaster CtBP corepressor (dCtBP) is essential for the quenching activity of three short-range sequence-specific repressors in the early Drosophila embryo: Krüppel, Knirps, and Snail. Here we demonstrate that dCtBP is dispensable for target enhancers that contain overlapping activator and repressor binding sites. However, it is essential when Krüppel and Knirps repressor sites do not overlap activator sites but are instead located adjacent to either activators or the core promoter. These findings provide evidence that competition is distinct from quenching and direct repression. Quenching and direct repression depend on dCtBP, whereas competition does not.


Parents' Attitudes to Risk and Injury to Children and Young People on Farms.
Children and young people growing up in a farm environment run a greater risk of being injured or dying in an accident than their non-farming counterparts. This study examines farming parents' attitudes and experiences of having their children grow up on farms, one of the most dangerous work environments as their home, everyday environment and playground. Data were collected using two ethnological methods, a question list and interviews, with a study population of 20 parents. The data were analysed phenomenologically. The analysis pursued four themes: i) the most dangerous places and situations on the farm; ii) children's tasks on the farm; iii) children as a safety risk on the farm; and iv) farm risk education for children. Most parents know the risks on their farm, but are sometimes careless when working under stress or exhaustion. Some parents wanted more information and some wanted compulsory preventative or safety measures by manufacturers, e.g. a safety belt as standard on the extra seat in tractors. Children's friends were described as one of the greatest risks for injury due to peer pressure. Some parents mentioned that people who grow up on farms are sometimes 'blind' to the dangers. Other parents seemed to overlook the risks and had their children carrying out tasks for which they were not mentally or physically equipped. Some of the tasks the children reportedly carried out on farms contravened Swedish legislation. It is thus important for farming parents to be repeatedly reminded of the risks to their children and to increase their awareness of how to prevent and eliminate risks in order to avoid accidents on the farm. The situation for farm children is highlighted in a critical discussion.


Premeiotic DNA Synthesis and the Time of Chromosome Pairing in Locusta migratoria.
Labeled spermatocytes from locusts killed 0, 1, 2, 3, 4, and 6 days after exposure to tritiated thymidine were examined with the electron microscope to determine their meiotic stage. It was found that tritiated thymidine uptake in young spermatocyte nuclei is completed some 24 hours before synaptinemal complexes are formed. It is concluded that in the locust, premeiotic DNA synthesis is completed well in advance of pairing of homologous chromosomes as marked by the formation of synaptinemal complexes. The G-1 and the S-phase are in the order of 24 hours each, while meiotic prophase lasts four to five days under the conditions used.


Overuse of Magnetic Resonance Imaging in the Diagnosis and Treatment of Moderate to Severe Osteoarthritis.
MRI in the evaluation of end-stage knee joint osteoarthritis (OA) is usually unnecessary when radiographic and clinical evidence of gonarthrosis is clear. The purpose of this study was to assess the prevalence of MRI scans ordered in patients with radiographically obvious gonarthrosis and to examine the characteristics of health care providers who ordered these imaging studies. We retrospectively identified 164 patients diagnosed with moderate to severe OA who were referred for total knee replacement (TKA) over a one-year period. The percentage of patients who had an MRI scan with or without X-ray, within the preceding 3 months prior to referral, were calculated. Subgroups were analyzed to identify characteristics that may influence the decision to order an MRI, including K-L grade, provider type, level of training, and practice location. Of 145 patients, 19 (13.1%) presented with an MRI scan. Between the number of MRI scans ordered, there was a significant difference when comparing physicians versus non-physicians, with physicians ordering less MRI scans (p=0.018). There was a significant difference when comparing non-academic versus academic, with academic providers ordering less MRI scans (p=0.044). There was no significant difference with fellowship training or provider proximity to our academic institution. In this study, 13.1% of patients with radiographically obvious knee OA obtained an MRI prior to referral for TKA. Non-physicians and non-academic physicians were more likely to order MRI scans. Improved education for referring providers may be necessary to decrease overuse of MRI in the diagnosis of moderate to severe arthritis. Level II.


Ethanol-induced conditioned place aversion in mice.
Previous studies have shown that ethanol produces conditioned place preference (CPP) in mice when injections are given immediately before exposure to the conditioned stimulus (CS). Paradoxically, however, injection of ethanol immediately after the CS produces conditioned place aversion (CPA). Four experiments were conducted to characterize the parametric boundaries of CPA produced by post-CS ethanol exposure. Experiment 1 showed that CPA is positively related to ethanol dose, with significant CPA at 2 and 4 g / kg, but not at 1 g / kg. Experiment 2 revealed an inverse relationship between CPA and trial duration, i.e. significant CPA occurred when the trial duration was 5, 15 or 30 min, but not when it was 60 or 90 min. Experiment 3 indicated that ethanol pre-exposure (eight daily injections) significantly reduced subsequent development of CPA. Finally, experiment 4 showed that repeated exposure to the CS alone (six 30 min exposures to each CS) after CS-ethanol pairings produced complete extinction of CPA. The same extinction procedure also completely eliminated CPP induced by pre-CS injections of ethanol. Overall, these studies demonstrate that CPA induced by post-CS ethanol injection is influenced by many of the same variables that affect CPP produced by pre-CS ethanol injection in mice. However, these findings do not resolve the issue of whether the 'before-versus-after' effect in ethanol place conditioning is better explained by assuming ethanol produces only rewarding effects or by assuming that ethanol produces both rewarding and aversive effects.


Procedures for designing an occupational therapy consultation contract.
Occupational therapists have been asked with increasing frequency to function as consultants, yet most of the research on consultation has been published in other fields. Issues that have been investigated include negotiating consultation sponsorship, conducting needs assessments, and evaluating the consultant's effectiveness. For the purposes of our research the literature was used to generate a list of steps for designing a consultation package. The steps were then used in a six-month pilot contract to assess their usefulness for occupational therapy practice.


CN: a consensus algorithm for inferring gene regulatory networks using the SORDER algorithm and conditional mutual information test.
Inferring Gene Regulatory Networks (GRNs) from gene expression data is a major challenge in systems biology. The Path Consistency (PC) algorithm is one of the popular methods in this field. However, as an order dependent algorithm, PC algorithm is not robust because it achieves different network topologies if gene orders are permuted. In addition, the performance of this algorithm depends on the threshold value used for independence tests. Consequently, selecting suitable sequential ordering of nodes and an appropriate threshold value for the inputs of PC algorithm are challenges to infer a good GRN. In this work, we propose a heuristic algorithm, namely SORDER, to find a suitable sequential ordering of nodes. Based on the SORDER algorithm and a suitable interval threshold for Conditional Mutual Information (CMI) tests, a network inference method, namely the Consensus Network (CN), has been developed. In the proposed method, for each edge of the complete graph, a weighted value is defined. This value is considered as the reliability value of dependency between two nodes. The final inferred network, obtained using the CN algorithm, contains edges with a reliability value of dependency of more than a defined threshold. The effectiveness of this method is benchmarked through several networks from the DREAM challenge and the widely used SOS DNA repair network in Escherichia coli. The results indicate that the CN algorithm is suitable for learning GRNs and it considerably improves the precision of network inference. The source of data sets and codes are available at .


Benzodiazepine receptor occupancy in vivo: correlation with brain concentrations and pharmacodynamic actions.
A tracer radioligand technique employing [3H]Ro 15-1788 was used to measure in vivo benzodiazepine receptor occupancy in mice. Animals were administered clonazepam (CNZ) or lorazepam (LRZ) i.p. or i.v., followed by [3H]Ro 15-1788. Plasma and cerebral cortical concentrations of the drug and cortical benzodiazepine receptor occupancy were determined at varying doses and times after administration. For both drugs, plasma and brain concentrations decreased in parallel with decreasing doses and with time, and the brain/plasma ratios remained constant. Receptor occupancy was maximal for CNZ and LRZ at doses above 1 and 4 mg/kg, respectively, and decreased with decreasing doses. Comparison of receptor occupancy with brain concentration yielded IC50 values of 21 ng/g for CNZ and 133 ng/g for LRZ. The apparent dissociation constant (Kd) for CNZ was 56 pmol/g and, for LRZ, 372 pmol/g. Hill plots yielded slopes of 1.30 for CNZ and 1.71 for LRZ. Alterations in the nonspecific uptake or elimination of Ro 15-1788 did not explain occupancy changes, inasmuch as brain concentrations of unlabeled Ro 15-1788 (6 mg/kg) were not changed by LRZ administration. The correlation between receptor occupancy and the pharmacodynamic actions of these drugs in blocking pentylenetetrazol seizures and inducing rotarod ataxia indicated that ED50 for these effects occurred at receptor occupancy of 30 to 60% for both drugs.


Shift-related sleep problems vary according to work schedule.
Shift-related sleep and sleepiness problems may be due to characteristics of both shifts (ie, day, evening and night shifts) and work schedules (ie, permanent vs rotational schedules). The Bergen Shift Work Sleep Questionnaire (BSWSQ) was used to investigate associations between shift-related sleep problems and work schedules. 1586 nurses completed the BSWSQ. Participants who, in relation to a shift, 'often' or 'always' experienced both a sleep problem and a tiredness/sleepiness problem were defined as having shift-related insomnia (separate for day, evening and night shifts and rest-days). Logistic regression analyses were conducted for day, evening, night, and rest-day insomnia with participants on both permanent and rotational schedules. Shift-related insomnia differed between the work schedules. The evening shift insomnia was more prevalent in the two-shift rotation schedule than the three-shift rotation schedule (29.8% and 19.8%, respectively). Night shift insomnia showed higher frequencies among three-shift rotation workers compared with permanent night workers (67.7% and 41.7%, respectively). Rest-day insomnia was more prevalent among permanent night workers compared with two- and three-shift rotations (11.4% compared with 4.2% and 3.6%, respectively). The prevalences of shift-related insomnia differed between the work schedules with higher frequencies for three-shift rotations and night shifts. However, sleep problems were present in all shifts and schedules. This suggests that both shifts and work schedules should be considered in the study of shift work-related sleep problems.


Development and validation of patient information leaflet for coronary heart disease patients.
Patient information leaflets (PILs) are effectively used to improve the patient's knowledge about medications, disease, diet, and lifestyle modifications. This study aims to develop and evaluate PILs for coronary heart disease patients. Primary, secondary, and tertiary resources were used to develop PILs. The developed PILs were validated by four doctors, four academic pharmacists, and one dietician. PILs design and layout was prepared using barker able leaflet design (BALD) criteria. PILs readability was assessed using the Flesch Reading Ease test (FRE), Flesch-Kincaid Grade Level (FKGL), and user readability methods. User opinion on PILs content and design was obtained from patients. The FRE and FKGL readability scores were 61.5 and 7.4, respectively. The BALD criteria scores for English, Kannada, and Malayalam PILs were 28, 27, and 26, respectively. The overall user testing readability means scores had significantly improved from 45 to 79.30. Nearly 82.55% of patients rated the PILs as good design and content. The developed leaflet met the standard criteria for easy reading and comprehension. The majority of the patients gave good opinion on the content and design of the PILs.


Genome size variation in the genus Avena.
Genome size is an indicator of evolutionary distance and a metric for genome characterization. Here, we report accurate estimates of genome size in 99 accessions from 26 species of Avena. We demonstrate that the average genome size of C genome diploid species (2C = 10.26 pg) is 15% larger than that of A genome species (2C = 8.95 pg), and that this difference likely accounts for a progression of size among tetraploid species, where AB < AC < CC (average 2C = 16.76, 18.60, and 21.78 pg, respectively). All accessions from three hexaploid species with the ACD genome configuration had similar genome sizes (average 2C = 25.74 pg). Genome size was mostly consistent within species and in general agreement with current information about evolutionary distance among species. Results also suggest that most of the polyploid species in Avena have experienced genome downsizing in relation to their diploid progenitors. Genome size measurements could provide additional quality control for species identification in germplasm collections, especially in cases where diploid and polyploid species have similar morphology.


NF-kappaB activity in transgenic mice: developmental regulation and tissue specificity.
The transcription factor family NF-kappaB/Rel is responsible for the regulation of a large number of cellular genes and some viruses. Since there is a strong similarity between the NF-kappaB/Rel family members and the Drosophila melanogaster protein DORSAL, which is activated early during embryogenesis, we were interested in determining the pattern of NF-kappaB activity during mouse development. Two lacZ reporter constructs, each driven by promoter elements that are dependent on the presence of nuclear NF-kappaB/Rel activity, were used to produce transgenic mice. The analysis of these mice did not identify nuclear NF-kappaB/Rel activity in early development prior to implantation or during the gastrulation processes. Earliest expression of the lacZ transgene was detected on day E12.5. Before birth lacZ expression was seen in discrete regions of the rhombencephalon of the developing brain, in the spinal medulla, in some of the blood vessels and in the thymus. After birth, the NF-kappaB/Rel activity in the thymus remained but nuclear activity was also found in the bone marrow, in the spleen and in the capsule of the lymph nodes. In the central nervous system, drastic changes in NF-kappaB/Rel activity could be observed in the first 3 weeks after birth, when the cortex and the cerebellum reach functional and morphological maturity. Considering the results of the p50, p65, relB and c-rel knock-out mice and our present findings, we believe that the NF-kappaB/Rel proteins known so far are probably not implicated in processes of early development and differentiation of the different tissues, but rather in maintaining their function once matured.


The nasomaxillary complex, the mandible, and sleep-disordered breathing.
This study aims to use clinical scales in a standardized fashion in evaluating the frequency of a high and narrow hard palate and/or small and retroplaced mandible in children with polysomnographically demonstrated sleep-disordered breathing (SDB). This is a retrospective review of clinical and polysomnographic data from children (2-17 years old) with SDB. Exclusion criteria were obesity, presence of a syndromic disorder, and incomplete chart information. Data on demographics, reason for referral, sleep history, Mallampati scale, size of the tonsils (Friedman scale), bite occlusion (dental positioning), and correlating clinical presentation and comparative physical exam of nasomaxillary and mandibular features (using subjective grading scales) were collected, as were results of pre- and post- treatment polysomnography. Data from 400 children were analyzed. With increasing age, fewer referrals were made for abnormal breathing during sleep and more were made for daytime impairment and generally poor sleep. There were 290 children (72.6%) who had tonsils graded 3+ or 4+, but 373 (93.3%) had craniofacial features considered to be risk factors for SDB, including small mandible and/or high and narrow hard palate associated with a narrow nasomaxillary complex. Mean pretreatment apnea-hypopnea index (AHI) was 14.6 ± 17.1 and AHI was similar in the three age groups. Initial treatment was adenotonsillectomy. Follow-up was obtained in 378 subjects, and 167 cases demonstrated residual AHI. Incomplete response to adenotonsillectomy was seen more often in children with Mallampati scale scores of 3 and 4. Non-obese children with SDB had different initial clinical complaints based on age. Independently of age, facial anatomic structures limiting nasal breathing and those considered to be risk factors for SDB were commonly seen in the total group. Clinical assessment of craniofacial features considered as risk factors for SDB and more particularly a Mallampati scale score of 3 or 4 can be useful in identifying children who may be more at risk for limited response to adenotonsillectomy, suggesting a subsequent need for post-surgery polysomnography.


Confocal scanning dark-field polarization microscopy.
Dark-field imaging is attained by use of a λ/4 plate and an analyzer in a confocal scanning microscope. This dark-field microscope detects only the edge-diffracted wave whose polarization is different from that of the incident beam. The fact that images of photoresist patterns taken by the microscope show only the edges of the patterns confirms the dark-field nature of the imaging.