Feasibility and satisfaction with a tailored web-based audit intervention for recalibrating radiologists' thresholds for conducting additional work-up.
To examine the feasibility of and satisfaction with a tailored web-based intervention designed to decrease radiologists' recommendation of inappropriate additional work-up after a screening mammogram. We developed a web-based educational intervention designed to reduce inappropriate recall. Radiologists were randomly assigned to participate in an early intervention group or a late (control) intervention group, the latter of which served as a control for a 9-month follow-up period, after which they were invited to participate in the intervention. Intervention content was derived from our prior research and included three modules: 1) an introduction to audit statistics for mammography performance; 2) a review of data showing radiologists' inflated perceptions of medical malpractice risks related to breast imaging, and 3) a review of data on breast cancer risk among women seen in their practices. Embedded within the intervention were individualized audit data for each participating radiologists obtained from the national Breast Cancer Surveillance Consortium. Seventy-four radiologists (37.8%; 74/196) consented to the intervention, which was completed by 67.5% (27/40) of those randomized to the early intervention group and 41.2% (14/34) of those randomized to the late (control) group. Thus, a total of 41 (55%) completed the intervention. On average, three log-ins were used to complete the program (range 1-14), which took approximately 1 hour. Ninety-five percent found the program moderately to very helpful in understanding how to calculate basic performance measures. Ninety-three percent found viewing their own performance measures moderately to very helpful, and 83% reported it being moderately to very important to learn that the breast cancer risk in their screening population program was lower than perceived. The percentage of radiologists who reported that the risk of medical malpractice influences their recall rates dropped from 36.3% preintervention to 17.8% after intervention with a similar drop in perceived influence of malpractice risk on their recommendations for breast biopsy (36.4 to 17.3%). More than 75% of radiologists answered the postintervention knowledge questions correctly, and the percent of time spent in breast imaging did not appear to influence responses. The majority (>92%) of participants correctly responded that the target recall rate in the United States is 9%. The mean self-reported recall rates were 13.0 for radiologists spending <40% time in breast imaging and 14.9% for those spending >40% time spent in breast imaging, which was highly correlated with their actual recall rates (0.991; P < .001). Radiologists who begin an internet-based tailored intervention designed to help reduce unnecessary recall will likely complete it, although only 55% who consented to the study actually undertook the intervention. Participants found the program useful in helping them understand why their recall rates may be elevated.


Spiral CT angiography and selective digital subtraction angiography of internal carotid artery stenosis.
To determine whether spiral CT angiography allows accurate, quantitative evaluation of anatomic abnormalities, including detection of additional lesions, delineation of plaque morphology, and estimation of degree of internal carotid artery stenosis. Spiral CT angiography with a maximum intensity projection technique was compared with selective digital subtraction angiography (DSA) in 92 carotid arteries. The category of stenosis was determined according to the North American Symptomatic Carotid Endarterectomy Trial: mild (0% to 29%), moderate (30% to 69%), severe (70% to 99%), and occlusion (100%). In 78 (85%) of the 92 cases, spiral CT angiography and selective DSA demonstrated the same degree of stenosis. All occlusions (n = 19) were diagnosed correctly with spiral CT angiography. Spiral CT angiography agreed with selective DSA in the classification of stenosis in 59% of the group with mild stenosis, in 82% of the group with moderate stenosis, and in 90% of the group with severe stenosis. In the groups with mild (n = 13), moderate (n = 9), and severe (n = 27) stenosis, correlation of spiral CT angiography with selective DSA was significant. Calcified plaques were readily diagnosed with the use of spiral CT angiography but delineation of ulcers was poor. Tandem lesions were not visible owing to the limited coverage. Spiral CT angiography is useful for the detection of proximal internal carotid stenoses that are greater than 30%. Depiction of mild stenoses appears to be limited. CT is superior for the detection of calcified plaques but it is not useful for the detection of ulcers.


Tau-Reactive Endogenous Antibodies: Origin, Functionality, and Implications for the Pathophysiology of Alzheimer's Disease.
In Alzheimer's disease (AD), tau pathology manifested by the accumulation of intraneuronal tangles and soluble toxic oligomers emerges as a promising therapeutic target. Multiple anti-tau antibodies inhibiting the formation and propagation of cytotoxic tau or promoting its clearance and degradation have been tested in clinical trials, albeit with the inconclusive outcome. Antibodies against tau protein have been documented both in the brain circulatory system and at the periphery, but their origin and role under normal conditions and in AD remain unclear. While it is tempting to assign them a protective role in regulating tau level and removal of toxic variants, the supportive evidence remains sporadic, requiring systematic analysis and critical evaluation. Herein, we review recent data showing the occurrence of tau-reactive antibodies in the brain and peripheral circulation and discuss their origin and significance in tau clearance. Based on the emerging evidence, we cautiously propose that impairments of tau clearance at the periphery by humoral immunity might aggravate the tau pathology in the central nervous system, with implication for the neurodegenerative process of AD.


Changes in Blood Constituents of Rabbits Subjected to Transportation under Hot, Humid Tropical Conditions.
Unlike Europe (particularly, Italy and Spain), where a number of studies have been conducted on the stressful effects of transport on rabbit welfare, few studies have been conducted on transportation of rabbits under hot, humid tropical conditions experienced in countries like Malaysia. We studied the effects of transportation in hot humid tropical conditions of Malaysia on physiometabolic changes in New Zealand white rabbits. Eighty experimental animals were divided into two groups of 40 bucks each and transported for either 3 or 1 h. Transportation caused a significant upsurge of aspartate aminotransferase, alanine aminotransferase and creatine kinase activities (p<0.001) though did not significantly affect lactate dehydrogenase (LDH) activity (p = 0.0706). Both transportation periods caused elevation in plasma glucose levels, lactic acidosis and dehydration as evidenced through elevated packed cell volume and plasma protein concentration. It was concluded that regardless of the duration, transport of rabbits under hot humid tropical conditions, resulted in heat distress since the rabbits showed hyperglycemia, hypercalcemia, lactacidemia, lymphocytopenia, dehydration and increase in blood enzyme activities.


Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions.
Large deletions of the NF1 gene region occur in approximately 5% of patients with neurofibromatosis type-1 (NF1) and are associated with particularly severe manifestations of the disease. However, until now, the genotype-phenotype relationship has not been comprehensively studied in patients harbouring large NF1 gene deletions of comparable extent (giving rise to haploinsufficiency of the same genes). We have performed the most comprehensive clinical/neuropsychological characterisation so far undertaken in NF1 deletion patients, involving 29 patients with precisely determined type-1 NF1 (1.4 Mb) deletions. Novel clinical features found to be associated with type-1 NF1 deletions included pes cavus (17% of patients), bone cysts (50%), attention deficit (73%), muscular hypotonia (45%) and speech difficulties (48%). Type-1 NF1 deletions were found to be disproportionately associated with facial dysmorphic features (90% of patients), tall stature (46%), large hands and feet (46%), scoliosis (43%), joint hyperflexibility (72%), delayed cognitive development and/or learning disabilities (93%) and mental retardation (IQ<70; 38%), as compared with the general NF1 patient population. Significantly increased frequencies (relative to the general NF1 population) of plexiform neurofibromas (76%), subcutaneous neurofibromas (76%), spinal neurofibromas (64%) and MPNSTs (21%) were also noted in the type-1 deletion patients. Further, 50% of the adult patients exhibited a very high burden of cutaneous neurofibromas (N>or=1000). These findings emphasise the importance of deletion analysis in NF1 since frequent monitoring of tumour presence and growth could potentiate early surgical intervention thereby improving patient survival.


Prescribed physical activity maintenance following exercise based cardiac rehabilitation: factors predicting low physical activity.
Physical activity is important to reduce mortality, morbidity and risk factors in patients with coronary heart disease. This report evaluates to what extent patients are still physically active following an exercise-based cardiac rehabilitation programme 12-14 months post-myocardial infarction and factors predicting why not. Data from the National Quality Registry Swedeheart with post-myocardial infarction patients ( n=368) admitted from July 2012 to November 2014 were collected with outcomes of physical activity after 12-14 months. Baseline data included demographics, clinical variables, participation in exercise programmes, prescribed physical activity, health-related quality of life and self-reported health (EQ-5D-3L/EQ-VAS). A direct binary logistic regression analysis was used to identify indicators of low physical activity. Physical activity frequency per week (PA/week) was low, i.e. zero to three times, in older patients over 64 years ( P=0.00) and in those having problems with pain/discomfort (138 PA/week vs. 195) ( P=0.01), problems with mobility (60 PA/week vs.273) ( P=0.04) and anxiety/depression (128 PA/week vs. 205) ( P=0.04). Indicators predicting low physical activity can be used targeting improved post-myocardial infarction care outlining person-centred rehabilitation programmes and specialist nursing-led programmes.


Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality.
Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1-/- donors. PD-L1-deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1-/- donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell-mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.


Increased and prolonged human norovirus infection in RAG2/IL2RG deficient gnotobiotic pigs with severe combined immunodeficiency.
Application of genetically engineered (GE) large animals carrying multi-allelic modifications has been hampered by low efficiency in production and extended gestation period compared to rodents. Here, we rapidly generated RAG2/IL2RG double knockout pigs using direct injection of CRISPR/Cas9 system into developing embryos. RAG2/IL2RG deficient pigs were immunodeficient, characterized by depletion of lymphocytes and either absence of or structurally abnormal immune organs. Pigs were maintained in gnotobiotic facility and evaluated for human norovirus (HuNoV) infection. HuNoV shedding lasted for 16 days in wild type pigs, compared to 27 days (until the end of trials) in RAG2/IL2RG deficient pigs. Additionally, higher HuNoV titers were detected in intestinal tissues and contents and in blood, indicating increased and prolonged HuNoV infection in RAG2/IL2RG deficient pigs and the importance of lymphocytes in HuNoV clearance. These results suggest that GE immunodeficient gnotobiotic pigs serve as a novel model for biomedical research and will facilitate HuNoV studies.


Cannabis Liberalization and Adolescent Cannabis Use: A Cross-National Study in 38 Countries.
To assess the associations between types of cannabis control policies at country level and prevalence of adolescent cannabis use. Multilevel logistic regressions were performed on 172,894 adolescents 15 year of age who participated in the 2001/2002, 2005/2006, or 2009/2010 cross-sectional Health Behaviour in School-Aged Children (HBSC) survey in 38 European and North American countries. Self-reported cannabis use status was classified into ever use in life time, use in past year, and regular use. Country-level cannabis control policies were categorized into a dichotomous measure (whether or not liberalized) as well as 4 detailed types (full prohibition, depenalization, decriminalization, and partial prohibition). Control variables included individual-level sociodemographic characteristics and country-level economic characteristics. Considerable intra-class correlations (.15-.19) were found at country level. With respect to the dichotomized cannabis control policy, adolescents were more likely to ever use cannabis (odds ratio (OR) = 1.10, p = .001), use in past year (OR = 1.09, p = .007), and use regularly (OR = 1.26, p = .004). Although boys were substantially more likely to use cannabis, the correlation between cannabis liberalization and cannabis use was smaller in boys than in girls. With respect to detailed types of policies, depenalization was associated with higher odds of past-year use (OR = 1.14, p = .013) and regular use (OR = 1.23, p = .038), and partial prohibition was associated with higher odds of regular use (OR = 2.39, p = .016). The correlation between cannabis liberalization and regular use was only significant after the policy had been introduced for more than 5 years. Cannabis liberalization with depenalization and partial prohibition policies was associated with higher levels of regular cannabis use among adolescents. The correlations were heterogeneous between genders and between short- and long-terms.


THE RELATION OF LESIONS OF THE ADRENAL GLAND TO CHRONIC NEPHRITIS AND TO ARTERIOSCLEROSIS; AN ANATOMICAL STUDY.
Vaquez and Aubertin advance three theories in explanation of the adrenal hyperplasia; first, that it may not be the cause of hypertension but "an antitoxic hyperplasia" caused by the retained products of metabolism which may be responsible also for the hypertension; second, that it may be the cause of hypertension but secondary to the renal lesion; third, that it may be the cause of hypertension but may antedate the renal lesion or be entirely independent of it. They, as well as other French writers, insist that this hyperplasia is almost constantly associated with chronic nephritis of the interstitial type and it is seldom found with the parenchymatous type of nephritis, or with other lesions. Hyperplasia of the adrenal, as far as my material enables one to judge, does not occur during the first and second decades. In the third decade it is relatively frequent in the absence of chronic arterial and renal disease but reaches the maximum in association with such disease after the fourth decade. It is an almost constant lesion in arteriosclerosis associated with chronic interstitial nephritis and left-sided heart hypertrophy, but occurs with almost equal frequency in arteriosclerosis with chronic nephritis of the parenchymatous type. It is a relatively frequent lesion of arteriosclerosis without chronic nephritis and of the latter without arteriosclerosis also. As the result of this analysis one is led to the view that while hyperplasia of the adrenal is a very frequent concomitant of chronic renal and arterial disease it is not exclusively a feature of either type of nephritis or yet of chronic vascular disease; but it probably represents the effect of some factor operating in that period of life in which chronic renal and arterial affections are most frequent. Worthy of special emphasis is the observation that the characteristic lesion of an adrenal, the seat of local arteriosclerosis, is of the type of the chronic productive inflammation seen in arteriosclerosis of the pancreas and kidney; that is, thickening of the vessels, increase of connective tissue and round cell infiltration. Associated with these changes is a hyperplasia which is very constant, and which may be, in part, of the nature of a compensatory hyperplasia similar to that seen in the liver of cirrhosis and acute yellow atrophy. A hyperplasia of this type, as has been shown, may occur in destructive lesions of the gland. This, however, does not explain hyperplasia in the absence of local vascular changes which fact is, possibly, as suggested by Landau, evidence, not of a correlation between kidney and adrenal, but of a vicarious hypertrophy depending upon lesions of some other organ of the body than the kidney, possibly some other ductless gland, affected by arteriosclerosis or other disease.


Naturalizing aesthetics: brain areas for aesthetic appraisal across sensory modalities.
We present here the most comprehensive analysis to date of neuroaesthetic processing by reporting the results of voxel-based meta-analyses of 93 neuroimaging studies of positive-valence aesthetic appraisal across four sensory modalities. The results demonstrate that the most concordant area of activation across all four modalities is the right anterior insula, an area typically associated with visceral perception, especially of negative valence (disgust, pain, etc.). We argue that aesthetic processing is, at its core, the appraisal of the valence of perceived objects. This appraisal is in no way limited to artworks but is instead applicable to all types of perceived objects. Therefore, one way to naturalize aesthetics is to argue that such a system evolved first for the appraisal of objects of survival advantage, such as food sources, and was later co-opted in humans for the experience of artworks for the satisfaction of social needs.


[Humanitarian ethics and the concept of justice].
The bases of humanitarian assistance, beyond a legal norm--which appears to be essential given the inalienable obligations that result for all participating bodies--are influenced by philosophical and political conceptualizations framed in an ethics of justice. Actors in the humanitarian field who adhere to the Rawlsian social contract model their actions based on a philosophy that assistance is a noble and desirable option that remains in the hands of those who offer aid, and who can freely choose to not offer such assistance. Peter Singer and Thomas Pogge propose nuances to the understanding of the duty of assistance. Not assisting would be bad, basically tantamount to killing. Assistance is no longer a caring act deserving of praise, but rather a moral obligation. The financial imperatives of associations, the growing complexity of activities and the development of an important element of communication lead to a professionalization of humanitarian medicine. A modern vision of humanitarian assistance requires an understanding of justice and solidarity and global outreach. We believe that ethics need to be embedded firmly in humanitarian actions that have clear political implications.


Using protein microarray technology to screen anti-ERCC1 monoclonal antibodies for specificity and applications in pathology.
An antibody with cross-reactivity can create unexpected side effects or false diagnostic reports if used for clinical purposes. ERCC1 is being explored as a predictive diagnostic biomarker for cisplatin-based chemotherapy. High ERCC1 expression is linked to drug resistance on cisplatin-based chemotherapy. 8F1 is one of the most commonly used monoclonal antibodies for evaluating ERCC1 expression levels in lung cancer patient tissues, but it has been noted that this antibody cross-reacts with an unknown protein. By using a high density protein microarray chip technology, we discovered that 8F1 not only reacts with its authentic target, ERCC1, but also cross-reacts with an unrelated nuclear membrane protein, PCYT1A. The cross-reactivity is due to a common epitope presented on these two unrelated proteins. Similar to the subcellular localization of ERCC1, IHC tests demonstrated that PCYT1A is localized mainly on nuclear membrane. In this study, we also discovered that the PCYT1A gene expression level is significantly higher than the ERCC1 gene expression level in a certain population of lung cancer patient tissue samples. To develop the best monoclonal antibody for ERCC1 IHC analysis, 18 monoclonal antibodies were generated and 6 of them were screened against our protein microarray chip. Two clones showed high mono-specificity on the protein microarray chip test and both worked for the IHC application. In summary, the 8F1 clone is not suitable for ERCC1 IHC assay due to its cross-reactivity with PCYT1A protein. Two newly generated monoclonal antibodies, 4F9 and 2E12, demonstrated ultra-specificity against ERCC1 protein and superior performance for IHC analyses.


Characteristics of non-fatal opioid overdoses attended by ambulance services in Australia.
To examine the feasibility of establishing a database on non-fatal opioid overdose in order to examine patterns and characteristics of these overdoses across Australia. Unit record data on opioid overdose attended by ambulances were obtained from ambulance services in the five mainland States of Australia for available periods, along with information on case definition and opioid overdose management within these jurisdictions. Variables common across States were examined including the age and sex of cases attended, the time of day and day of week of the attendance, and the transportation outcome (whether the victim was left at the scene or transported to hospital). The monthly rate of non-fatal opioid overdose attended by ambulance was generally highest in Victoria (Melbourne) followed by NSW, with the rates substantially lower in the remaining States over the period January 1999 to February 2001. Non-fatal opioid overdose victims were most likely to be male in all States, with the proportion of males highest in Victoria (77%), and were aged around 28 years with ages lowest in Western Australia (m=26) and highest in NSW (m=30). Most of the attendances occurred in the afternoon/early evening and towards the later days of the working week in all States. The rates of transportation varied according to ambulance service practice across the States with around 94% of cases transported in Western Australia and around 18% and 29% of cases transported in Melbourne and NSW respectively. It is feasible to establish a database of comparable data on non-fatal opioid overdoses attended by ambulances in Australia. This compilation represents a useful adjunct to existing surveillance systems on heroin (and other opioid) use and related harms.


Dynamics of carbon monoxide dissociation on Co(112[combining macron]0).
The dissociative chemisorption dynamics of CO on rigid Co(112[combining macron]0) is investigated using a quasi-classical trajectory method on a new global six-dimensional potential energy surface (PES). The PES is fit using a neural network method to represent 24 630 density functional energies in various configurations. The reaction path features deep chemisorption wells and a late barrier for dissociation, agreeing well with previous calculations. The activation energy for dissociation ranges from 0.1 eV at the hollow site to 2.46 eV on the top site, indicating a highly corrugated PES. Effects of the incidence energy of the impinging molecule, its initial orientation, vibrational and rotational excitations, and site specificity are examined. Despite the presence of a low barrier, the initial dissociation probability is very small, even at high incident energies, as a large percentage of trajectories is either trapped or desorbed back to the gas phase. The low reactivity is attributed to inefficient energy transfer into the dissociation reaction coordinate in the chemisorption well where thermal equilibrium is not reached. This system underscores the importance of dynamics in understanding reactions at gas-surface interfaces and in kinetic modeling of catalytic processes.


(D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model.
Patients with familial type 17 of Parkinson's disease (PARK17) manifest autosomal dominant pattern and late-onset parkinsonian syndromes. Heterozygous (D620N) mutation of vacuolar protein sorting 35 (VPS35) is genetic cause of PARK17. We prepared heterozygous VPS35D620N/+ knockin mouse, which is an ideal animal model of (D620N) VPS35-induced autosomal dominant PARK17. Late-onset loss of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons and motor deficits of Parkinson's disease were found in 16-month-old VPS35D620N/+ mice. Normal function of VPS35-containing retromer is needed for activity of Wnt/β-catenin cascade, which participates in protection and survival of SNpc DAergic neurons. It was hypothesized that (D620N) VPS35 mutation causes the malfunction of VPS35 and resulting impaired activity of Wnt/β-catenin pathway. Protein levels of Wnt1 and nuclear β-catenin were reduced in SN of 16-month-old VPS35D620N/+ knockin mice. Downregulated protein expression of survivin, which is a target gene of nuclear β-catenin, and upregulated protein levels of active caspase-8 and active caspase-9 were observed in SN of VPS35D620N/+ mice at age of 16 months. VPS35 is involved in controlling morphology and function of mitochondria. Impaired function of VPS35 caused by (D620N) mutation could lead to abnormal morphology and malfunction of mitochondria. A significant decrease in mitochondrial size and resulting mitochondrial fragmentation was found in tyrosine hydroxylase-positive and neuromelanin-positive SNpc DAergic neurons of 16-month-old VPS35D620N/+ mice. Mitochondrial complex I activity or complex IV activity was reduced in SN of 16-month-old VPS35D620N/+ mice. Increased level of mitochondrial ROS and oxidative stress were found in SN of 16-month-old VPS35D620N/+ mice. Levels of cytosolic cytochrome c and active caspase-3 were increased in SN of VPS35D620N/+ mice aged 16 months. Our results suggest that PARK17 mutant (D620N) VPS35 impairs activity of Wnt/β-catenin signaling pathway and causes abnormal morphology and dysfunction of mitochondria, which could lead to neurodegeneration of SNpc DAergic cells.


Activation of mitogen-activating protein kinase by glucose is not required for insulin secretion.
In the insulinoma cell line INS-1, a model system for glucose-regulated insulin secretion, the mitogen-activating protein (MAP) kinases/extracellular signal-regulated protein kinases, ERK1 and ERK2 are activated up to 15-fold by physiological concentrations of glucose, in the range of 3-12 mM. The related MAP kinase family members, the c-Jun-N-terminal kinases/stress-activated protein kinases are insensitive to glucose, while the p38 MAP kinase is slightly glucose responsive (1.5-fold). ERK activation is dependent on glucose metabolism and the subsequent increase in calcium influx. Inhibiting activation of ERK1 and ERK2 with the MEK1/2 inhibitor PD98059 has no effect on insulin secretion, indicating that ERK activity is not necessary for secretion under these conditions. Glucose activates ERK1 and ERK2 in cytosolic and purified nuclear fractions of INS-1 cells and more of each is found in nuclei from glucose-treated cells. These findings suggest that some of the glucose-dependent actions of ERKs will be exerted in the nucleus.


Fabrication of channel waveguides from sol-gel-processed polyvinylpyrrolidone/ SiO(2) composite materials.
Sol-gel-processed composite materials of polyvinylpyrrolidone (PVP) and SiO(2) were studied for optical waveguide applications. PVP is a polymer that can be crosslinked, so it is expected to have high thermal stability after crosslinking. However, thermal crosslinking and thermal decomposition of pure PVP take place around the same temperature, 200 °C, therefore pure PVP had a high optical propagation loss as a result of the absorption of the decomposed molecules after crosslinking. The incorporation of sol-gel-processed SiO(2) prevented the thermal decomposition of PVP and provided remarkably low optical propagation losses. The PVP/SiO(2)composite material also produced thick (>2-µm) crack-free films when the PVP concentration was 50% or higher. An optical propagation loss of 0.2 dB/cm was achieved at 633 nm in the 50% PVP/SiO(2) composite planar waveguide. Several aspects of the thermal stability of the waveguides were evaluated. The slab waveguide was then used for fabrication of channel waveguides with a selective laser-densification technique. This technique used metal lines fabricated with photolithography on the slab waveguide as a light absorbent, and these metal lines were heated by an Ar laser. The resultant channel waveguide had an optical propagation loss of 0.9 dB/ cm at 633 nm. This technique provides lower absorption loss and scattering loss compared with the direct laser-densification technique, which uses UV lasers, and produces narrow waveguides that are difficult to fabricate with a CO(2) laser.


Antiviral activity of the proteasome on incoming human immunodeficiency virus type 1.
Following cell surface receptor binding and membrane fusion, human immunodeficiency virus (HIV) virion cores are released in the cytoplasm. Incoming viral proteins represent potential targets for cytosolic proteases. We show that treatment of target cells with the proteasome inhibitors MG132 and lactacystin increased the efficiency of HIV infection. Proteasome inhibitors were active at the early steps of the viral cycle. Incoming p24Gag proteins accumulated in the cytosol, and larger amounts of proviral DNA were synthesized. In vitro, purified 20S proteasome degraded HIV virion components. Thus, degradation of incoming viral proteins by the proteasome represents an early intracellular defense against infection.


Non-rigid Face Tracking with Local Appearance Consistency Constraint.
In this paper we present a new discriminative approach to achieve consistent and efficient tracking of non-rigid object motion, such as facial expressions. By utilizing both spatial and temporal appearance coherence at the patch level, the proposed approach can reduce ambiguity and increase accuracy. Recent research demonstrates that feature based approaches, such as constrained local models (CLMs), can achieve good performance in non-rigid object alignment/tracking using local region descriptors and a non-rigid shape prior. However, the matching performance of the learned generic patch experts is susceptible to local appearance ambiguity. Since there is no motion continuity constraint between neighboring frames of the same sequence, the resultant object alignment might not be consistent from frame to frame and the motion field is not temporally smooth. In this paper, we extend the CLM method into the spatio-temporal domain by enforcing the appearance consistency constraint of each local patch between neighboring frames. More importantly, we show that the global warp update can be optimized jointly in an efficient manner using convex quadratic fitting. Finally, we demonstrate that our approach receives improved performance for the task of non-rigid facial motion tracking on the videos of clinical patients.


Single amino acid substitution in aquaporin 11 causes renal failure.
A screen of recessive mutations generated by the chemical mutagen n-ethyl-n-nitrosourea (ENU) mapped a new mutant locus (5772SB) termed sudden juvenile death syndrome (sjds) to chromosome 7 in mice. These mutant mice, which exhibit severe proximal tubule injury and formation of giant vacuoles in the renal cortex, die from renal failure, a phenotype that resembles aquaporin 11 (Aqp11) knockout mice. In this report, the ENU-induced single-nucleotide variant (sjds mutation) is identified. To determine whether this variant, which causes an amino acid substitution (Cys227Ser) in the predicted E-loop region of aquaporin 11, is responsible for the sjds lethal renal phenotype, Aqp11-/sjds compound heterozygous mice were generated from Aqp11 +/sjds and Aqp11 +/- intercrosses. The compound heterozygous Aqp11 -/sjds offspring exhibited a lethal renal phenotype (renal failure by 2 wk), similar to the Aqp11 sjds/sjds and Aqp11-/- phenotypes. These results demonstrate that the identified mutation causes renal failure in Aqp11 sjds/sjds mutant mice, providing a model for better understanding of the structure and function of aquaporin 11 in renal physiology.


Emergency nurses' utilization of ultrasound guidance for placement of peripheral intravenous lines in difficult-access patients.
Emergency nurses (ENs) typically place peripheral intravenous (IV) lines, but if repeated attempts fail, emergency physicians have to obtain peripheral or central access. The authors describe the patient population for which ultrasound (US)-guided peripheral IVs are used and evaluate the success rates for such lines by ENs. This was a prospective observational study of ENs in a Level I trauma center with a census of 75,000, performing US-guided IV line placement on difficult-to-stick patients (repeated blind IV placement failure or established history). ENs were trained on an inanimate model after a 45-minute lecture. Surveys were filled out after each US-guided IV attempt on a patient. ENs could decline to fill out surveys, which recorded the reason for use of US, type of patient, and success. Successful cannulation was confirmed by drawing blood and flushing fluids. Descriptive statistics were used to evaluated data. A total of 321 surveys were collected in a five-month period no ENs declined to participate. There were 280 (87%) successful attempts. Twelve (29%) of the 41 failure patients required central lines, 9 (22%) received external jugular IVs, and 20 (49%) had peripheral IV access placed under US guidance by another nurse or physician. Twenty-eight percent (90) of all patients were obese, 18% (57) had sickle cell anemia, 10% (31) were renal dialysis patients, 12% (40) were IV drug abusers, and 19% (61) had unspecified chronic illness. The remainder had no reason for difficult access given. There were four arterial punctures. ENs had a high success rate and few complications with use of US guidance for vascular access in a variety of difficult-access patients.


MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis.
MicroRNA-122 (miR-122), which accounts for 70% of the liver's total miRNAs, plays a pivotal role in the liver. However, its intrinsic physiological roles remain largely undetermined. We demonstrated that mice lacking the gene encoding miR-122a (Mir122a) are viable but develop temporally controlled steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). These mice exhibited a striking disparity in HCC incidence based on sex, with a male-to-female ratio of 3.9:1, which recapitulates the disease incidence in humans. Impaired expression of microsomal triglyceride transfer protein (MTTP) contributed to steatosis, which was reversed by in vivo restoration of Mttp expression. We found that hepatic fibrosis onset can be partially attributed to the action of a miR-122a target, the Klf6 transcript. In addition, Mir122a(-/-) livers exhibited disruptions in a range of pathways, many of which closely resemble the disruptions found in human HCC. Importantly, the reexpression of miR-122a reduced disease manifestation and tumor incidence in Mir122a(-/-) mice. This study demonstrates that mice with a targeted deletion of the Mir122a gene possess several key phenotypes of human liver diseases, which provides a rationale for the development of a unique therapy for the treatment of chronic liver disease and HCC.


Human cytomegalovirus UL27 is not required for viral replication in human tissue implanted in SCID mice.
Inhibition of the human cytomegalovirus UL97 kinase by maribavir is thought to be responsible for the antiviral activity of this compound. Some mutations that confer resistance to maribavir map to UL97, however additional mutations that also confer resistance to the drug were mapped to UL27. These open reading frames share a low level of homology, yet the function of pUL27 remains unknown. A recombinant virus with a deletion in the UL27 open reading frame was reported previously to exhibit a slight replication deficit, but a more important function in vivo was hypothesized given its homology to the UL97 kinase. The potential for an important function in vivo was investigated by determining if these knockout viruses could replicate in human tissue implanted in SCID mice. None of the AD169 derived viruses replicated well in the implanted thymus/liver tissue, and is consistent with previous observations, although all of the viruses replicated to some degree in retinal tissue implants. Replication of the parent viruses was observed at 7 days post inoculation, whereas no replication was detected with any of the recombinant viruses with deletions in UL27. By day 14, replication was detected in two of the three knockout viruses and in all of the viruses by day 42. These data are consistent with minimal defects observed in cell culture, but are not consistent with an important role for UL27 in vivo. We conclude that UL27 is not required for viral replication in vivo.


Using temperature-sensitive smart polymers to regulate DNA-mediated nanoassembly and encoded nanocarrier drug release.
In this paper we describe the use of a temperature-responsive polymer to regulate DNA interactions in both a DNA-mediated assembly system and a DNA-encoded drug delivery system. A thermoresponsive pNIPAAm-co-pAAm polymer, with a transition temperature (TC) of 51 °C, was synthesized with thiol modification and grafted onto gold nanoparticles (Au NPs) also containing single-stranded oligonucleotides (ssDNA). The thermoresponsive behavior of the polymer regulated the accessibility of the sequence-specific hybridization between complementary DNA-functionalized Au NPs. At T < TC, the polymer was hydrophilic and extended, blocking interaction between the complementary sequences at the periphery of the hydrodynamic diameter. In contrast, at T > TC, the polymer shell undergoes a hydrophilic to -phobic phase transition and collapses, shrinking below the outer ssDNA, allowing for the sequence-specific hybridization to occur. The potential application of this dynamic interface for drug delivery is shown, in which the chemotherapy drug doxorubicin (DOX) is bound to double-stranded DNA (dsDNA)-functionalized Au NPs whose sequences are known to be high-affinity intercalation points for it. The presence of the polymer capping is shown to decrease drug release kinetics and equilibrium at T < TC, but increase release at T > TC, thus improving the cytotoxicity of the encoded nanocarrier design.


Characteristics and Young's Modulus of Collagen Fibrils from Expanded Skin Using Anisotropic Controlled Rate Self-Inflating Tissue Expander.
Mechanical properties of expanded skin tissue are different from normal skin, which is dependent mainly on the structural and functional integrity of dermal collagen fibrils. In the present study, mechanical properties and surface topography of both expanded and nonexpanded skin collagen fibrils were evaluated. Anisotropic controlled rate self-inflating tissue expanders were placed beneath the skin of sheep's forelimbs. The tissue expanders gradually increased in height and reached equilibrium in 2 weeks. They were left in situ for another 2 weeks before explantation. Expanded and normal skin samples were surgically harvested from the sheep (n = 5). Young's modulus and surface topography of collagen fibrils were measured using an atomic force microscope. A surface topographic scan showed organized hierarchical structural levels: collagen molecules, fibrils and fibers. No significant difference was detected for the D-banding pattern: 63.5 ± 2.6 nm (normal skin) and 63.7 ± 2.7 nm (expanded skin). Fibrils from expanded tissues consisted of loosely packed collagen fibrils and the width of the fibrils was significantly narrower compared to those from normal skin: 153.9 ± 25.3 and 106.7 ± 28.5 nm, respectively. Young's modulus of the collagen fibrils in the expanded and normal skin was not statistically significant: 46.5 ± 19.4 and 35.2 ± 27.0 MPa, respectively. In conclusion, the anisotropic controlled rate self-inflating tissue expander produced a loosely packed collagen network and the fibrils exhibited similar D-banding characteristics as the control group in a sheep model. However, the fibrils from the expanded skin were significantly narrower. The stiffness of the fibrils from the expanded skin was higher but it was not statistically different.


Analysis of neurosteroid levels in attention deficit hyperactivity disorder.
Neurosteroids are important neuroactive substrates with demonstrated involvement in several neurophysiological and disease processes. Attention deficit hyperactivity disorder (ADHD) has been associated with dysregulation of the catecholaminergic and serotonergic systems, however its relationship to irregularities or changes in neurosteroid levels remains unknown. We examined the relationship between blood levels of dehydroepiandrosterone (DHEA), its principal precursor pregnenolone and its principal metabolite dehydroepiandrosterone sulphate (DHEAS) in 29 young male subjects aged 7-15 years with DSM-IV criteria of ADHD. Subjects were evaluated by a specially designed scale, following which patients were divided into two groups according to severity of symptomatology. Results indicated significant inverse correlations between clinical symptomatology and levels of DHEA and pregnenolone in the total group. These inverse correlations were particularly evident in the less severe group of subjects. Levels of DHEA and DHEAS were inversely correlated with the hyperactivity subscale. Furthermore, using median blood levels as a cut-off indicator, higher blood levels of DHEA and DHEAS were associated with fewer ADHD symptoms, in particular hyperactivity symptomatology. Our findings suggest a possible protective effect of various neurosteroids on the expression of ADHD symptomatology.


The role of docking interactions in mediating signaling input, output, and discrimination in the yeast MAPK network.
Cells use a network of mitogen-activated protein kinases (MAPKs) to coordinate responses to diverse extracellular signals. Here, we examine the role of docking interactions in determining connectivity of the yeast MAPKs Fus3 and Kss1. These closely related kinases are activated by the common upstream MAPK kinase Ste7 yet generate distinct output responses, mating and filamentous growth, respectively. We find that docking interactions are necessary for communication with the kinases and that they can encode subtle differences in pathway-specific input and output. The cell cycle arrest mediator Far1, a mating-specific substrate, has a docking motif that selectively binds Fus3. In contrast, the shared partner Ste7 has a promiscuous motif that binds both Fus3 and Kss1. Structural analysis reveals that Fus3 interacts with specific and promiscuous peptides in conformationally distinct modes. Induced fit recognition may allow docking peptides to achieve discrimination by exploiting subtle differences in kinase flexibility.


Mammalian-wide interspersed repeat (MIR)-derived enhancers and the regulation of human gene expression.
Mammalian-wide interspersed repeats (MIRs) are the most ancient family of transposable elements (TEs) in the human genome. The deep conservation of MIRs initially suggested the possibility that they had been exapted to play functional roles for their host genomes. MIRs also happen to be the only TEs whose presence in-and-around human genes is positively correlated to tissue-specific gene expression. Similar associations of enhancer prevalence within genes and tissue-specific expression, along with MIRs' previous implication as providing regulatory sequences, suggested a possible link between MIRs and enhancers. To test the possibility that MIRs contribute functional enhancers to the human genome, we evaluated the relationship between MIRs and human tissue-specific enhancers in terms of genomic location, chromatin environment, regulatory function, and mechanistic attributes. This analysis revealed MIRs to be highly concentrated in enhancers of the K562 and HeLa human cell-types. Significantly more enhancers were found to be linked to MIRs than would be expected by chance, and putative MIR-derived enhancers are characterized by a chromatin environment highly similar to that of canonical enhancers. MIR-derived enhancers show strong associations with gene expression levels, tissue-specific gene expression and tissue-specific cellular functions, including a number of biological processes related to erythropoiesis. MIR-derived enhancers were found to be a rich source of transcription factor binding sites, underscoring one possible mechanistic route for the element sequences co-option as enhancers. There is also tentative evidence to suggest that MIR-enhancer function is related to the transcriptional activity of non-coding RNAs. Taken together, these data reveal enhancers to be an important cis-regulatory platform from which MIRs can exercise a regulatory function in the human genome and help to resolve a long-standing conundrum as to the reason for MIRs' deep evolutionary conservation.


Targeted overexpression of vitamin D receptor in osteoblasts increases calcium concentration without affecting structural properties of bone mineral crystals.
Increased cross-sectional area and strength of long bones has been observed in transgenic mice with 2-fold (OSV9) and 3-fold (OSV3) elevation of osteoblast vitamin D receptor (VDR) levels. In the present study, mineralization density distributions, including typical calcium content (Ca(Peak)) and homogeneity of mineralization (Ca(Width)) of femoral bone and growth plate cartilage, were determined by quantitative backscattered electron imaging (qBEI). Fourier-transform infrared (FTIR) microspectroscopy was used to examine mineral content, collagen and crystal maturation, and scanning small angle X-ray scattering (scanning-SAXS) for studying mineral particle thickness and alignment. In addition, X-ray diffraction (XRD) of distal tibiae revealed mineral particle c-axis size. In trabecular bone, the increase in Ca(Peak) was significant for both OSV9 (+ 3.14%, P = 0.03) and OSV3 (+ 3.43%, P = 0.02) versus controls with 23.61 +/- 0.45 S.D. wt% Ca baseline values. In cortical bone, Ca(Peak) was enhanced for the OSV3 mice (+ 1.84%, P = 0.02) versus controls with 26.61 +/- 0.28 S.D. wt% Ca, and OSV9 having intermediate values. Additionally, there was significantly increased homogeneity of mineralization as denoted by a reduction of Ca(Width) (-8.4%, P = 0.01) in primary spongiosa. FTIR microspectroscopy, with the exception of an increased collagen maturity in OSV3 trabecular bone (+ 9.9%, P = 0.02), XRD, and scanning-SAXS indicated no alterations in the nanostructure of transgenic bone. These findings indicate that elevation of osteoblastic vitamin D response led to formation of normal bone with higher calcium content. These material properties, together with indications of decreased bone resorption in secondary spongiosa and increased cortical periosteal bone formation, appear to contribute to the improved mechanical properties of their long bones and suggest an important physiological role of the vitamin D-endocrine system in normal bone mineralization.


Strong advocacy led to successful implementation of smokefree Mexico City.
To describe the approval process and implementation of the 100% smokefree law in Mexico City and a competing federal law between 2007 and 2010. Reviewed smokefree legislation, published newspaper articles and interviewed key informants. Strong efforts by tobacco control advocacy groups and key policymakers in Mexico City in 2008 prompted the approval of a 100% smokefree law following the WHO FCTC. As elsewhere, the tobacco industry utilised the hospitality sector to block smokefree legislation, challenged the City law before the Supreme Court and promoted the passage of a federal law that required designated smoking areas. These tactics disrupted implementation of the City law by causing confusion over which law applied in Mexico City. Despite interference, the City law increased public support for 100% smokefree policies and decreased the social acceptability of smoking. In September 2009, the Supreme Court ruled in favour of the City law, giving it the authority to go beyond the federal law to protect the fundamental right of health for all citizens. Early education and enforcement efforts by tobacco control advocates promoted the City law in 2008 but advocates should still anticipate continuing opposition from the tobacco industry, which will require continued pressure on the government. Advocates should utilise the Supreme Court's ruling to promote 100% smokefree policies outside Mexico City. Strong advocacy for the City law could be used as a model of success throughout Mexico and other Latin American countries.


Early skeletal muscle adaptations to short-term high-fat diet in humans before changes in insulin sensitivity.
The purpose of this investigation was to understand the metabolic adaptations to a short-term (5 days), isocaloric, high-fat diet (HFD) in healthy, young males. Two studies were undertaken with 12 subjects. Study 1 investigated the effect of the HFD on skeletal muscle substrate metabolism and insulin sensitivity. Study 2 assessed the metabolic and transcriptional responses in skeletal muscle to the transition from a fasted to fed state using a high-fat meal challenge before and after 5 days of the HFD. Study 1 showed no effect of a HFD on skeletal muscle metabolism or insulin sensitivity in fasting samples. Study 2 showed that a HFD elicits significant increases in fasting serum endotoxin and disrupts the normal postprandial excursions of serum endotoxin, as well as metabolic and transcriptional responses in skeletal muscle. These effects after 5 days of the HFD were accompanied by an altered fasting and postprandial response in the ratio of phosphorylated- to total-p38 protein. These changes all occurred in the absence of alterations in insulin sensitivity. Our findings provide evidence for early biological adaptations to high-fat feeding that proceed and possibly lead to insulin resistance.


Photoelectron spectroscopy of wet and gaseous samples through graphene membranes.
Photoelectron spectroscopy (PES) and microscopy are highly important for exploring morphologically and chemically complex liquid-gas, solid-liquid and solid-gas interfaces under realistic conditions, but the very small electron mean free path inside dense media imposes serious experimental challenges. Currently, near ambient pressure PES is conducted using dexterously designed electron energy analyzers coupled with differentially pumped electron lenses which make it possible to conduct PES measurements at a few hPa. This report proposes an alternative ambient pressure approach that can be applied to a broad class of samples and be implemented in conventional PES instruments. It uses ultrathin electron transparent but molecular impermeable membranes to isolate the high pressure sample environment from the high vacuum PES detection system. We demonstrate that the separating graphene membrane windows are both mechanically robust and sufficiently transparent for electrons in a wide energy range to allow soft X-ray PES of liquid and gaseous water. The performed proof-of-principle experiments confirm the possibility to probe vacuum-incompatible toxic or reactive samples placed inside such hermetic, gas flow or fluidic environmental cells.


Transitions in gambling participation during late adolescence and young adulthood.
The purpose of this study was to examine transitions in gambling participation from late adolescence into emerging adulthood and to identify factors (i.e., gender, race, intervention status, lunch status, conduct disorder, parental monitoring, neighborhood environment, and substance use) that might influence these transitions. Markov modeling was used to describe the movement between past-year gambling states (i.e., nongambling and gambling) across 5 years. Annual data on the past-year gambling behavior and substance use were collected from 515 young men and women starting at the age of 17 years. Past-year gambling declined from 51% prevalence at the age of 17 years to 21% prevalence at the age of 22 years. Participants who reported no past-year gambling at a particular annual assessment had more than an 80% probability of also reporting no past-year gambling at the following assessment. Men were 1.07-2.82 times more likely than women to transition from past-year nongambling to gambling year to year, and women were 1.27-5.26 times more likely than men to transition from past-year gambling to nongambling year to year. In addition, gender and past-year tobacco use interacted such that men who used tobacco were most likely (and men who did not use tobacco least likely) to gamble at baseline. Transition rates between gambling states appear to be relatively stable over time from late adolescence into emerging adulthood; however, men and those who engage in substance use may be at an increased risk of gambling participation.


Repeatability and reproducibility of Goldmann applanation, dynamic contour, and ocular response analyzer tonometry.
To evaluate the repeatability and interoperator reproducibility of the Pascal dynamic contour tonometry (DCT), ocular response analyzer (ORA), and Goldmann applanation tonometer (GAT) in a single population of normal individuals. The study included 52 eyes from 26 normal individuals. One operator measured the intraocular pressure (IOP) with each tonometer 3 times while 2 additional operators each measured the IOP with each tonometer once. Repeatability and reproducibility were assessed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Agreement among tonometers was also assessed using Bland-Altman plots. The mean age of included participants was 31.5±8.8 years and 15 (58%) were female individuals. In general, both intraoperator repeatability and interoperator reproducibility were significantly higher for DCT compared with the other tonometers. Intraoperator DCT (CV=3.7, ICC=0.89), GAT (CV=9.7, ICC=0.79), IOPg (CV=7.0, ICC=0.79), and IOPcc (CV=9.8, ICC=0.57). Interoperator DCT (CV=6.1, ICC=0.73), GAT (CV=9.0, ICC=0.82), and IOPg (CV=10.8, ICC=0.63), IOPcc (CV=11.7, ICC=0.49). Overall, DCT was significantly more repeatable and reproducible than GAT, IOPg and IOPcc. The better reproducibility of the DCT may result in more precise measurements for monitoring IOP changes over time compared to GAT and ORA.


Transmyocardial laser revascularization in the patient with unmanageable unstable angina.
Transmyocardial laser revascularization (TMR) provides relief for patients with chronic angina, nonamenable to direct coronary revascularization. Unmanageable, unstable angina (UUA) defines a subset of patients with refractory angina who are at high risk for myocardial infarction and death. Patients were classified in the UUA group when they had been admitted to the critical care unit with unstable angina for 7 days with three failed attempts at weaning them off intravenous antianginal medications. Seventy-six treated patients were analyzed to determine if TMR is a viable option for patients with unmanageable unstable angina. These patients were compared with 91 routine protocol patients (protocol group [PG]) undergoing TMR for chronic angina not amenable to standard revascularization. The procedure was performed through a left thoracotomy without cardiopulmonary bypass. These patients were followed for 12 months after the TMR procedure. Both unmanageable and chronic angina patients had a high incidence of at least one prior surgical revascularization (87% and 91%, respectively). Perioperative mortality (< or = 30 days post-TMR) was higher in the UUAG versus PG (16% vs 3%, p = 0.005). Late mortality, up to 1 year of follow-up, was similar (13% vs 11%, UUAG vs PG; p = 0.83). A majority of the adverse events in the UUAG occurred within the first 3 months post-TMR, and patients surviving this interval did well, with reduced angina of at least two classes occurring in 69%, 82%, and 82% of patients at 3, 6, and 12 months, respectively. The percent improvement in angina class from baseline was statistically significant at 3, 6, and 12 months. A comparable improvement in angina was found in the protocol group of patients. TMR carried a significantly higher risk in unmanageable, unstable angina than in patients with chronic angina. In the later follow-up intervals, however, both groups demonstrated similar and persistent improvement in their angina up to 12 months after the procedure. TMR may be considered in the therapy of patients with unmanageable, unstable angina who otherwise have no recourse to effective therapy in the control of their disabling angina.


Detection and characterisation of bone destruction in murine rheumatoid arthritis using statistical shape models.
Rheumatoid arthritis (RA) is an autoimmune disease in which chronic inflammation of the synovial joints can lead to destruction of cartilage and bone. Pre-clinical studies attempt to uncover the underlying causes by emulating the disease in genetically different mouse strains and characterising the nature and severity of bone shape changes as indicators of pathology. This paper presents a fully automated method for obtaining quantitative measurements of bone destruction from volumetric micro-CT images of a mouse hind paw. A statistical model of normal bone morphology derived from a training set of healthy examples serves as a template against which a given pathological sample is compared. Abnormalities in bone shapes are identified as deviations from the model statistics, characterised in terms of type (erosion / formation) and quantified in terms of severity (percentage affected bone area). The colour-coded magnitudes of the deviations superimposed on a three-dimensional rendering of the paw show at a glance the severity of malformations for the individual bones and joints. With quantitative data it is possible to derive population statistics characterising differences in bone malformations for different mouse strains and in different anatomical regions. The method was applied to data acquired from three different mouse strains. The derived quantitative indicators of bone destruction have shown agreement both with the subjective visual scores and with the previous biological findings. This suggests that pathological bone shape changes can be usefully and objectively identified as deviations from the model statistics.


Can aging in place be cost effective? A systematic review.
To systematically review cost, cost-minimization and cost-effectiveness studies for assisted living technologies (ALTs) that specifically enable older people to 'age in place' and highlight what further research is needed to inform decisions regarding aging in place. People aged 65+ and their live-in carers (where applicable), using an ALT to age in place at home opposed to a community-dwelling arrangement. Studies were identified using a predefined search strategy on two key economic and cost evaluation databases NHS EED, HEED. Studies were assessed using methods recommended by the Campbell and Cochrane Economic Methods Group and presented in a narrative synthesis style. Eight eligible studies were identified from North America spread over a diverse geographical range. The majority of studies reported the ALT intervention group as having lower resource use costs than the control group; though the low methodological quality and heterogeneity of the individual costs and outcomes reported across studies must be considered. The studies suggest that in some cases ALTs may reduce costs, though little data were identified and what there were was of poor quality. Methods to capture quality of life gains were not used, therefore potential effects on health and wellbeing may be missed. Further research is required using newer developments such as the capabilities approach. High quality studies assessing the cost-effectiveness of ALTs for ageing in place are required before robust conclusion on their use can be drawn.


Regulation of microRNA biosynthesis and expression in 2102Ep embryonal carcinoma stem cells is mirrored in ovarian serous adenocarcinoma patients.
Tumours with high proportions of differentiated cells are considered to be of a lower grade to those containing high proportions of undifferentiated cells. This property may be linked to the differentiation properties of stem cell-like populations within malignancies. We aim to identify molecular mechanism associated with the generation of tumours with differing grades from malignant stem cell populations with different differentiation potentials. In this study we assessed microRNA (miRNA) regulation in two populations of malignant Embryonal Carcinoma (EC) stem cell, which differentiate (NTera2) or remain undifferentiated (2102Ep) during tumourigenesis, and compared this to miRNA regulation in ovarian serous carcinoma (OSC) patient samples. miRNA expression was assessed in NTera2 and 2102Ep cells in the undifferentiated and differentiated states and compared to that of OSC samples using miRNA qPCR. Our analysis reveals a substantial overlap between miRNA regulation in 2102Ep cells and OSC samples in terms of miRNA biosynthesis and expression of mature miRNAs, particularly those of the miR-17/92 family and clustering to chromosomes 14 and 19. In the undifferentiated state 2102Ep cells expressed mature miRNAs at up to 15,000 fold increased levels despite decreased expression of miRNA biosynthesis genes Drosha and Dicer. 2102Ep cells avoid differentiation, which we show is associated with consistent levels of expression of miRNA biosynthesis genes and mature miRNAs while expression of miRNAs clustering to chromosomes 14 and 19 is deemphasised. OSC patient samples displayed decreased expression of miRNA biosynthesis genes, decreased expression of mature miRNAs and prominent clustering to chromosome 14 but not 19. This indicates that miRNA biosynthesis and levels of miRNA expression, particularly from chromosome 14, are tightly regulated both in progenitor cells and in tumour samples. miRNA biosynthesis and expression of mature miRNAs, particularly the miR-17/92 family and those clustering to chromosomes 14 and 19, are highly regulated in both progenitor cells and tumour samples. Strikingly, 2102Ep cells are not simply malfunctioning but respond to differentiation specifically, a mechanism that is highly relevant to OSC samples. Our identification and future manipulation of these miRNAs may facilitate generation of lower grade malignancies from these high-grade cells.


Pharmaceutical counterfeiting and the RFID technology intervention.
Both nationally and internationally, pharmaceutical counterfeiting has become a problem that is threatening economic stability and public health. The purpose of the present research study review was to analyze the scope and severity of pharmaceutical counterfeiting and to establish if the implantation of the Radio Frequency Identification Device (RFID) model can more efficiently be used within the pharmaceutical supply chain to reduce the problem counterfeit drugs impose on public health and international economic stability. Results indicated that implementing the RFID model for tracking drugs at the item level in the pharmaceutical supply chain has potential to alleviate the scope of the counterfeit drug problem. Recommendations for how the pharmaceutical industry may sooner adopt the RFID model are made.


Comparison of brain monoamine content in three populations of Lymnaea that correlates with taste-aversive learning ability.
To find a causal mechanism of learning and memory is a heuristically important topic in neuroscience. In the pond snail Lymnaea stagnalis, the following experimental facts have accrued regarding a classical conditioning procedure known as conditioned taste aversion (CTA): (1) one-day food-deprived Dutch snails have superior CTA memory formation; (2) the one-day food-deprived snails have a low monoamine content (e.g., serotonin, dopamine, octopamine) in their central nervous system (CNS); (3) fed or five-day food-deprived snails have poorer CTA memory and a higher monoamine content; (4) the Dutch snails form better CTA memory than the Canadian TC1 strain; and, (5) the F1 cross snails between the Dutch and Canadian TC1 strains also form poor CTA memory. Here, in one-day food-deprived snails, we measured the monoamine content in the CNSs of the 3 populations. In most instances, the monoamine content of the Dutch strain was lower than in the other two populations. The F1 cross snails had the highest monoamine content. A lower monoamine content is correlated with the better CTA memory formation.


Comparison of valaciclovir and acyclovir for the treatment of herpes zoster in immunocompetent patients over 50 years of age: a cost-consequence model.
A method was developed for modeling the costs and consequences of treating varicella zoster viral infections to clinical data generated in a pivotal phase III clinical trial of valaciclovir versus acyclovir for the treatment of acute herpes zoster in immunocompetent patients over 50 years of age. Direct medical costs and indirect costs (productivity losses) were modeled using unit costs applicable in the United States. Compared with acyclovir, valaciclovir reduced average direct medical costs per patient by 17% ($60.01) and indirect costs by an average of 25% ($46.54). Median duration of pain was reduced by 13 days for valaciclovir compared with acyclovir in the intent-to-treat population or by 19 days in patients with pain after rash healing. The cost variables described in the model (drug costs, cost of treating long-term pain, physician visits, hospitalization, treatment of severe ocular involvement, productivity losses) were tested by sensitivity analysis. Total costs associated with valaciclovir treatment remained lower than those with acyclovir over the range of the analysis.


Vitamin D regulating TGF-β induced epithelial-mesenchymal transition.
Subepithelial fibrosis is a characteristic hallmark of airway remodeling in asthma. A critical regulator of fibrosis, transforming growth factor β (TGF-β), can induce airway remodeling in epithelial cells through induction of epithelial-mesenchymal transition (EMT). Vitamin D has immunomodulatory functions, however, its effect on controlling subepithelial fibrosis is not known. Human bronchial epithelial cells (BEAS-2B) were exposed to calcitriol followed by stimulation with TGF-β1 or TGF-β2. The protein expression and mRNA transcripts for E-cadherin, Snail, vimentin, and N-cadherin were analyzed by Western blot and qPCR. An invasion assay and scratch wound assay were performed to identify the migratory properties of the cells following treatments. TGF-β1 decreased E-cadherin expression and increased protein expression and mRNA transcripts of Snail, vimentin, and N-cadherin together with increased cell invasion and migration. TGF-β2 elicited migratory response similar to TGF-β1 but induced the expression of EMT markers differently from that by TGF-β1. Calcitriol attenuated TGF-β1- and TGF-β2-induced cell motility. Also, calcitriol inhibited the expression of EMT markers in TGF-β1-treated epithelial cells with less effect on TGF-β2. These data suggest that calcitriol inhibits both migration and invasion induced by TGF-β1 and TGF-β2 in human airway epithelial cells. However, the regulatory effect of vitamin D in epithelial-mesenchymal transition was more effective to TGF-β1-induced changes. Thus, calcitriol could be a potential therapeutic agent in the prevention and management of subepithelial fibrosis and airway remodeling.


Linear discrete diffraction and transverse localization of light in two-dimensional backbone lattices.
We study the linear discrete diffraction characteristics of light in two-dimensional backbone lattices. It is found that, as the refractive index modulation depth of the backbone lattice increases, high-order band gaps become open and broad in sequence, and the allowed band curves of the Floquet-Bloch modes become flat gradually. As a result, the diffraction pattern at the exit face converges gradually for both the on-site and off-site excitation cases. Particularly, when the refractive index modulation depth of the backbone lattice is high enough, for example, on the order of 0.01 for a square lattice, the light wave propagating in the backbone lattice will be localized in transverse dimension for both the on-site and off-site excitation cases. This is because only the first several allowed bands with nearly flat band curves are excited in the lattice, and the transverse expansion velocities of the Floquet-Bloch modes in these flat allowed bands approach to zero. Such a linear transverse localization of light may have potential applications in navigating light propagation dynamics and optical signal processing.


Effect of massage therapy on pain, anxiety, and tension in cardiac surgical patients: a pilot study.
To assess the role of massage therapy in the cardiac surgery postoperative period. Specific aims included determining the difference in pain, anxiety, tension, and satisfaction scores of patients before and after massage compared with patients who received standard care. A randomized controlled trial comparing outcomes before and after intervention in and across groups. Saint Marys Hospital, Mayo Clinic, Rochester, Minnesota. Patients undergoing cardiovascular surgical procedures (coronary artery bypass grafting and/or valvular repair or replacement) (N=58). Patients in the intervention group received a 20-minute session of massage therapy intervention between postoperative days 2 and 5. Patients in the control group received standard care and a 20-minute quiet time between postoperative days 2 and 5. Linear Analogue Self-assessment scores for pain, anxiety, tension, and satisfaction. Statistically and clinically significant decreases in pain, anxiety, and tension scores were observed for patients who received a 20-minute massage compared with those who received standard care. Patient feedback was markedly positive. This pilot study showed that massage can be successfully incorporated into a busy cardiac surgical practice. These results suggest that massage may be an important therapy to consider for inclusion in the management of postoperative recovery of cardiovascular surgical patients.


Fragment-based optimization of small molecule CXCL12 inhibitors for antagonizing the CXCL12/CXCR4 interaction.
The chemokine CXCL12 and its G protein-coupled receptor (GPCR) CXCR4 are high-priority clinical targets because of their involvement in metastatic cancers (also implicated in autoimmune disease and cardiovascular disease). Because chemokines interact with two distinct sites to bind and activate their receptors, both the GPCRs and chemokines are potential targets for small molecule inhibition. A number of chemokines have been validated as targets for drug development, but virtually all drug discovery efforts focus on the GPCRs. However, all CXCR4 receptor antagonists with the exception of MSX-122 have failed in clinical trials due to unmanageable toxicities, emphasizing the need for alternative strategies to interfere with CXCL12/CXCR4-guided metastatic homing. Although targeting the relatively featureless surface of CXCL12 was presumed to be challenging, focusing efforts at the sulfotyrosine (sY) binding pockets proved successful for procuring initial hits. Using a hybrid structure-based in silico/NMR screening strategy, we recently identified a ligand that occludes the receptor recognition site. From this initial hit, we designed a small fragment library containing only nine tetrazole derivatives using a fragment-based and bioisostere approach to target the sY binding sites of CXCL12. Compound binding modes and affinities were studied by 2D NMR spectroscopy, X-ray crystallography, molecular docking and cell-based functional assays. Our results demonstrate that the sY binding sites are conducive to the development of high affinity inhibitors with better ligand efficiency (LE) than typical protein-protein interaction inhibitors (LE ≤ 0.24). Our novel tetrazole-based fragment 18 was identified to bind the sY21 site with a K(d) of 24 μM (LE = 0.30). Optimization of 18 yielded compound 25 which specifically inhibits CXCL12-induced migration with an improvement in potency over the initial hit 9. The fragment from this library that exhibited the highest affinity and ligand efficiency (11: K(d) = 13 μM, LE = 0.33) may serve as a starting point for development of inhibitors targeting the sY12 site.


Effect of Tinospora cordifolia on physical and cardiovascular performance induced by physical stress in healthy human volunteers.
In Ayurveda Tinospora cordifolia (Willd.) Miers., has been used for its Rasayana, Deepana, Jwaranashana, Tridosha Shamaka properties. It is an immunomodulator, useful in stress, hyperlipidemia, pyrexia. T. cordifolia was evaluated for adaptogenic activity in healthy volunteers during exercise. The primary objective of this study was to evaluate the effect of T. cordifolia on physical performance, and secondary objectives were to evaluate muscle power, maximal oxygen consumption, and sympathetic activity in comparison with placebo when subjected to physical stress. A total of thirty participants were randomly assigned into three groups (n = 10 each) namely placebo, TC 150 and TC 300. Placebo group received maize starch capsule, TC 150 and TC 300 received 150 mg and 300 mg, respectively of T. cordifolia aqueous extract in capsule form once daily in the morning for 28 days. The assessment was performed at baseline visit, day 14 and 28. Physical stressors were cycle ergometer exercise, Jammer's hand-held dynamometer, and cold pressor tests. Physical performance evaluated was maximum distance and speed, oxygen consumption (VO2 max), and hand grip strength. Cardiovascular response was assessed by multiple heart rate (HR) and blood pressure (BP) measurements during each test. On day 28, TC 150 mg group showed a significant increase in mean maximum speed compared to placebo. On day 14 and 28, TC 300 mg group showed a significant decrease in mean systolic BP (SBP) and HR on fixed workload exercise compared to placebo. There was significant increasing dose effect of both TC groups on SBP on day 14 and 28 and on HR on day 28 only. On day 14 and 28, TC 300 mg showed a significant decrease in mean HR on the cold pressor test, compared to placebo. T. cordifolia improved physical performance and suppressed over activation of the sympathetic nervous system showing its adaptogenic property.


Dissociative adsorption of CH₃X (X = Br and Cl) on a silicon(100) surface revisited by density functional theory.
During the dissociative adsorption on a solid surface, the substrate usually participates in a passive manner to accommodate fragments produced upon the cleavage of the internal bond(s) of a (transient) molecular adsorbate. This simple picture, however, neglects the flexibility of surface atoms. Here, we report a Density Functional Theory study to revisit our early studies of the dissociative adsorption of CH3X (X = Br and Cl) on Si(100). We have identified a new reaction pathway, which involves a flip of a silicon dimer; this new pathway agrees better with experiments. For our main exemplar of CH3Br, insights have been gained using a simple model that involves a three-atom reactive center, Br-C-Si. When the silicon dimer flips, the interaction between C and Si in the Br-C-Si center is enhanced, evident in the increased energy-split of the frontier orbitals. We also examine how the dissociation dynamics of CH3Br is altered on a heterodimer (Si-Al, Si-P, and Si-Ge) in a Si(100) surface. In each case, we conclude, on the basis of computed reaction pathways, that no heterodimer flipping is involved before the system transverses the transition state to dissociative adsorption.


Olfactory cues modulate facial attractiveness.
We report an experiment designed to investigate whether olfactory cues can influence people's judgments of facial attractiveness. Sixteen female participants judged the attractiveness of a series of male faces presented briefly on a computer monitor using a 9-point visual rating scale. While viewing each face, the participants were simultaneously presented with either clean air or else with 1 of 4 odorants (the odor was varied on a trial-by-trial basis) from a custom-built olfactometer. We included 2 pleasant odors (geranium and a male fragrance) and 2 unpleasant odors (rubber and body odor) as confirmed by pilot testing. The results showed that the participants rated the male faces as being significantly less attractive in the presence of an unpleasant odor than when the faces were presented together with a pleasant odor or with clean air (these conditions did not differ significantly). These results demonstrate the cross-modal influence that unpleasant odors can have on people's judgments of facial attractiveness. Interestingly, this pattern of results was unaffected by whether the odors were body relevant (the body odor and the male fragrance) or not (the rubber and geranium odors).


Quantitation of Endothelial Cell Adhesiveness In Vitro.
One of the cardinal processes of inflammation is the infiltration of immune cells from the lumen of the blood vessel to the surrounding tissue. This occurs when endothelial cells, which line blood vessels, become adhesive to circulating immune cells such as monocytes. In vitro measurement of this adhesiveness has until now been done by quantifying the total number of monocytes that adhere to an endothelial layer either as a direct count or by indirect measurement of the fluorescence of adherent monocytes. While such measurements do indicate the average adhesiveness of the endothelial cell population, they are confounded by a number of factors, such as cell number, and do not reveal the proportion of endothelial cells that are actually adhesive. Here we describe and demonstrate a method which allows the enumeration of adhesive cells within a tested population of endothelial monolayer. Endothelial cells are grown on glass coverslips and following desired treatment are challenged with monocytes (that may be fluorescently labeled). After incubation, a rinsing procedure, involving multiple rounds of immersion and draining, the cells are fixed. Adhesive endothelial cells, which are surrounded by monocytes are readily identified and enumerated, giving an adhesion index that reveals the actual proportion of endothelial cells within the population that are adhesive.


Spatial Evidential Clustering With Adaptive Distance Metric for Tumor Segmentation in FDG-PET Images.
While the accurate delineation of tumor volumes in FDG-positron emission tomography (PET) is a vital task for diverse objectives in clinical oncology, noise and blur due to the imaging system make it a challenging work. In this paper, we propose to address the imprecision and noise inherent in PET using Dempster-Shafer theory, a powerful tool for modeling and reasoning with uncertain and/or imprecise information. Based on Dempster-Shafer theory, a novel evidential clustering algorithm is proposed and tailored for the tumor segmentation task in three-dimensional. For accurate clustering of PET voxels, each voxel is described not only by the single intensity value but also complementarily by textural features extracted from a patch surrounding the voxel. Considering that there are a large amount of textures without consensus regarding the most informative ones, and some of the extracted features are even unreliable due to the low-quality PET images, a specific procedure is included in the proposed clustering algorithm to adapt distance metric for properly representing the clustering distortions and the similarities between neighboring voxels. This integrated metric adaptation procedure will realize a low-dimensional transformation from the original space, and will limit the influence of unreliable inputs via feature selection. A Dempster-Shafer-theory-based spatial regularization is also proposed and included in the clustering algorithm, so as to effectively quantify the local homogeneity. The proposed method has been compared with other methods on the real-patient FDG-PET images, showing good performance.


Coral reef disturbance and recovery dynamics differ across gradients of localized stressors in the Mariana Islands.
The individual contribution of natural disturbances, localized stressors, and environmental regimes upon longer-term reef dynamics remains poorly resolved for many locales despite its significance for management. This study examined coral reefs in the Commonwealth of the Northern Mariana Islands across a 12-year period that included elevated Crown-of-Thorns Starfish densities (COTS) and tropical storms that were drivers of spatially-inconsistent disturbance and recovery patterns. At the island scale, disturbance impacts were highest on Saipan with reduced fish sizes, grazing urchins, and water quality, despite having a more favorable geological foundation for coral growth compared with Rota. However, individual drivers of reef dynamics were better quantified through site-level investigations that built upon island generalizations. While COTS densities were the strongest predictors of coral decline as expected, interactive terms that included wave exposure and size of the overall fish assemblages improved models (R2 and AIC values). Both wave exposure and fish size diminished disturbance impacts and had negative associations with COTS. However, contrasting findings emerged when examining net ecological change across the 12-year period. Wave exposure had a ubiquitous, positive influence upon the net change in favorable benthic substrates (i.e. corals and other heavily calcifying substrates, R2 = 0.17 for all reeftypes grouped), yet including interactive terms for herbivore size and grazing urchin densities, as well as stratifying by major reeftypes, substantially improved models (R2 = 0.21 to 0.89, lower AIC scores). Net changes in coral assemblages (i.e., coral ordination scores) were more sensitive to herbivore size or the water quality proxy acting independently (R2 = 0.28 to 0.44). We conclude that COTS densities were the strongest drivers of coral decline, however, net ecological change was most influenced by localized stressors, especially herbivore sizes and grazing urchin densities. Interestingly, fish size, rather than biomass, was consistently a better predictor, supporting allometric, size-and-function relationships of fish assemblages. Management implications are discussed.


Aurora kinase-C-T191D is constitutively active mutant.
Aurora kinases (Aurora-A, B and C) belong to a family of conserved serine/threonine kinases which are key regulators of cell cycle progression. Aurora-A and Aurora-B are expressed in somatic cells and involved in cell cycle regulation while aurora-C is meiotic chromosome passenger protein. As Aurora kinase C is rarely expressed in normal somatic cells and has been found over expressed in many cancer lines. It is suggested that Aurora-C-T191D is not hyperactive mutant. Aurora-C-T191D variant form was investigated and compared with wild type. The overexpression of Aurora-C-T191D was observed that it behaves like Aurora-C wild type (aurC-WT). Both Aurora-C-T191D and aurC-WT induce abnormal cell division resulting in centrosome amplification and multinucleation in transiently transfected cells as well as in stable cell lines. Similarly, Aurora-C-T191D and aurC-WT formed foci of colonies when grown on soft agar, indicating that a gain of Aurora-C activity is sufficient to transform cells. Furthermore, we reported that NIH-3 T3 stable cell lines overexpressing Aurora-C-T191D and its wild type partner induced tumour formation when injected into nude mice, demonstrating the oncogenic activity of enzymatically active Aurora kinase C. Interestingly enough tumour aggressiveness was positively correlated with the rate of kinase activity, making Aurora-C a potential anti-cancer therapeutic target. These findings proved that Aurora C-T191D is not hyperactive but is constitutively active mutant.


LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis.
Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOX-mediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer.


Potentiation of thrombin generation in hemophilia A plasma by coagulation factor VIII and characterization of antibody-specific inhibition.
Development of inhibitory antibodies to coagulation factor VIII (fVIII) is the primary obstacle to the treatment of hemophilia A in the developed world. This adverse reaction occurs in 20-30% of persons with severe hemophilia A treated with fVIII-replacement products and is characterized by the development of a humoral and neutralizing immune response to fVIII. Patients with inhibitory anti-fVIII antibodies are treated with bypassing agents including recombinant factor VIIa (rfVIIa). However, some patients display poor hemostatic response to bypass therapy and improved treatment options are needed. Recently, we demonstrated that fVIII inhibitors display widely variable kinetics of inhibition that correlate with their respective target epitopes. Thus, it was hypothesized that for antibodies that display slow rates of inhibition, supplementation of rfVIIa with fVIII would result in improved thrombin generation and be predictive of clinical responses to this novel treatment regimen. In order to test this hypothesis, 10 murine monoclonal antibodies (MAbs) with non-overlapping epitopes spanning fVIII, differential inhibition titers, and inhibition kinetics were studied using a thrombin generation assay. Of the 3 MAbs with high inhibitory titers, only the one with fast and complete (classically defined as "type I") kinetics displayed significant inhibition of thrombin generation with no improvement upon supplementation of rfVIIa with fVIII. The other two MAbs that displayed incomplete (classically defined as "type II") inhibition did not suppress the potentiation of thrombin generation by fVIII. All antibodies that did not completely inhibit fVIII activity demonstrated potentiation of thrombin generation by the addition of fVIII as compared to rfVIIa alone. In conclusion, fVIII alone or in combination with rfVIIa corrects the thrombin generation defect produced by the majority of anti-fVIII MAbs better than single agent rfVIIa. Therefore, combined fVIII/rfVIIa therapy may provide better hemostatic control than current therapy in some patients with anti-fVIII inhibitors.


Mechanisms of stimulation of interleukin-1 beta and tumor necrosis factor-alpha by Mycobacterium tuberculosis components.
The granulomatous immune response in tuberculosis is characterized by delayed hypersensitivity and is mediated by various cytokines released by the stimulated mononuclear phagocytes, including tumor necrosis factor-alpha (TNF alpha) and IL-1 beta. We have demonstrated that Mycobacterium tuberculosis cell wall component lipoarabinomannan (LAM), mycobacterial heat shock protein-65 kD, and M. tuberculosis culture filtrate, devoid of LPS as assessed by the Amebocyte Lysate assay, stimulate the production of TNF alpha and IL-1 beta proteins and mRNA from mononuclear phagocytes (THP-1 cells). The effect of LAM on the release of these cytokines was specific, as only LAM stimulation was inhibited by anti-LAM monoclonal antibody. Interestingly, we found that LAM and Gram-negative bacterial cell wall-associated endotoxin LPS may share a similar mechanism in their stimulatory action as demonstrated by inhibition of TNF alpha and IL-1 beta release by monoclonal antibodies to CD14. Anti-CD14 monoclonal antibody MY4 inhibited both TNF alpha and IL-1 beta release with LAM and LPS but no effect was observed with other mycobacterial proteins. An isotype antibody control did not inhibit release of cytokines under the same experimental conditions. M. tuberculosis and its components upregulated IL-1 beta and TNF alpha mRNAs in THP-1 cells. Nuclear run-on assay for IL-1 beta demonstrated that LAM increased the transcription rate. The induction of IL-1 beta was regulated at the transcriptional level, in which these stimuli acted through cis-acting element(s) on the 5' flanking region of the IL-1 beta genomic DNA. M. tuberculosis cell wall component LAM acts similarly to LPS in activating mononuclear phagocyte cytokine TNF alpha and IL-1 beta release through CD14 and synthesis at the transcriptional level; both cytokines are key participants in the host immune response to tuberculosis.


Surgical Burn Care by Médecins Sans Frontières-Operations Center Brussels: 2008 to 2014.
Humanitarian organizations care for burns during crisis and while supporting healthcare facilities in low-income and middle-income countries. This study aimed to define the epidemiology of burn-related procedures to aid humanitarian response. In addition, operational data collected from humanitarian organizations are useful for describing surgical need otherwise unmet by national health systems. Procedures performed in operating theatres run by Médecins Sans Frontières-Operations Centre Brussels (MSF-OCB) from July 2008 through June 2014 were reviewed. Surgical specialist missions were excluded. Burn procedures were quantified, related to demographics and reason for humanitarian response, and described. A total of 96,239 operations were performed at 27 MSF-OCB projects in 15 countries between 2008 and 2014. Of the 33,947 general surgical operations, 4,280 (11%) were for burns. This proportion steadily increased from 3% in 2008 to 24% in 2014. People receiving surgical care from conflict relief missions had nearly twice the odds of having a burn operation compared with people requiring surgery in communities affected by natural disaster (adjusted odds ratio, 1.94; 95% confidence interval, 1.46-2.58). Nearly 70% of burn procedures were planned serial visits to the theatre. A diverse skill set was required. Unmet humanitarian assistance needs increased US$400 million dollars in 2013 in the face of an increasing number of individuals affected by crisis and a growing surgical burden. Given the high volume of burn procedures performed at MSF-OCB projects and the resource intensive nature of burn management, requisite planning and reliable funding are necessary to ensure quality for burn care in humanitarian settings.


Generation of a high-quality partially coherent dark hollow beam with a multimode fiber.
We report the experimental generation of a high-quality partially coherent dark hollow beam (DHB) by coupling a partially coherent beam into a multimode fiber (MMF) with a suitable incidence angle. The interference experiment of the generated partially coherent DHB passing through double slits is demonstrated. It is found that the coupling efficiency of the MMF, the quality, and the coherence of the generated partially coherent DHB are closely controlled by the coherence of the input beam.


An anti-Wnt5a antibody suppresses metastasis of gastric cancer cells in vivo by inhibiting receptor-mediated endocytosis.
Wnt5a is a representative ligand that activates the β-catenin-independent pathway in Wnt signaling. It was reported that the expression of Wnt5a in human gastric cancer is associated with aggressiveness and poor prognosis and that knockdown of Wnt5a reduces the ability of gastric cancer cells to metastasize in nude mice. Therefore, Wnt5a and its signaling pathway might be important targets for the therapy of gastric cancer. The aim of this study was to examine whether an anti-Wnt5a antibody affects metastasis of gastric cancer cells. One anti-Wnt5a polyclonal antibody (pAb5a-5) inhibited migration and invasion activities in vitro of gastric cancer cells with a high expression level of Wnt5a. Previously, it was shown that Wnt5a induces the internalization of receptors, which is required for Wnt5a-dependent activation of Rac1. pAb5a-5 inhibited Wnt5a-dependent internalization of receptors, thereby suppressed Wnt5a-dependent activation of Rac1. Laminin γ2 is one of target genes of Wnt5a signaling and Rac1 was involved in its expression. pAb5a-5 also inhibited Wnt5a-dependent expression of laminin γ2. In an experimental liver metastasis assay, gastric cancer cells were introduced into the spleens of nude mice. Laminin γ2 was required for liver metastatic ability of gastric cancer cells in vivo. Furthermore, intraperitoneal injection of pAb5a-5 inhibited the metastatic ability of gastric cancer cells. These results suggest that an anti-Wnt5a antibody was capable of suppressing Wnt5a-dependent internalization of receptors, resulting in the prevention of metastasis of gastric cancer cells by inhibiting the activation of Rac1 and the expression of laminin γ2.


Autologous mesenchymal stem cell-derived dopaminergic neurons function in parkinsonian macaques.
A cell-based therapy for the replacement of dopaminergic neurons has been a long-term goal in Parkinson's disease research. Here, we show that autologous engraftment of A9 dopaminergic neuron-like cells induced from mesenchymal stem cells (MSCs) leads to long-term survival of the cells and restoration of motor function in hemiparkinsonian macaques. Differentiated MSCs expressed markers of A9 dopaminergic neurons and released dopamine after depolarization in vitro. The differentiated autologous cells were engrafted in the affected portion of the striatum. Animals that received transplants showed modest and gradual improvements in motor behaviors. Positron emission tomography (PET) using [11C]-CFT, a ligand for the dopamine transporter (DAT), revealed a dramatic increase in DAT expression, with a subsequent exponential decline over a period of 7 months. Kinetic analysis of the PET findings revealed that DAT expression remained above baseline levels for over 7 months. Immunohistochemical evaluations at 9 months consistently demonstrated the existence of cells positive for DAT and other A9 dopaminergic neuron markers in the engrafted striatum. These data suggest that transplantation of differentiated autologous MSCs may represent a safe and effective cell therapy for Parkinson's disease.