Recognizing Actions Through Action-Specific Person Detection.
Action recognition in still images is a challenging problem in computer vision. To facilitate comparative evaluation independently of person detection, the standard evaluation protocol for action recognition uses an oracle person detector to obtain perfect bounding box information at both training and test time. The assumption is that, in practice, a general person detector will provide candidate bounding boxes for action recognition. In this paper, we argue that this paradigm is suboptimal and that action class labels should already be considered during the detection stage. Motivated by the observation that body pose is strongly conditioned on action class, we show that: 1) the existing state-of-the-art generic person detectors are not adequate for proposing candidate bounding boxes for action classification; 2) due to limited training examples, the direct training of action-specific person detectors is also inadequate; and 3) using only a small number of labeled action examples, the transfer learning is able to adapt an existing detector to propose higher quality bounding boxes for subsequent action classification. To the best of our knowledge, we are the first to investigate transfer learning for the task of action-specific person detection in still images. We perform extensive experiments on two benchmark data sets: 1) Stanford-40 and 2) PASCAL VOC 2012. For the action detection task (i.e., both person localization and classification of the action performed), our approach outperforms methods based on general person detection by 5.7% mean average precision (MAP) on Stanford-40 and 2.1% MAP on PASCAL VOC 2012. Our approach also significantly outperforms the state of the art with a MAP of 45.4% on Stanford-40 and 31.4% on PASCAL VOC 2012. We also evaluate our action detection approach for the task of action classification (i.e., recognizing actions without localizing them). For this task, our approach, without using any ground-truth person localization at test time, outperforms on both data sets state-of-the-art methods, which do use person locations.


Background rejection and signal-to-noise optimization in confocal and alternative fluorescence microscopes.
In the confocal microscope, tightly focused illumination and spatially filtered detection are combined to reduce out-of-focus background and to produce high-quality images that display thin optical sections within thick fluorescent specimens. We define background as the detected light that originates outside a resolution volume and signal as the detected light that originates within the same volume. Background rejection is measured by the signal-to-background ratio (S/B) and is calculated for confocal, spinning-disk, line-illumination, slit-detection, and conventional fluorescence microscopes as a function of both the spatial filter size and the specimen thickness. Spatial filter sizes that reject background and optimize the signal-to-noise ratio (S/N) are calculated for each microscope. These calculations are normalized so that the time-averaged illumination at each point in the specimen is the same for each microscope. For thick specimens, we show that the S/B obtained with a confocal microscope can be more than 100 times greater than the S/B available with a conventional microscope, and we find that the optimal confocal S/N can be a factor of 10 greater than the S/N in the conventional microscope.


Toward fully quantum modelling of ultrafast photodissociation imaging experiments. Treating tunnelling in the ab initio multiple cloning approach.
We present an account of our recent effort to improve simulation of the photodissociation of small heteroaromatic molecules using the Ab Initio Multiple Cloning (AIMC) algorithm. The ultimate goal is to create a quantitative and converged technique for fully quantum simulations which treats both electrons and nuclei on a fully quantum level. We calculate and analyse the total kinetic energy release (TKER) spectra and Velocity Map Images (VMI), and compare the results directly with experimental measurements. In this work, we perform new extensive calculations using an improved AIMC algorithm that now takes into account the tunnelling of hydrogen atoms. This can play an extremely important role in photodissociation dynamics.


Cerebrospinal Fluid Concentrations of Neuronal Proteins Are Reduced in Primary Angiitis of the Central Nervous System.
Primary angiitis of the central nervous system (PACNS) is a rare autoimmune vasculitis limited to the CNS often causing substantial disability. Understanding of this disease is impaired by the lack of available biomaterial. Here, we collected cerebrospinal fluid (CSF) from patients with PACNS and matched controls and performed unbiased proteomics profiling using ion mobility mass spectrometry to identify novel disease mechanisms and candidate biomarkers. We identified 14 candidate proteins, including amyloid-beta A4 protein (APP), with reduced abundance in the CSF of PACNS patients and validated APP by Enzyme-linked Immunosorbent Assay (ELISA) in an extended cohort of patients with PACNS. Subsequent functional annotation surprisingly suggested neuronal pathology rather than immune activation in PACNS. Our study is the first to employ mass spectrometry to local immune reactions in PACNS and it identifies candidates such as APP with pathogenic relevance in PACNS to improve patient care in the future.


Polarization-independent, differential-phase-shift, quantum-key distribution system using upconversion detectors.
We propose and demonstrate a polarization-independent, differential-phase-shift, quantum-key distribution system with upconversion detectors. Even though the detectors have polarization dependency, use of alternative polarization modulation and a two-bit delay interferometer achieves polarization-insensitive operation. In an experiment, sifted key bits were polarization-independently generated over 50 km fiber.


Genome-wide control of RNA polymerase II activity by cohesin.
Cohesin is a well-known mediator of sister chromatid cohesion, but it also influences gene expression and development. These non-canonical roles of cohesin are not well understood, but are vital: gene expression and development are altered by modest changes in cohesin function that do not disrupt chromatid cohesion. To clarify cohesin's roles in transcription, we measured how cohesin controls RNA polymerase II (Pol II) activity by genome-wide chromatin immunoprecipitation and precision global run-on sequencing. On average, cohesin-binding genes have more transcriptionally active Pol II and promoter-proximal Pol II pausing than non-binding genes, and are more efficient, producing higher steady state levels of mRNA per transcribing Pol II complex. Cohesin depletion frequently decreases gene body transcription but increases pausing at cohesin-binding genes, indicating that cohesin often facilitates transition of paused Pol II to elongation. In many cases, this likely reflects a role for cohesin in transcriptional enhancer function. Strikingly, more than 95% of predicted extragenic enhancers bind cohesin, and cohesin depletion can reduce their association with Pol II, indicating that cohesin facilitates enhancer-promoter contact. Cohesin depletion decreases the levels of transcriptionally engaged Pol II at the promoters of most genes that don't bind cohesin, suggesting that cohesin controls expression of one or more broadly acting general transcription factors. The multiple transcriptional roles of cohesin revealed by these studies likely underlie the growth and developmental deficits caused by minor changes in cohesin activity.


Comparative Genomic Analysis of a Multidrug-Resistant Listeria monocytogenes ST477 Isolate.
Listeria monocytogenes is an opportunistic human foodborne pathogen that causes severe infections with high hospitalization and fatality rates. Clonal complex 9 (CC9) contains a large number of sequence types (STs) and is one of the predominant clones distributed worldwide. However, genetic characteristics of ST477 isolates, which also belong to CC9, have never been examined, and little is known about the detail genomic traits of this food-associated clone. In this study, we sequenced and constructed the whole-genome sequence of an ST477 isolate from a frozen food sample in China and compared it with 58 previously sequenced genomes of 25 human-associated, 5 animal, and 27 food isolates consisting of 6 CC9 and 52 other clones. Phylogenetic analysis revealed that the ST477 clustered with three Canadian ST9 isolates. All phylogeny revealed that CC9 isolates involved in this study consistently possessed the invasion-related gene vip. Mobile genetic elements (MGEs), resistance genes, and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system were elucidated among CC9 isolates. Our ST477 isolate contained a Tn554-like transposon, carrying five arsenical-resistance genes (arsA-arsD, arsR), which was exclusively identified in the CC9 background. Compared with the ST477 genome, three Canadian ST9 isolates shared nonsynonymous nucleotide substitutions in the condensin complex gene smc and cell surface protein genes ftsA and essC. Our findings preliminarily indicate that the extraordinary success of CC9 clone in colonization of different geographical regions is likely due to conserved features harboring MGEs, functional virulence and resistance genes. ST477 and three ST9 genomes are closely related and the distinct differences between them consist primarily of changes in genes involved in multiplication and invasion, which may contribute to the prevalence of ST9 isolates in food and food processing environment.


Fibrillarin is essential for early development and required for accumulation of an intron-encoded small nucleolar RNA in the mouse.
Fibrillarin, a protein component of C/D box small nucleolar ribonucleoproteins (snoRNPs), directs 2'-O-methylation of rRNA and is also involved in other aspects of rRNA processing. A gene trap screen in embryonic stem (ES) cells resulted in an insertion mutation in the fibrillarin gene. This insertion generated a fusion protein that contained the N-terminal 132 amino acids of fibrillarin fused to a beta-galactosidase-neomycin phosphotransferase reporter. As a result, the N-terminal GAR domain was present in the fusion protein but the methyltransferase-like domain was missing. The ES cell line with the targeted fibrillarin allele was transmitted through the mouse germ line, creating heterozygous animals. Western blot analyses showed a reduction in fibrillarin protein levels in the heterozygous knockout animals. Animals homozygous for the mutation were inviable, and massive apoptosis was observed in early Fibrillarin(-/-) embryos, showing that fibrillarin is essential for development. Fibrillarin(+/-) live-born mice displayed no obvious growth defect, but heterozygous intercrosses revealed a reduced ratio of +/- to +/+ mice, showing that some of the Fibrillarin heterozygous embryos die in utero. Analyses of tissue samples and cultured embryonic fibroblasts showed no discernible alteration in pre-rRNA processing or the level of the U3 snoRNA. However, the level of the intron-encoded box C/D snoRNA U76 was clearly reduced. This suggests a high requirement for snoRNA synthesis during an early stage in development.


The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells.
The homeobox gene Prox1 is crucial for mammalian lymphatic vascular development. In the absence of Prox1, lymphatic endothelial cells (LECs) are not specified. The maintenance of LEC identity also requires the constant expression of Prox1. However, the mechanisms controlling the expression of this gene in LECs remain poorly understood. The SRY-related gene Sox18 is required to induce Prox1 expression in venous LEC progenitors. Although Sox18 is also expressed in embryonic arteries, these vessels do not express Prox1, nor do they give rise to LECs. This finding suggests that some venous endothelial cell-specific factor is required for the activation of Prox1. Here we demonstrate that the nuclear hormone receptor Coup-TFII is necessary for the activation of Prox1 in embryonic veins by directly binding a conserved DNA domain in the regulatory region of Prox1. In addition, we show that the direct interaction between nuclear hormone receptors and Prox1 is also necessary for the maintenance of Prox1 expression during early stages of LEC specification and differentiation.


Expression of human fetal brain antigens by human tumors of neuroectodermal origin as defined by monoclonal antibodies.
The antigenic relationships between human tumors of neuroectodermal origin and fetal brain were investigated by the production of hybridoma antibodies derived from a fusion of P3-NS1/1-Ag 4-1 (NS1) myeloma cells with splenocytes from a mouse multiply immunized with an homogenate of second-trimester human fetal brain tissue. Two monoclonal antibodies (MAs), 4D2cl 6 and 7H10cl 4, were studied in detail by cell surface radioimmunoassay (CS-RIA), quantitative absorption, indirect immunofluorescence, and peroxidase-anti-peroxidase (PAP) immunohistology. MA 4D2cl 6 binds to 5 of 14 glioblastoma (GBM) cell lines, 1 of 2 melanoma cell lines, 1 of 3 neuroblastoma cell lines, and 1 of 5 fetal fibroblast lines by CS-RIA and to 13 of 13 GBM, 1 neuroblastoma, and fetal brain, liver, spleen, and adult spleen unfixed frozen tissue by PAP analysis. MA 7H10cl 4 binds to 13 of 14 GBM, 1 of 3 neuroblastoma, and 1 medulloblastoma cell line(s) by CS-RIA analysis and to 13 of 13 GBM, 1 neuroblastoma, fetal brain, liver, spleen, thymus, and adult spleen by PAP analysis. Control non-central nervous system tumors and normal adult tissue, including brain, were unreactive with both MAs by CS-RIA, PAP, and absorption analysis. Tissue distribution and localization analyses established that MAs 4D2cl 6 and 7H10cl 4 recognize specificities of shared fetal-neuroectodermal-lymphoid distribution which are operationally specific within the adult central nervous system and which are not related to previously described oncofetal or onconeural antigens.


Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling.
Germline mutations in the cylindromatosis (CYLD) gene have been described in families with cylindromas, trichoepitheliomas, and/or spiradenomas. Brooke-Spiegler syndrome (BSS) is the autosomal dominant predisposition to skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. We review the clinical features, molecular genetics, and the animal models of BSS. To date, a total of 51 germline CYLD mutations have been reported, occurring in exons 9-20, in 73 families with diverse ethnic and racial backgrounds. Of 51 mutations, 86% are expected to lead to truncated proteins. The seven missense mutations reported to date occur only within the ubiquitin (Ub)-specific protease (USP) domain of the CYLD protein and most are associated exclusively with multiple familial trichoepithelioma (MFT). CYLD functions as a tumor suppressor gene. CYLD encodes a deubiquitinating (DUB) enzyme that negatively regulates the nuclear factor (NF)-kappaB and c-Jun N-terminal kinase (JNK) pathways. CYLD DUB activity is highly specific for lysine 63 (K63)-linked Ub chains but has been shown to act on K48-linked Ub chains as well. In 2008, the CYLD USP domain was crystallized, revealing that the truncated Fingers subdomain confers CYLD's unique specificity for K63-linked Ub chains. Recent work using animal models revealed new roles for CYLD in immunity, lipid metabolism, spermatogenesis, osteoclastogenesis, antimicrobial defense, and inflammation.


The effect of treatment on the two-year course of late-life depression.
The purpose of this study was to examine the effect of treatment on the long-term course of geriatric depression. Eighty-four elderly patients who had responded to treatment of the index episode of major depression were maintained on full-dose antidepressant medication and followed on a monthly basis for two years. Relapse and recurrence were treated in a systematic manner. The cumulative probability of surviving for two years without relapse or recurrence was 74%. Of the 14 patients who suffered recurrence following recovery from the index episode, all responded to a change of treatment, and 71% remained well for the remainder of the study. The risk of recurrence was significantly increased by a delayed response to treatment of the index episode. Continuation and maintenance treatment with full-dose antidepressant medication, frequent follow-up, and vigorous treatment of relapses and recurrences, were associated with a good outcome in this group of elderly patients.


Principles of Breast Re-Reduction: A Reappraisal.
This article examines outcomes following breast re-reduction surgery using a random pattern blood supply to the nipple and vertical scar reduction. A retrospective review was conducted of patients who underwent bilateral breast re-reduction surgery performed by a single surgeon over a 12-year period. Patient demographics, surgical technique, and outcomes were analyzed. Ninety patients underwent breast re-reduction surgery. The average interval between primary and secondary surgery was 14 years (range, 0 to 42 years). The majority of patients had previously undergone primary breast reduction using an inferior pedicle [n = 37 (41 percent)]. Breast re-reduction surgery was most commonly performed using a random pattern blood supply, rather than recreating the primary pedicle [n = 77 (86 percent)]. The nipple-areola complex was repositioned in 60 percent of patients (n = 54). The mean volume of tissue resected was 250 g (range, 22 to 758 g) from the right breast and 244 g (range, 15 to 705 g) from the left breast. Liposuction was also used adjunctively in all cases (average, 455 cc; range, 50 to 1750 cc). Two patients experienced unilateral minor partial necrosis of the areolar edge but not of the nipple itself (2 percent). Breast re-reduction can be performed safely and predictably, even when the previous technique is not known. Four key principles were developed: (1) the nipple-areola complex can be elevated by deepithelialization rather than recreating or developing a new pedicle; (2) breast tissue is removed where it is in excess, usually inferiorly and laterally; (3) the resection is complemented with liposuction to elevate the bottomed-out inframammary fold; and (4) skin should not be excised horizontally below the inframammary fold. Therapeutic, IV.


Effect of cleansers on denture base resins' structural properties.
We assessed the effect of different available denture cleansers on the roughness and hardness of polyetherketoneketone, thermoinjection-molded polyamide, and polymethylmethacrylate. A total of 150 disc-shaped specimens were fabricated (10 mm × 2 mm) from these three denture base resins, and divided into five subgroups ( n = 10) according to immersion procedures. One of these groups subjected to distilled water served as control, whereas other groups were subjected to daily cleansing with four denture cleansers (Corega, Protefix, Curaprox, and Perlodent) for 8 h a day for 140 days. The surface roughness and hardness values of specimens were recorded by measuring twice at baseline, and again after application of chemical solutions. Topography alterations after treatments were assessed with scanning electron microscopy. The data were subjected to statistical analysis and comparison among groups was done using Kruskal Wallis and Wilcoxon Signed Ranks tests. P-value <0.05 was considered significant. The surface roughness of polyetherketoneketone, polymethylmethacrylate, and polyamide dentures was increased significantly by chemical solutions of denture cleansers. While the hardness value of polyetherketoneketone was not affected significantly after immersion in denture cleansers, those of polymethylmethacrylate and polyamide decreased significantly. Compared with Curaprox, the effervescent tablets significantly altered the surface hardness and roughness of polyamide. Denture cleansers can considerably alter the surface roughness and hardness of denture base resins and should be used carefully depending on the material.


Personalized biochemistry and biophysics.
Whole human genome sequencing of individuals is becoming rapid and inexpensive, enabling new strategies for using personal genome information to help diagnose, treat, and even prevent human disorders for which genetic variations are causative or are known to be risk factors. Many of the exploding number of newly discovered genetic variations alter the structure, function, dynamics, stability, and/or interactions of specific proteins and RNA molecules. Accordingly, there are a host of opportunities for biochemists and biophysicists to participate in (1) developing tools to allow accurate and sometimes medically actionable assessment of the potential pathogenicity of individual variations and (2) establishing the mechanistic linkage between pathogenic variations and their physiological consequences, providing a rational basis for treatment or preventive care. In this review, we provide an overview of these opportunities and their associated challenges in light of the current status of genomic science and personalized medicine, the latter often termed precision medicine.


Social stereotypes and information-processing strategies: the impact of task complexity.
Subjects read information about a defendant in a criminal trial with initial instructions to judge either his guilt (guilt judgment objective) or his aggressiveness (trait judgment objective). The defendant was either Hispanic or ethnically nondescript. After considering the evidence, subjects made both guilt and aggressiveness judgments (regardless of which type of judgment they were instructed to make at the time they read the information) and then recalled as much of the information they read as they could. Results favored the hypothesis that when subjects face a complex judgmental situation, they use stereotypes (when available and relevant) as a way of simplifying the judgment. Specifically, they use the stereotype as a central theme around which they organize presented evidence that is consistent with it, and they neglect inconsistent information. Subjects with a (complex) guilt judgment objective judged the defendant to be relatively more guilty and aggressive and recalled more negative information about him if he was Hispanic than if he was ethnically nondescript. In contrast, subjects with a (simple) trait judgment objective did not perceive either the guilt or aggressiveness of the two defendants to be appreciably different, and did not display any significant bias in their recall of the evidence. These and other results are discussed in terms of the information-processing strategies subjects are likely to use when they expect to make different types of judgments.


The economic evaluation of human papillomavirus vaccination strategies against cervical cancer in women in Lao PDR: a mathematical modelling approach.
Cervical cancer, a preventable disease, is the third leading cause of cancer morbidity and mortality in the Lao People's Democratic Republic (Lao PDR). Since many cervical cancers are linked to human papilloma virus (HPV) infection, vaccination against this virus may lead to a reduction in these types of cancer. The study described here is the first to compare the cost-effectiveness of different HPV vaccination options in Lao PDR. A dynamic compartment model was created. The model included routine screening activities already in place, as well as theoretical interventions that included a 10-year old girl-only vaccination programme combined with/without a 10-year old boy vaccination programme and/or a catch-up component. The simulation was run over 100 years. In base case analyses, we assumed 70 % vaccination coverage with lifelong protection and 100 % efficacy against HPV types 16/18. The outcomes of interest were the incremental cost per Disability-Adjusted Life Year (DALY) averted. In base case analyses, according to the WHO definition of cost-effectiveness thresholds, vaccinating 10-year-old girls was very cost-effective. Adding a catch-up vaccination element for females aged 11-25 years was also very cost-effective, costing 1559 international dollars (I$) per DALY averted. Increasing the age limit of the catch-up vaccination component to 75 years old showed that this remained a cost-effective option (I$ 5840 per DALY averted). Adding a vaccination programme for 10-year-old boys was not found to be cost-effective unless a short time simulation (30 years or less) was considered, along with a catch-up vaccination component for both males and females. Adding a catch-up female vaccination component is more attractive than adding a 10-year-old boy vaccination component.


Integrated analysis of genome-wide DNA methylation, gene expression and protein expression profiles in molecular subtypes of WHO II-IV gliomas.
Glioma is the most common malignant primary brain tumor among adults, among which glioblastoma (GBM) exhibits the highest malignancy. Despite current standard chemoradiation, glioma is still invariably fatal. A further insight into the molecular background of glioma is required to improve patient outcomes. Previous studies evaluated molecular genetic differences through comparing different grades of glioma. Here, we integrated DNA methylation, RNA sequencing and protein expression data sets of WHO grade II to IV gliomas, to screen for dysregulated genes in subtypes during malignant progression of glioma. We propose a list of universal genes (UG) as novel glioma biomarkers: 977 up-regulated genes and 114 down-regulated genes, who involved in cell cycle, Wnt receptor signaling pathway and fatty acid metabolic process. Poorer survival was associated significantly with the high expression of 977 up-regulated genes and low expression of 114 down-regulated in UG (P <0.001). To our knowledge, this was the first study that focused on subtypes to detect dysregulated genes that could contribute to malignant progression. Furthermore, the differentially expressed genes profile may lead to the identification of new therapeutic targets for glioma patients.


Prophylactic effects of intrathecal Meperidine and intravenous Ondansetron on shivering in patients undergoing lower extremity orthopedic surgery under spinal anesthesia.
Intraoperative hypothermia is a common problem with anesthesia. Spinal anesthesia, the same as general anesthesia, affects the process of temperature regulation. The aim of this study was to compare the prophylactic effect of intravenous (IV) ondansetron with intrathecal (IT) meperidine on prevention of shivering during spinal anesthesia in patients underwent orthopedic surgery of the lower limb. In this study, 120 patients with American Society of Anesthesiologists physical status I to II, between the ages 16 and 65 were randomized into three groups. Group O and Group M were given IV ondansetron 8 mg and IT meperidine 0.2 mg/kg, before spinal anesthesia, respectively. Group C received IV saline 0.9%. The core and ambient temperatures, the incidence and intensity of shivering, blood pressure, heart rate, and maximum level of sensory block were recorded. Shivering was observed in 15%, 2.5%, and 37.5% of patients in Groups O, M, and C, respectively. There was a significant difference between Group O and M compared to Group C (P = 0.023 for Group O vs. Group C, P < 0.001 for Group M vs. Group C, P = 0.049 for Group M vs. Group O). Shivering incidence and intensity in Group M was significantly lower than Group O (P = 0.049 and P = 0.047, respectively). Twenty-two patients required additional IV meperidine among which 15 patients were from Group C (37.5%), six patients from Group O (15%) and one patient from Group M (2.5%). We concluded that IT meperidine and IV ondansetron comparably can decrease intensity and incidence of shivering compared to control group as well as decreasing the requirement to additional doses of meperidine for shivering the control without any hemodynamic side effect.


Characteristics and Clinical Manifestations of Pigmented Purpuric Dermatosis.
Pigmented purpuric dermatoses (PPD) are a spectrum of disorders characterized by a distinct purpuric rash. Although PPD can be easily diagnosed, the disease entity remains an enigma and a therapeutic challenge. The purpose of this study was to investigate the characteristics and clinical manifestations of PPD and to elucidate the relationship between assumed etiologic factors and the clinical manifestations of PPD and treatment responses. Retrograde analyses were performed to identify appropriate PPD patients who visited Korea University Medical Center Anam Hospital from 2002 to 2012. Information on 113 patients with PPD was analyzed, and 38 subjects with skin biopsy were included for this study. Schamberg's disease was the most frequent clinical type (60.5%). Concomitant diseases included hypertension (15.8%), diabetes (10.5%), and others. Associated medication histories included statins (13.2%), beta blockers (10.5%), and others. Possibly associated etiologic factors were recent upper respiratory infection (5.3%), high orthostatic pressure due to prolonged standing (2.6%), and strenuous exercise (2.6%). A total of 36 patients (94.7%) were treated with one or more treatment methods, including oral antihistamines, pentoxifylline, topical steroids, and/or phototherapy. There was no significant difference in disease progress according to underlying diseases, medications, or association factors (p>0.05). Our overall results were grossly consistent with the existing literature, excluding several findings. Although a possible relationship between PPD and cardiovascular disease or cardiovascular medication was proposed at the beginning of the study, no statistically significant correlations were found according to the specific clinical types and treatment responses (p>0.05).


Tracking the implementation to identify gaps in integrated disease surveillance program in a block of district jhajjar (haryana).
To strengthen the surveillance system in India, Integrated Disease Surveillance Program (IDSP) was launched in 2004. The frequent occurrence of epidemics even after the launching of the IDSP was an indication toward inadequacy of the system. The responsibility for effective implementation of IDSP at the sub-center level lies with the health workers. The aim of the following study was to assess the knowledge and practice of health workers regarding IDSP and to assess the quality of IDSP reports at the sub-center level. It was cross-sectional study carried out in the area under Community Health Center Dighal which is the rural field practice area attached to Post Graduate Institute of Medical Sciences, Rohtak in the State of Haryana, India. All the 24 sub-centers in the area were visited and 46 health workers (22 male; 24 female) who met the inclusion criteria i.e. who had completed 1 year of their service or had been trained for IDSP, were included in the study. Data were collected on a self-designed, semi-structured and pre-tested schedule by interviewing the study subjects and observation of the records/reports. Percentages and proportions. Only 14/46 (~30%) of the workers could expand the abbreviation "IDSP" correctly. Only 4/46 (~9%) workers could narrate any of the trigger events and none could tell all the trigger events. Only at 12 such sub-centers, diagnoses were being written in their out-patient registers according to the defined syndromes. 43/46 (~93%) workers were not aware of the zero reporting. The surveillance system is much less alert and intense than the desired level and needs to be strengthened.


Development and validation of a delirium predictive score in older people.
delirium is frequently under diagnosed in older hospitalised patients. Predictive models have not been widely incorporated in clinical practice. to develop and validate a predictive score for incident delirium. two consecutive observational prospective cohorts (development and validation) in a university affiliated hospital. inpatients 65 years and older. in the development cohort patients were assessed within the first 48 h of admission, and every 48 h thereafter, using the confusion assessment method to diagnose delirium and data were collected on comorbidity, illness severity, functional status and laboratory. Delirium predictive score (DPS) was constructed in the development cohort using variables associated with incident delirium in the multivariate analysis (P < 0.05), and then tested in a validation cohort of comparable patients, admitted without delirium. Receiver operating characteristic (ROC) analysis and likelihood ratio (LR) were calculated. the development cohort included 374 patients, incident delirium occurred in 25. After multivariate analysis incident delirium was independently associated with lower functional status (Barthel Index) and a proxy for dehydration (elevated urea to creatinine ratio). Using these variables, DPS was constructed with a performance in the ROC curve area of 0.86 (95% CI: 0.82-0.91) and (-) LR = 0.16 and (+) LR = 3.4. The validation cohort included 104 patients and the performance of the score was ROC 0.78 (95% CI: 0.66-0.90). This simple predictive model highlights functional status and a proxy for dehydration as a useful tool for identifying older patients that may benefit from close monitoring and preventive care for early diagnosis of delirium.


Gamma rhythmic bursts: coherence control in networks of cortical pyramidal neurons.
Much evidence indicates that synchronized gamma-frequency (20-70 Hz) oscillation plays a significant functional role in the neocortex and hippocampus. Chattering neuron is a possible neocortical pacemaker for the gamma oscillation. Based on our recent model of chattering neurons, here we study how gamma-frequency bursting is synchronized in a network of these neurons. Using a phase oscillator description, we first examine how two coupled chattering neurons are synchronized. The analysis reveals that an incremental change of the bursting mode, such as from singlet to doublet, always accompanies a rapid transition from antisynchronous to synchronous firing. The state transition occurs regardless of what changes the bursting mode. Within each bursting mode, the neuronal activity undergoes a gradual change from synchrony to antisynchrony. Since the sensitivity to Ca(2+) and the maximum conductance of Ca(2+)-dependent cationic current as well as the intensity of input current systematically control the bursting mode, these quantities may be crucial for the regulation of the coherence of local cortical activity. Numerical simulations demonstrate that the modulations of the calcium sensitivity and the amplitude of the cationic current can induce rapid transitions between synchrony and asynchrony in a large-scale network of chattering neurons. The rapid synchronization of chattering neurons is shown to synchronize the activities of regular spiking pyramidal neurons at the gamma frequencies, as may be necessary for selective attention or binding processing in object recognition.


Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease.
Niemann-Pick type C1 (NPC) disease is a lysosomal storage disease caused by mutations in the NPC1 gene, leading to an increase in unesterified cholesterol and several sphingolipids, and resulting in hepatic disease and progressive neurological disease. We show that subcutaneous administration of the pharmaceutical excipient 2-hydroxypropyl-β-cyclodextrin (HPβCD) to cats with NPC disease ameliorated hepatic disease, but doses sufficient to reduce neurological disease resulted in pulmonary toxicity. However, direct administration of HPβCD into the cisterna magna of presymptomatic cats with NPC disease prevented the onset of cerebellar dysfunction for greater than a year and resulted in a reduction in Purkinje cell loss and near-normal concentrations of cholesterol and sphingolipids. Moreover, administration of intracisternal HPβCD to NPC cats with ongoing cerebellar dysfunction slowed disease progression, increased survival time, and decreased the accumulation of brain gangliosides. An increase in hearing threshold was identified as a potential adverse effect. These studies in a feline animal model have provided critical data on efficacy and safety of drug administration directly into the central nervous system that will be important for advancing HPβCD into clinical trials.


Iminosugars in combination with interferon and ribavirin permanently eradicate noncytopathic bovine viral diarrhea virus from persistently infected cells.
We evaluated interferon (IFN) and ribavirin (RBV) as dual therapy and as part of triple-combination therapies with the iminosugars N-butyl-deoxynojirimycin (NB-DNJ), N-nonyl-deoxynojirimycin, and N-7-oxanonyl-6-deoxymethyl-galactonojirimycin. The ability of these compounds to clear bovine viral diarrhea virus (BVDV), a surrogate model for hepatitis C virus (HCV), from a persistently infected Madin-Darby bovine kidney cells cell line was determined by monitoring the secretion of viral RNA and the infectivity of secreted virions. In the BVDV system, after treatment with IFN-RBV alone, viral rebound was observed immediately after removal of the drugs. In contrast, we demonstrate that a triple drug combination of IFN, RBV, and an iminosugar eradicated the BVDV infection in a time- and a dose-dependent manner, leading to sustained viral clearance. Importantly, in the case of NB-DNJ, the sustained viral clearance was achieved by using physiologically relevant and tolerated drug concentrations. Therefore, the use of a triple-combination therapy that includes an iminosugar may prove to be of greater therapeutic value for the treatment of HCV infection than the use of IFN-RBV alone.


Effect of Sequential Inoculum of Beta-Glucosidase Positive and Probiotic Strains on Brine Fermentation to Obtain Low Salt Sicilian Table Olives.
In the present study, the β-glucosidase positive strain Lactobacillus plantarum F3. 3 was used as starter during the fermentation of Sicilian table olives (Nocellara Etnea cultivar) at two different salt concentrations (5 and 8%), in order to accelerate the debittering process. The latter was monitored through the increase of hydroxytyrosol compound. In addition, the potential probiotic Lactobacillus paracasei N24 strain was added after 60 days of fermentation. Un-inoculated brine samples at 5 and 8% of salt were used as control. The fermentation was monitored till 120 days through physico-chemical and microbiological analyses. In addition, volatile organic compounds and sensorial analyses were performed during the process and at the end of the fermentation, respectively. Lactic acid bacteria and yeasts were, in depth, studied by molecular methods and the occurrence of the potential probiotic N24 strain in the final products was determined. Results highlighted that inoculated brines exhibited a higher acidification and debittering rate than control ones. In addition, inoculated brines at 5% of salt exhibited higher polyphenols (hydoxytyrosol, tyrosol, and verbascoside) content compared to samples at 8% of NaCl, suggesting a stronger oleuropeinolytic activity of the starter at low salt concentration. Lactobacilli and yeasts dominated during the fermentation process, with the highest occurrence of L. plantarum and Wickerhamomyces anomalus, respectively. Moreover, the potential probiotic L. paracasei N24 strain was able to survive in the final product. Hence, the sequential inoculum of beta-glucosidase positive and potential probiotic strains could be proposed as a suitable technology to produce low salt Sicilian table olives.


Analysis of anisotropic viscoelastoplastic properties of cortical bone tissues.
Bone fractures affect the health of many people and have a significant social and economic effect. Often, bones fracture due to impacts, sudden falls or trauma. In order to numerically model the fracture of a cortical bone tissue caused by an impact it is important to know parameters characterising its viscoelastoplastic behaviour. These parameters should be measured for various orientations in a bone tissue to assess bone's anisotropy linked to its microstructure. So, the first part of this study was focused on quantification of elastic-plastic behaviour of cortical bone using specimens cut along different directions with regard to the bone axis-longitudinal (axial) and transverse. Due to pronounced non-linearity of the elastic-plastic behaviour of the tissue, cyclic loading-unloading uniaxial tension tests were performed to obtain the magnitudes of elastic moduli not only from the initial loading part of the cycle but also from its unloading part. Additional tests were performed with different deformation rates to study the bone's strain-rate sensitivity. The second part of this study covered creep and relaxation properties of cortical bone for two directions and four different anatomical positions-anterior, posterior, medial and lateral-to study the variability of bone's properties. Since viscoelastoplasticity of cortical bone affects its damping properties due to energy dissipation, the Dynamic Mechanical Analysis (DMA) technique was used in the last part of our study to obtain magnitudes of storage and loss moduli for various frequencies. Based on analysis of elastic-plastic behaviour of the bovine cortical bone tissue, it was found that magnitudes of the longitudinal Young's modulus for four cortical positions were in the range of 15-24 GPa, while the transversal modulus was lower--between 10 and 15 GPa. Axial strength for various anatomical positions was also higher than transversal strength with significant differences in magnitudes for those positions. Quantitative data obtained in creep and relaxation tests exhibited no significant position-specific differences. DMA results demonstrated relatively low energy-loss capability due to viscosity of bovine cortical bone that has a loss factor in the range of 0.035-0.1.


Inbreeding reveals mode of past selection on male reproductive characters in Drosophila melanogaster.
Directional dominance is a prerequisite of inbreeding depression. Directionality arises when selection drives alleles that increase fitness to fixation and eliminates dominant deleterious alleles, while deleterious recessives are hidden from it and maintained at low frequencies. Traits under directional selection (i.e., fitness traits) are expected to show directional dominance and therefore an increased susceptibility to inbreeding depression. In contrast, traits under stabilizing selection or weakly linked to fitness are predicted to exhibit little-to-no inbreeding depression. Here, we quantify the extent of inbreeding depression in a range of male reproductive characters and then infer the mode of past selection on them. The use of transgenic populations of Drosophila melanogaster with red or green fluorescent-tagged sperm heads permitted in vivo discrimination of sperm from competing males and quantification of characteristics of ejaculate composition, performance, and fate. We found that male attractiveness (mating latency) and competitive fertilization success (P2) both show some inbreeding depression, suggesting they may have been under directional selection, whereas sperm length showed no inbreeding depression suggesting a history of stabilizing selection. However, despite having measured several sperm quality and quantity traits, our data did not allow us to discern the mechanism underlying the lowered competitive fertilization success of inbred (f = 0.50) males.


Transcriptional responses of Burkholderia cenocepacia to polymyxin B in isogenic strains with diverse polymyxin B resistance phenotypes.
Burkholderia cenocepacia is a Gram-negative opportunistic pathogen displaying high resistance to antimicrobial peptides and polymyxins. We identified mechanisms of resistance by analyzing transcriptional changes to polymyxin B treatment in three isogenic B. cenocepacia strains with diverse polymyxin B resistance phenotypes: the polymyxin B-resistant parental strain K56-2, a polymyxin B-sensitive K56-2 mutant strain with heptoseless lipopolysaccharide (LPS) (RSF34), and a derivative of RSF34 (RSF34 4000B) isolated through multiple rounds of selection in polymyxin B that despite having a heptoseless LPS is highly polymyxin B-resistant. A heptoseless LPS mutant of B. cenocepacia was passaged through multiple rounds of selection to regain high levels of polymyxin B-resistance. This process resulted in various phenotypic changes in the isolate that could contribute to polymyxin B resistance and are consistent with LPS-independent changes in the outer membrane. The transcriptional response of three B. cenocepacia strains to subinhibitory concentrations of polymyxin B was analyzed using microarray analysis and validated by quantitative Real Time-PCR. There were numerous baseline changes in expression between the three strains in the absence of polymyxin B. In both K56-2 and RSF34, similar transcriptional changes upon treatment with polymyxin B were found and included upregulation of various genes that may be involved in polymyxin B resistance and downregulation of genes required for the synthesis and operation of flagella. This last result was validated phenotypically as both swimming and swarming motility were impaired in the presence of polymyxin B. RSF34 4000B had altered the expression in a larger number of genes upon treatment with polymyxin B than either K56-2 or RSF34, but the relative fold-changes in expression were lower. It is possible to generate polymyxin B-resistant isolates from polymyxin B-sensitive mutant strains of B. cenocepacia, likely due to the multifactorial nature of polymyxin B resistance of this bacterium. Microarray analysis showed that B. cenocepacia mounts multiple transcriptional responses following exposure to polymyxin B. Polymyxin B-regulated genes identified in this study may be required for polymyxin B resistance, which must be tested experimentally. Exposure to polymyxin B also decreases expression of flagellar genes resulting in reduced swimming and swarming motility.


When psychiatric diagnosis becomes an overworked tool.
A psychiatric diagnosis today is asked to serve many functions-clinical, research, medicolegal, delimiting insurance coverage, service planning, defining eligibility for state benefits (eg, for unemployment or disability), as well as providing rallying points for pressure groups and charities. These contexts require different notions of diagnosis to tackle the particular problem such a designation is meant to solve. In a number of instances, a 'status' definition (ie, a diagnostic label or category) is employed to tackle what is more appropriately seen as requiring a 'functional' approach (ie, how well the person is able to meet the demands of a test of performance requiring certain capabilities, aptitudes or skills). In these instances, a diagnosis may play only a subsidiary role. Some examples are discussed: the criteria for involuntary treatment; the determination of criminal responsibility; and, assessing entitlements to state benefits. I suggest that the distinction between 'status' versus 'function' has not been given sufficient weight in discussions of diagnosis. It is in the functional domain that some of the problematic relationships between clinical psychiatry and the social institutions with which it rubs shoulders are played out. A status, signified by a diagnosis, has often been encumbered with demands for which it is poorly equipped. It is a reductive way of solving problems of management, allocation or disposal for which a functional approach should be given greater weight.


Variation in use of active surveillance among men undergoing expectant treatment for early stage prostate cancer.
We examined variation in active surveillance use in Medicare eligible men undergoing expectant treatment for early stage prostate cancer. Using SEER (Surveillance, Epidemiology and End Results) and Medicare data we identified 49,192 men diagnosed with localized prostate cancer from 2004 through 2007. Of 7,347 patients who did not receive treatment (ie expectant management) within 12 months of diagnosis we assessed the prevalence of active surveillance (ie repeat prostate biopsy and prostate specific antigen measurement) vs watchful waiting across health care markets. We fit multivariable logistic regression models to examine associations of active surveillance with patient demographics, cancer severity and health care market characteristics. During the study interval use of active surveillance vs watchful waiting increased significantly in patients treated expectantly from 9.7% in 2004 to 15.3% in 2007 (p <0.001). Active surveillance was less common in older patients, those with high risk tumors and those with more comorbidities (each p <0.001). Patients who were white and had higher socioeconomic status were more likely to receive active surveillance (each p <0.05). After adjusting for patient and tumor characteristics significant differences in the predicted probability of active surveillance persisted across health care markets (range 2.4% to 30.1%). No significant variation in active surveillance use was associated with specific health care market characteristics, including intensity of end of life care, Medicare reimbursement or provider density. Active surveillance has been relatively uncommon in Medicare beneficiaries with localized prostate cancer. Its use relative to watchful waiting varies based on patient demographics, tumor severity and geographic location.


Effect of salvianolic acid A, a depside from roots of Salvia miltiorrhiza, on gastric H+,K(+)-ATPase.
Salvianolic acid A, a depside from the roots of Salvia miltiorrhiza, inhibited pig gastric H+,K(+)-ATPase and pNPPase with 50% inhibition values (IC50) of 5.2 x 10(-7) M and 1.7 x 10(-6) M, respectively. Kinetic studies revealed that the inhibition patterns induced by salvianolic acid A were competitive with respect to ATP and noncompetitive with respect to K+. Salvianolic acid A (25 mg/kg, i.p.) significantly inhibited acid secretion in pylorus-ligated rats. At the same dose it also showed a significant reduction in the formation of gastric lesion induced by water immersion and restraint stress. These results suggest that salvianolic acid A shows antisecretory and antiulcer activity by inhibiting the gastric H+,K(+)-ATPase.


Contact forces in roughness discrimination.
Roughness perception through fingertip contact with a textured surface can involve spatial and temporal cues from skin indentation and vibration respectively. Both types of cue may be affected by contact forces when feeling a surface and we ask whether, on a given trial, discrimination performance relates to contact forces. We examine roughness discrimination performance in a standard psychophysical method (2-interval forced choice, in which the participant identifies which of two spatial textures formed by parallel grooves feels rougher) while continuously measuring the normal and tangential forces applied by the index finger. Fourteen participants discriminated spatial gratings in fine (spatial period of 320-580 micron) and coarse (1520-1920 micron) ranges using static pressing or sliding contact of the index finger. Normal contact force (mean and variability) during pressing or sliding had relatively little impact on accuracy of roughness judgments except when pressing on surfaces in the coarse range. Discrimination was better for sliding than pressing in the fine but not the coarse range. In contrast, tangential force fluctuations during sliding were strongly related to roughness judgment accuracy.


Self-Control Moderates the Association Between Perceived Severity of Coronavirus Disease 2019 (COVID-19) and Mental Health Problems Among the Chinese Public.
Coronavirus disease 2019 (COVID-19) has caused thousands of deaths in China. Prior research suggests that individuals' perceived severity of COVID-19 is related to a range of negative emotional and behavioral reactions among the Chinese public. However, scant research has examined the underlying mechanisms. Drawing upon the risk-resilience model, this study proposes that self-control, as a resilient factor, would potentially moderate the association between perceived severity of COVID-19 and mental health problems. Data from a national survey was used to examine this idea. Participants were 4607 citizens from 31 regions in China (Mage = 23.71 years, 72.5% female) who completed a national survey at the beginning of February 2020. Results of hierarchical regression showed that after controlling for a number of demographic variables, perceived severity of COVID-19 and self-control were positively and negatively related to mental health problems, respectively. More importantly, self-control moderated the "perceived severity of COVID-19-mental health problems" association, with this link attenuating as the levels of self-control increased. These findings suggest that compared to those with high self-control, individuals with low self-control are more vulnerable and are more in need of psychological aids to maintain mental health in the encounter of the COVID-19 outbreak. Practically, enhancing individuals' self-control ability might be a promising way to improve individuals' mental health during the early period of the COVID-19 outbreak.


A summary of recent findings on birth outcomes and developmental effects of prenatal ETS, PAH, and pesticide exposures.
Inner-city minority populations are high-risk groups for adverse birth outcomes and also more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), benzo[a]pyrene B[a]P, other ambient polycyclic aromatic hydrocarbons (global PAHs), and residential pesticides. The Columbia Center for Children's Environmental Health (CCCEH) is conducting a prospective cohort study of 700 northern Manhattan pregnant women and newborns to examine the effects of prenatal exposure to these common toxicants on fetal growth, early neurodevelopment, and respiratory health. This paper summarizes results of three published studies demonstrating the effects of prenatal ETS, PAH, and pesticides on birth outcomes and/or neurocognitive development [Perera FP, Rauh V, Whyatt RM, Tsai WY, Bernert JT, Tu YH, et al. Molecular evidence of an interaction between prenatal environment exposures on birth outcomes in a multiethnic population. Environ Health Perspect 2004;12:630-62; Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, et al. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicol Teratol 2004;26:373-85; Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R, et al. Prenatal insecticide exposures, birth weight and length among an urban minority cohort. Environ Health Perspect, in press]. To evaluate the effects of prenatal exposure to ETS, PAHs, and pesticides, researchers analyzed questionnaire data, cord blood plasma (including biomarkers of ETS and pesticide exposure), and B[a]P-DNA adducts (a molecular dosimeter of PAHs). Self-reported ETS was associated with decreased head circumference (P = 0.04), and there was a significant interaction between ETS and adducts such that combined exposure had a significant multiplicative effect on birth weight (P = 0.04) and head circumference (P = 0.01) after adjusting for confounders. A second analysis examined the neurotoxic effects of prenatal ETS exposure and postpartum material hardship (unmet basic needs in the areas of food, housing, and clothing) on 2-year cognitive development. Both exposures depressed cognitive development (P < 0.05), and there was a significant interaction such that children with exposure to both ETS and material hardship exhibited the greatest cognitive deficit (7.1 points). A third analysis found that cord chlorpyrifos, and a combined measure of cord chlorpyrifos, diazinon, and propoxur-metabolite, were inversely associated with birth weight and/or length (P < 0.05). These results underscore the importance of policies that reduce exposure to ETS, air pollution, and pesticides with potentially adverse effects on fetal growth and child neurodevelopment.


From COVID-19 research to vaccine application: why might it take 17 months not 17 years and what are the wider lessons?
It is often said that it takes 17 years to move medical research from bench to bedside. In a coronavirus disease (COVID-19) world, such time-lags feel intolerable. In these extraordinary circumstances could years be made into months? If so, could those lessons be used to accelerate medical research when the crisis eases?To measure time-lags in health and biomedical research as well as to identify ways of reducing them, we developed and published (in 2015) a matrix consisting of overlapping tracks (or stages/phases) in the translation from discovery research to developed products, policies and practice. The matrix aids analysis by highlighting the time and actions required to develop research (and its translation) both (1) along each track and (2) from one track to another, e.g. from the discovery track to the research-in-humans track. We noted four main approaches to reducing time-lags, namely increasing resources, working in parallel, starting or working at risk, and improving processes.Examining these approaches alongside the matrix helps interpret the enormous global effort to develop a vaccine for the 2019 novel coronavirus SARS-CoV-2, the causative agent of COVID-19. Rapid progress in the discovery/basic and human research tracks is being made through a combination of large-scale funding, work being conducted in parallel (between different teams globally and through working in overlapping tracks), working at greater (but proportionate) risk to safety than usual, and adopting various new processes. The overlapping work of some of the teams involves continuing animal research whilst entering vaccine candidates into Phase I trials alongside planning their Phase II trials. The additional funding available helps to reduce some of the usual financial risks in moving so quickly. Going forward through the increasingly large human trials for safety, dosage and efficacy, it will be vital to overlap work in parallel in the often challenging public policy and clinical tracks. Thus, regulatory and reimbursement bodies are beginning and preparing rapid action to pull vaccines proving to be safe and effective through to extraordinarily rapid application to the general population. Monitoring the development of a COVID-19 vaccine using the matrix (modified as necessary) could help identify which of the approaches speeding development and deployment could be usefully applied more widely in the future.


PEG-b-PPS diblock copolymer aggregates for hydrophobic drug solubilization and release: cyclosporin A as an example.
Micelles formed from amphiphilic block copolymers have been explored in recent years as carriers for hydrophobic drugs. In an aqueous environment, the hydrophobic blocks form the core of the micelle, which can host lipophilic drugs, while the hydrophilic blocks form the corona or outer shell and stabilize the interface between the hydrophobic core and the external medium. In the present work, mesophase behavior and drug encapsulation were explored in the AB block copolymeric amphiphile composed of poly(ethylene glycol) (PEG) as a hydrophile and poly(propylene sulfide) PPS as a hydrophobe, using the immunosuppressive drug cyclosporin A (CsA) as an example of a highly hydrophobic drug. Block copolymers with a degree of polymerization of 44 on the PEG and of 10, 20 and 40 on the PPS respectively (abbreviated as PEG44-b-PPS10, PEG44-b-PPS20, PEG44-b-PPS40) were synthesized and characterized. Drug-loaded polymeric micelles were obtained by the cosolvent displacement method as well as the remarkably simple method of dispersing the warm polymer melt, with drug dissolved therein, in warm water. Effective drug solubility up to 2 mg/mL in aqueous media was facilitated by the PEG- b-PPS micelles, with loading levels up to 19% w/w being achieved. Release was burst-free and sustained over periods of 9-12 days. These micelles demonstrate interesting solubilization characteristics, due to the low glass transition temperature, highly hydrophobic nature, and good solvent properties of the PPS block.


Prevalence, distribution and clinical correlates of myocardial fibrosis in systemic lupus erythematosus: a cardiac magnetic resonance study.
To assess the prevalence, distribution and clinical correlates of myocardial fibrosis, as detected by cardiac magnetic resonance (CMR), in systemic lupus erythematosus (SLE). Forty-one subjects (average age 39 ± 12 years and 80% female) with SLE underwent CMR imaging at 1.5T, using late gadolinium enhancement (LGE) to quantify the area of myocardial fibrosis in the left ventricle (LV). Subjects also underwent transthoracic echocardiography (TTE) and exercise testing. LGE was detected in 15/41 subjects, 11 with localized LGE (<15% LV mass) and four with extensive LGE (>15% LV mass). The commonest site of LGE was the interventricular septum, with all but one case demonstrating an intramural or inflammatory pattern. The mean age of the >15% LGE group (55 ± 15 years) was significantly higher than the <15% or absent LGE subgroups. Based on both CMR and TTE measurements, subjects with LGE > 15% demonstrated a reduced E/A ratio of 0.9 ± 0.4 relative to the <15% and absent LGE subgroups. LV end-systolic volume (ESVi), end-diastolic volume (EDVi) and maximum exercise capacity were also reduced in the >15% LGE group. Mid-wall myocardial fibrosis occurs frequently in SLE and is strongly associated with advancing subject age, but not with SLE duration or severity. Extensive LGE may be associated with diastolic dysfunction and impaired exercise capacity, although this may be an epiphenomenon of age. Cardiac magnetic resonance with quantitative assessment of LGE may provide a basis for cardiac risk stratification in SLE.


Exploration of the resilience construct in posttraumatic stress disorder severity and functional correlates in military combat veterans who have served since September 11, 2001.
This study evaluated the relationship between resilience and psychological functioning in military veterans deployed to a region of military conflict in support of Operation Enduring Freedom or Operation Iraqi Freedom. 497 military veterans completed a structured psychiatric interview and questionnaires measuring psychological symptoms, resiliency, and trauma exposure. The study had 2 primary aims: (1) to examine whether the association between trauma exposure and PTSD was moderated by resilience and (2) to examine whether resilience was uniquely associated with functional outcomes after accounting for PTSD. Measures included the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (for PTSD diagnosis), the Connor-Davidson Resilience Scale, and the Traumatic Life Events Questionnaire. Data were collected between June 2005 and February 2009. Evaluating the association of resilience and trauma exposure with PTSD revealed main effects for combat exposure, lifetime trauma exposure, and resilience. Additionally, there was a significant (P < .05) interaction between combat exposure and resilience such that higher levels of resilience were particularly protective among individuals with high combat exposure. After controlling for age, gender, minority status, trauma exposure, and PTSD diagnosis, resilience was uniquely associated with decreased suicidality, reduced alcohol problems, lower depressive symptom severity, and fewer current health complaints and lifetime and past-year medical problems. These results suggest that resilience is a construct that may play a unique role in the occurrence of PTSD and severity of other functional correlates among deployed veterans. Future studies in this area would benefit from a prospective design, the evaluation of other possible protective processes (e.g., social support), and specific examination of particular aspects of resilience and how resilience may be increased.


SI-MOIRAI: a new method to identify and quantify the metabolic fate of nucleotides.
Since the discovery of nucleotides over 100 years ago, extensive studies have revealed the importance of nucleotides for homeostasis, health and disease. However, there remains no established method to investigate quantitatively and accurately intact nucleotide incorporation into RNA and DNA. Herein, we report a new method, Stable-Isotope Measure Of Influxed Ribonucleic Acid Index (SI-MOIRAI), for the identification and quantification of the metabolic fate of ribonucleotides and their precursors. SI-MOIRAI, named after Greek goddesses of fate, combines a stable isotope-labelling flux assay with mass spectrometry to enable quantification of the newly synthesized ribonucleotides into r/m/tRNA under a metabolic stationary state. Using glioblastoma (GBM) U87MG cells and a patient-derived xenograft (PDX) GBM mouse model, SI-MOIRAI analyses showed that newly synthesized GTP was particularly and disproportionally highly utilized for rRNA and tRNA synthesis but not for mRNA synthesis in GBM in vitro and in vivo. Furthermore, newly synthesized pyrimidine nucleotides exhibited a significantly lower utilization rate for RNA synthesis than newly synthesized purine nucleotides. The results reveal the existence of discrete pathways and compartmentalization of purine and pyrimidine metabolism designated for RNA synthesis, demonstrating the capacity of SI-MOIRAI to reveal previously unknown aspects of nucleotide biology.


Soft-Tissue Balancing Technology for Total Knee Arthroplasty.
» Improperly balanced total knee arthroplasties are at increased risk for complications including residual pain and/or instability, which are often corrected by a revision surgical procedure. » Because of the morbidity and financial burden associated with revision total knee arthroplasty, different technological applications, such as tibial insert sensors and computer-assisted gap balancing, are being used to assist with soft-tissue balancing during primary total knee arthroplasty. » Computer-assisted gap balancing increases the accuracy of mechanical alignment and improves the precision of balancing flexion and extension gaps during total knee arthroplasty. It is unclear whether this translates to improved short-term or long-term outcome measures. Considerations of this technology include increased cost, increased operative time, and a steep learning curve. » Intraoperative sensors increase the accuracy of balancing by quantifying the mediolateral intercompartmental load distribution through the range of motion, which may lead to improved outcome scores, patient satisfaction, higher activity levels, and decreased pain. The advantages of this technology compared with computer assistance include decreased cost and no disruption of operative time or workflow. Limited availability with constrained implants, limited implant choices, and a lack of long-term follow-up data have reduced utilization of intraoperative sensors. » Computer-assisted gap balancing and intraoperative sensors are not yet universally accepted, and the cost-benefit ratio associated with their use remains a consideration in today's cost-conscious health-care environment. Future research should focus on longer-term follow-up to evaluate implant survivorship, cost-effectiveness, and clinical outcomes.


DNA supercoiling and its role in DNA decatenation and unknotting.
Chromosomal and plasmid DNA molecules in bacterial cells are maintained under torsional tension and are therefore supercoiled. With the exception of extreme thermophiles, supercoiling has a negative sign, which means that the torsional tension diminishes the DNA helicity and facilitates strand separation. In consequence, negative supercoiling aids such processes as DNA replication or transcription that require global- or local-strand separation. In extreme thermophiles, DNA is positively supercoiled which protects it from thermal denaturation. While the role of DNA supercoiling connected to the control of DNA stability, is thoroughly researched and subject of many reviews, a less known role of DNA supercoiling emerges and consists of aiding DNA topoisomerases in DNA decatenation and unknotting. Although DNA catenanes are natural intermediates in the process of DNA replication of circular DNA molecules, it is necessary that they become very efficiently decatenated, as otherwise the segregation of freshly replicated DNA molecules would be blocked. DNA knots arise as by-products of topoisomerase-mediated intramolecular passages that are needed to facilitate general DNA metabolism, including DNA replication, transcription or recombination. The formed knots are, however, very harmful for cells if not removed efficiently. Here, we overview the role of DNA supercoiling in DNA unknotting and decatenation.


Molecular evolution of the vertebrate mechanosensory cell and ear.
The molecular basis of mechanosensation, mechanosensory cell development and mechanosensory organ development is reviewed with an emphasis on its evolution. In contrast to eye evolution and development, which apparently modified a genetic program through intercalation of genes between the master control genes on the top (Pax6, Eya1, Six1) of the hierarchy and the structural genes (rhodopsin) at the bottom, the as yet molecularly unknown mechanosensory channel precludes such a firm conclusion for mechanosensors. However, recent years have seen the identification of several structural genes which are involved in mechanosensory tethering and several transcription factors controlling mechanosensory cell and organ development; these warrant the interpretation of available data in very much the same fashion as for eye evolution: molecular homology combined with potential morphological parallelism. This assertion of molecular homology is strongly supported by recent findings of a highly conserved set of microRNAs that appear to be associated with mechanosensory cell development across phyla. The conservation of transcription factors and their regulators fits very well to the known or presumed mechanosensory specializations which can be mostly grouped as variations of a common cellular theme. Given the widespread distribution of the molecular ability to form mechanosensory cells, it comes as no surprise that structurally different mechanosensory organs evolved in different phyla, presenting a variation of a common theme specified by a conserved set of transcription factors in their cellular development. Within vertebrates and arthropods, some mechanosensory organs evolved into auditory organs, greatly increasing sensitivity to sound through modifications of accessory structures to direct sound to the specific sensory epithelia. However, while great attention has been paid to the evolution of these accessory structures in vertebrate fossils, comparatively less attention has been spent on the evolution of the inner ear and the central auditory system. Recent advances in our molecular understanding of ear and brain development provide novel avenues to this neglected aspect of auditory neurosensory evolution.


Differential basal-to-apical accessibility of lamin A/C epitopes in the nuclear lamina regulated by changes in cytoskeletal tension.
Nuclear lamins play central roles at the intersection between cytoplasmic signalling and nuclear events. Here, we show that at least two N- and C-terminal lamin epitopes are not accessible at the basal side of the nuclear envelope under environmental conditions known to upregulate cell contractility. The conformational epitope on the Ig-domain of A-type lamins is more buried in the basal than apical nuclear envelope of human mesenchymal stem cells undergoing osteogenesis (but not adipogenesis), and in fibroblasts adhering to rigid (but not soft) polyacrylamide hydrogels. This structural polarization of the lamina is promoted by compressive forces, emerges during cell spreading, and requires lamin A/C multimerization, intact nucleoskeleton-cytoskeleton linkages (LINC), and apical-actin stress-fibre assembly. Notably, the identified Ig-epitope overlaps with emerin, DNA and histone binding sites, and comprises various laminopathy mutation sites. Our findings should help decipher how the physical properties of cellular microenvironments regulate nuclear events.


Mouse urinary biomarkers provide signatures of maturation, diet, stress level, and diurnal rhythm.
Body fluids such as urine potentially contain a wealth of information pertaining to age, sex, social and reproductive status, physiologic state, and genotype of the donor. To explore whether urine could encode information regarding environment, physiology, and development, we compared the volatile compositions of mouse urine using solid-phase microextraction and gas chromatography-mass spectrometry (SPME-GC/MS). Specifically, we identified volatile organic compounds (VOCs) in individual urine samples taken from inbred C57BL/6J-H-2(b) mice under several experimental conditions-maturation state, diet, stress, and diurnal rhythms, designed to mimic natural variations. Approximately 1000 peaks (i.e., variables) were identified per comparison and of these many were identified as potential differential biomarkers. Consistent with previous findings, we found groups of compounds that vary significantly and consistently rather than a single unique compound to provide a robust signature. We identified over 49 new predictive compounds, in addition to identifying several published compounds, for maturation state, diet, stress, and time-of-day. We found a considerable degree of overlap in the chemicals identified as (potential) biomarkers for each comparison. Chemometric methods indicate that the strong group-related patterns in VOCs provide sufficient information to identify several parameters of natural variations in this strain of mice including their maturation state, stress level, and diet.


Association Between Parkinson Disease and Risk of Cancer in Taiwan.
Parkinson disease (PD) has been reported to be associated with a general reduced risk of cancer. These studies were mainly carried out in Western populations and little was known about associations in East Asians. To analyze the association between PD and risk of cancer. In this cohort study, the data were obtained from the Taiwan National Health Insurance Research Database, which contained information on approximately 24.7 million insured individuals. The cohort included individuals with newly diagnosed as having PD between 2004 and 2010. An age- and sex-matched systematic random-sampling method was used for subject selection in the reference non-PD cohort. Multivariate Cox proportional hazard regression analysis was used to determine the effects of PD on the risks of cancer, as shown by hazard ratios (HRs) with 95% CIs. The Taiwan Population Census and National Cancer Registry Databases were used to identify patients with cancer. The last follow-up date was December 31, 2012. In 62 023 patients with PD, the HR for all subsequent cancers combined was 1.58 (95% CI, 1.50-1.65). Of the 19 types of cancer, Parkinson disease was not associated with breast, ovarian, or thyroid cancers. Increased HRs were found in the remaining 16 cancers, including malignant brain tumors (HR, 3.42; 95% CI, 1.84-6.38), gastrointestinal tract cancers (esophageal [HR, 1.81; 95% CI, 1.28-2.57], stomach [HR, 1.59; 95% CI, 1.30-1.94], colorectal [HR, 1.47; 95% CI, 1.31-1.65], liver [HR, 1.89; 95% CI, 1.67-2.14]; gallbladder [HR, 1.73; 95% CI, 1.16-2.57], and pancreas [HR, 1.48; 95% CI, 1.09-2.02]) (P < .05 for all comparisons), lung cancers (HR, 1.56; 95% CI, 1.38-1.76), some hormone-related cancers (uterine [HR, 1.83; 95% CI, 1.12-3.01], cervical [HR, 1.36; 95% CI, 1.05-1.76], and prostate [HR, 1.80; 95% CI, 1.52-2.13; P < .05 for all comparisons), urinary tract cancers (kidney and bladder cancers; HRs, 1.59 and 1.99, respectively; P < .001 for both comparisons), lymphoma and/or leukemia (HR, 1.62; 95% CI, 1.31-2.01), melanoma (HR, 2.75; 95% CI, 1.35-5.59), and other skin cancers (HR, 1.81; 95% CI, 1.46-2.23). For hepatocellular carcinoma, the highest HR resided in the 50- to 59-year-old group (HR, 2.57; 95% CI, 1.7-3.89). Our study concludes that PD is is associated with most cancers in Taiwan. Further studies are needed to clarify whether our findings can be applied to other East Asian populations. The differences between our study and most previous cohorts suggest the importance of ethnicity and environmental exposures in disease pathogenesis.


Impaired Cerebellum to Primary Motor Cortex Associative Plasticity in Parkinson's Disease and Spinocerebellar Ataxia Type 3.
Functional perturbation of the cerebellum (CB)-motor cortex (M1) interactions may underlie pathophysiology of movement disorders, such as Parkinson's disease (PD) and spinocerebellar ataxia type 3 (SCA3). Recently, M1 motor excitability can be bidirectionally modulated in young subjects by corticocortical paired associative stimulation (PAS) on CB and contralateral M1 with transcranial magnetic stimulation (TMS), probably through the cerebello-dentato-thalamo-cortical (CDTC) circuit. In this study, we investigated the CB to M1-associative plasticity in healthy elderly PD and SCA3. Ten right-handed PD patients, nine gene-confirmed SCA3 patients, and 10 age-matched healthy controls (HC) were studied. One hundred and twenty pairs of TMS of the left M1 preceded by right lateral CB TMS at an interstimulus interval of 2 (CB → M1 PAS2ms) and 6 ms (CB → M1 PAS6ms) were, respectively, applied with at least 1-week interval. M1 excitability was assessed by motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and cerebellar inhibition (CBI) at the first dorsal interosseous muscle of the right hand before and after the CB → M1 PAS. The M1 excitability represented by MEP amplitude was significantly facilitated and suppressed in the HC group by CB → M1 PAS2ms and CB → M1 PAS6ms, respectively. The bidirectional modulation on MEP amplitude was absent in the PD and SCA3 groups. SICI and the baseline CBI were significantly reduced in the SCA3 group compared to those of the HC group irrespective of the CB → M1 PAS protocols. There was a significant reduction of CBI immediately and 60 min after the CB → M1 PAS protocols in the HC group but not in the patient groups. No significant change of ICF was found. Corticocortical CB → M1 PAS can induce bidirectional motor cortical plasticity in M1 for healthy aged subjects. The modulation may be independent of the inhibitory neurocircuits, such as SICI and CBI, and the facilitatory mechanism like ICF. Both patients with PD and SCA3 showed impairment of such plasticity, suggesting significant functional perturbation of the CDTC circuit.


Asymmetric dimethylarginine blocks nitric oxide-mediated alcohol-stimulated cilia beating.
The airway epithelium is exposed to alcohol during drinking through direct exhalation of volatized ethanol from the bronchial circulation. Alcohol exposure leads to a rapid increase in the cilia beat frequency (CBF) of bronchial epithelial cells followed by a chronic desensitization of cilia stimulatory responses. This effect is governed in part by the nitric oxide regulation of cyclic guanosine and adenosine monophosphate-dependent protein kinases (PKG and PKA) and is not fully understood. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is implicated in the pathogenesis of several pulmonary disorders. We hypothesized that the inhibition of nitric oxide synthase by ADMA blocks alcohol-stimulated increases in CBF. To test this hypothesis, ciliated primary bovine bronchial epithelial cells (BBEC) were preincubated with ADMA (100 µM) and stimulated with 100 mM ethanol. CBF was measured and PKA assayed. By 1 hr, ethanol activated PKA, resulting in elevated CBF. Both alcohol-induced PKA activation and CBF were inhibited in the presence of ADMA. ADMA alone had no effect on PKA activity or CBF. Using a mouse model overexpressing the ADMA-degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), we examined PKA and CBF in precision-cut mouse lung slices. Alcohol-stimulated increases in lung slice PKA and CBF were temporally enhanced in the DDAH mice versus control mice.


The truly disadvantaged? Midlife outcome dynamics of individuals with experiences of out-of-home care.
Little is known about developmental outcomes in midlife of persons who were placed in out-of-home care (OHC) in childhood. Utilizing longitudinal Swedish data from a cohort of more than 14,000 individuals who we can follow from birth (1953) to the age of 55 (2008), this study examines midlife trajectories of social, economic, and health-related disadvantages with a specific focus on the complexity, timing, and duration of disadvantage in individuals with and without childhood experience of OHC. Roughly half of the OHC alumni did not have disadvantaged outcomes in midlife. However, experience of OHC was associated with a two-fold risk for various forms of permanent disadvantage, net of confounding factors. Implications for research, policy, and practice are discussed.


[Effect of radiation and other factors on the pathogenesis of various histologic types of lung cancer in workers of radiochemical plants].
Adenocarcinoma frequency in Pu incorporation-related lung cancer patients among plutonium workers was found to be 74% versus 33% in control. Each histological pattern of lung cancer appeared to be related to several etiological factors but in varying degree. Incorporated Pu proved the strongest factor in adenocarcinoma development. Its odds ratio (OR) was 6.9, while that for smoking-4.3. However, smoking appeared to be the most significant factor in squamous cell carcinoma genesis (OR-6.8). Among other factors were chronic obstructive pathology of the lung (OR-3.9) and reduced body weight (OR-2.1). The OR for Pu incorporation was 3.9. Squamous cell carcinomas were traced to reduced body weight (OR-2.9), heavy smoking (smoking index more than 500) (OR-3.5). However, no significant relationship has been established between carcinogenesis and Pu incorporation.


The association of birth weight with arterial stiffness at mid-adulthood: the Bogalusa Heart Study.
Birth weight has been found to predict cardiovascular morbidity and mortality. Pulse wave velocity (PWV), a marker of arterial stiffness, has been associated with cardiovascular risk factors. An association between birth weight and blood pressure (BP) has previously been reported. In this study, the association of birth weight with PWV, and the relationship between birth weight, pulse wave velocity and BP in mid-adulthood were investigated. The Bogalusa Heart Study (BHS) is a population-based longitudinal study to investigate the natural development of cardiovascular risk factors. In the 2001 survey, brachial-ankle PWV (baPWV) was measured as an indicator of arterial stiffness. Of the 1203 participants in that survey, 707 had complete data on birth weight and PWV, which were utilised for this study. In this study, birth weight was inversely correlated with baPWV, pulse pressure, and systolic and diastolic BP (r = -0.10; r = -0.10; r = -0.13 and r = -0.09, respectively; p< or =0.01 for all). After adjustment, birth weight was inversely associated with baPWV. On average, baPWV decreased by 0.23 m/s (95% CI -0.44 to -0.03 m/s) for each 1 kg increase in birth weight. Birth weight (inversely) and baPWV were independently associated with systolic BP (B = -2.05; 95% CI -3.27 to -0.84 and B = 2.99; 95% CI 2.58 to 3.40 respectively). Lower birth weight is associated with higher baPWV. The link between birth weight and systolic BP may be partially explained by the association of birth weight with PWV.


Effects of benzo[a]pyrene DNA adducts on Escherichia coli DNA polymerase I (Klenow fragment) primer-template interactions: evidence for inhibition of the catalytically active ternary complex formation.
Benzo[a]pyrene diol epoxide (B[a]PDE) adducts are strong blocks of DNA replication in vitro, allowing the rare incorporation of a nucleotide across from the lesion and negligibly small extent of further bypass. To study the mechanistic details of this process, a gel-retardation assay was used to measure the dissociation constants for the binding of DNA polymerase I (Klenow fragment) (KF) to the primer-templates containing a (+)-trans- or (+)-cis-B[a]P-N(2)-dG adduct. When the primer was terminated one nucleotide before the adduct, the presence of a (+)-trans-B[a]P-N(2)-dG adduct did not affect the binding while a (+)-cis-B[a]P-N(2)-dG adduct caused a slight decrease in affinity. The presence of any dNTP decreased the affinity of KF to the modified primer-templates. (In contrast, a strong increase of the affinity to unmodified primer-templates was observed in the presence of the next correct dNTP.) Limited protease digestion experiments indicated that a closed ternary complex of KF with the modified primer-templates was not detectable in the presence of any dNTP, whereas it was clearly observed with unmodified template in the presence of the next correct nucleotide. These findings suggest that these adducts may interfere with the conformational change to the catalytically active closed ternary complex and/or cause significant destabilization of this complex. When the primers extended to the position across from the adduct, the affinity of KF was significantly decreased irrespective of the identity of the base across from the adduct, possibly explaining the low bypass of the lesion. Interestingly, the stability of these DNA-polymerase complexes correlated with nucleotide insertion kinetics for the unmodified and (+)-trans-B[a]PDE-modified templates.


BRN2 suppresses apoptosis, reprograms DNA damage repair, and is associated with a high somatic mutation burden in melanoma.
Whether cell types exposed to a high level of environmental insults possess cell type-specific prosurvival mechanisms or enhanced DNA damage repair capacity is not well understood. BRN2 is a tissue-restricted POU domain transcription factor implicated in neural development and several cancers. In melanoma, BRN2 plays a key role in promoting invasion and regulating proliferation. Here we found, surprisingly, that rather than interacting with transcription cofactors, BRN2 is instead associated with DNA damage response proteins and directly binds PARP1 and Ku70/Ku80. Rapid PARP1-dependent BRN2 association with sites of DNA damage facilitates recruitment of Ku80 and reprograms DNA damage repair by promoting Ku-dependent nonhomologous end-joining (NHEJ) at the expense of homologous recombination. BRN2 also suppresses an apoptosis-associated gene expression program to protect against UVB-, chemotherapy- and vemurafenib-induced apoptosis. Remarkably, BRN2 expression also correlates with a high single-nucleotide variation prevalence in human melanomas. By promoting error-prone DNA damage repair via NHEJ and suppressing apoptosis of damaged cells, our results suggest that BRN2 contributes to the generation of melanomas with a high mutation burden. Our findings highlight a novel role for a key transcription factor in reprogramming DNA damage repair and suggest that BRN2 may impact the response to DNA-damaging agents in BRN2-expressing cancers.


Plant cell-based intimin vaccine given orally to mice primed with intimin reduces time of Escherichia coli O157:H7 shedding in feces.
Intimin is the primary adhesin of Escherichia coli O157:H7, the most common infectious cause of bloody diarrhea in the United States and the leading cause of acute kidney failure in children who develop hemolytic uremic syndrome. Cattle are the primary reservoir of E. coli O157:H7. Indeed, most cases of E. coli O157:H7 infection in the United States occur after ingestion of contaminated undercooked hamburger or produce that had contact with bovine manure. Because intimin is required for persistent colonization of neonatal calves and adult cattle, we hypothesized that an intimin-based vaccination strategy in calves would reduce colonization of cattle with E. coli O157:H7. To test this concept in a small-animal model, we developed transgenic tobacco plant cells that express the carboxy-terminal host cell-binding domain of E. coli O157:H7 intimin. Mice were either immunized intraperitoneally with intimin expressed from the plant cells, fed transgenic plant cells, or both. Here we show that these mice generated an intimin-specific mucosal immune response when primed parenterally and then boosted orally and also exhibited a reduced duration of E. coli O157:H7 fecal shedding after challenge.


Sarcoglycan complex in masseter and sternocleidomastoid muscles of baboons: an immunohistochemical study.
The sarcoglycan complex consists of a group of single-pass transmembrane glycoproteins that are essential to maintain the integrity of muscle membranes. Any mutation in each sarcoglycan gene causes a series of recessive autosomal dystrophin-positive muscular dystrophies. Negative fibres for sarcoglycans have never been found in healthy humans and animals. In this study, we have investigated whether the social ranking has an influence on the expression of sarcoglycans in the skeletal muscles of healthy baboons. Biopsies of masseter and sternocleidomastoid muscles were processed for confocal immunohistochemical detection of sarcoglycans. Our findings showed that baboons from different social rankings exhibited different sarcoglycan expression profiles. While in dominant baboons almost all muscles were stained for sarcoglycans, only 55% of muscle fibres showed a significant staining. This different expression pattern is likely to be due to the living conditions of these primates. Sarcoglycans which play a key role in muscle activity by controlling contractile forces may influence the phenotype of muscle fibres, thus determining an adaptation to functional conditions. We hypothesize that this intraspecies variation reflects an epigenetic modification of the muscular protein network that allows baboons to adapt progressively to a different social status.


Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma.
The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma (MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune cell interactions and cytokine signaling. Here we examined the in vitro effects of IMiDs on cytokine signaling triggered by interaction of effector cells with MM cells and BM stroma cells. IMiDs diminished interleukin-2, interferonγ, and IL-6 regulator suppressor of cytokine signaling (SOCS)1 expression in immune (CD4T, CD8T, natural-killer T, natural-killer) cells from both BM and PB of MM patients. In addition, coculture of MM cells with healthy PBMCs induced SOCS1 expression in effector cells; conversely, treatment with IMiDs down-regulated the SOCS1 expression. SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing-MM cells than unmodified MM cells. These data therefore demonstrate that modulation of SOCS1 may enhance immune response and efficacy of IMiDs in MM.


Phenotypic characterization of metaplastic intestinal glands and ductular hepatocytes in cholangiofibrotic lesions rapidly induced in the caudate liver lobe of rats treated with furan.
In order to investigate the early cellular changes in liver associated with furan cholangiocarcinogenesis, young adult male Fischer 344 rats were administered furan by gavage once a day, 5 days a wk for 2 to 3 wk at doses ranging from 15 to 60 mg/kg of body weight per day. The most conspicuous feature observed in the liver of animals receiving the higher doses of furan was a rapidly developed cholangiofibrosis characterized by the presence of bile ductular hyperplasia, intestinal metaplasia, and fibrosis. Moreover, this lesion was found to be almost exclusively localized to the caudate liver lobe, which by morphometric analysis was further determined to be largely replaced by cholangiofibrotic tissue. Both the hyperplastic bile ductular epithelial cells and the intestinal-like epithelial cells in these areas selectively exhibited a strongly positive immunohistochemical staining for cytokeratin 19 and were supported by well-developed basement membranes enriched in both laminin and type IV collagen. However, in contrast to the hyperplastic bile ductules, electron microscopy of the metaplastic intestinal glands revealed them to be composed mostly of columnar epithelial cells with well-developed striated borders, less numerous mucin-secreting goblet cells, and occasional neuroendocrine-like cells, thus closely resembling in their cellular composition that of intestinal mucosa. These metaplastic glands also showed a more heterogeneous pattern of staining for both gamma-glutamyl transpeptidase and the placental form of glutathione S-transferase than did the hyperplastic bile ductules. At the 60-mg/kg/day furan dose, cholangiolar-like structures composed of biliary epithelial cells and ductular hepatocytic cells at different stages of morphological differentiation were also observed. Phenotypically, the biliary epithelial and "ductular hepatocytes" of these cholangioles shared a common basement membrane containing laminin and type IV collagen, as well as a luminal plasma membrane gamma-glutamyl transpeptidase. On the other hand, only the biliary epithelial cells of the newly appearing mixed cell cholangioles stained positive for cytokeratin 19. Interestingly, unlike hepatocarcinogen-induced oval cells, alpha-fetoprotein expression was not detected in any of the cell types comprising the furan-induced cholangiofibrotic tissue. These results support a novel in vivo model for investigating cell lineages in the development in liver of intestinal metaplasia, "ductular hepatocytes," and cholangiofibrosis in relation to intrahepatic cholangiocarcinogenesis.


Colposcopy in oral epithelial dysplasia: seeing the unseen, a pilot study.
The diagnosis of malignant and potentially malignant epithelial lesions of oral mucosa cannot be based solely on clinical findings. The histologic evaluation of a representative biopsy specimen thus becomes necessary. The site for biopsy, however, is always a subjective choice that sometimes raises doubts about its representativeness. So far, no simple and reliable method is available for the selection of the most appropriate area for biopsy. Colposcopy is helpful in the selection of these sites of epithelial dysplasia depending upon the vascular patterns. The study was planned to assess the role of colposcopic examination in the selection of biopsy site in patients with varying grades of oral epithelial dysplasia at various sites. Fifty patients between the ages of 30-60 years clinically diagnosed with leukoplakia and carcinoma buccal mucosa were included in the study. For each of the subject, a thorough clinical examination followed by colposcopic assessment was carried out for the selection of biopsy site from the involved mucosa. The histopathological findings were then compared in the two cases and results analyzed. The statistical analysis was done using paired t-test. In our study, sensitivity and specificity for the selection of biopsy site by colposcopic examination came out to be higher for leukoplakia than carcinoma buccal mucosa patients. It was concluded that colposcopic examination was found more significant in the selection of biopsy site for leukoplakia patients while clinical criterion was found to be more appropriate for carcinoma buccal mucosa cases.


Impact of protein domains on PE_PGRS30 polar localization in Mycobacteria.
PE_PGRS proteins are unique to the Mycobacterium tuberculosis complex and a number of other pathogenic mycobacteria. PE_PGRS30, which is required for the full virulence of M. tuberculosis (Mtb), has three main domains, i.e. an N-terminal PE domain, repetitive PGRS domain and the unique C-terminal domain. To investigate the role of these domains, we expressed a GFP-tagged PE_PGRS30 protein and a series of its functional deletion mutants in different mycobacterial species (Mtb, Mycobacterium bovis BCG and Mycobacterium smegmatis) and analysed protein localization by confocal microscopy. We show that PE_PGRS30 localizes at the mycobacterial cell poles in Mtb and M. bovis BCG but not in M. smegmatis and that the PGRS domain of the protein strongly contributes to protein cellular localization in Mtb. Immunofluorescence studies further showed that the unique C-terminal domain of PE_PGRS30 is not available on the surface, except when the PGRS domain is missing. Immunoblot demonstrated that the PGRS domain is required to maintain the protein strongly associated with the non-soluble cellular fraction. These results suggest that the repetitive GGA-GGN repeats of the PGRS domain contain specific sequences that contribute to protein cellular localization and that polar localization might be a key step in the PE_PGRS30-dependent virulence mechanism.