A snapshot of physical activity programs targeting Aboriginal and Torres Strait Islander people in Australia.
Issue addressed Participation in physical activity programs can be an effective strategy to reduce chronic disease risk factors and improve broader social outcomes. Health and social outcomes are worse among Aboriginal and Torres Strait Islanders than non-Indigenous Australians, who represent an important group for culturally specific programs. The extent of current practice in physical activity programs is largely unknown. This study identifies such programs targeting this population group and describes their characteristics. Methods Bibliographic and Internet searches and snowball sampling identified eligible programs operating between 2012 and 2015 in Australia (phase 1). Program coordinators were contacted to verify sourced information (phase 2). Descriptive characteristics were documented for each program. Results A total of 110 programs were identified across urban, rural and remote locations within all states and territories. Only 11 programs were located through bibliographic sources; the remainder through Internet searches. The programs aimed to influence physical activity for health or broader social outcomes. Sixty five took place in community settings and most involved multiple sectors such as sport, health and education. Almost all were free for participants and involved Indigenous stakeholders. The majority received Government funding and had commenced within the last decade. More than 20 programs reached over 1000 people each; 14 reached 0-100 participants. Most included process or impact evaluation indicators, typically reflecting their aims. Conclusion This snapshot provides a comprehensive description of current physical activity program provision for Aboriginal and Torres Strait Islander people across Australia. The majority of programs were only identified through the grey literature. Many programs collect evaluation data, yet this is underrepresented in academic literature. So what? Capturing current practice can inform future efforts to increase the impact of physical activity programs to improve health and social indicators. Targeted, culturally relevant programs are essential to reduce levels of disadvantage experienced by Aboriginal and Torres Strait Islanders.


Integrating Mental Health In Care For Noncommunicable Diseases: An Imperative For Person-Centered Care.
Mental disorders such as depression and alcohol use disorders often co-occur with other common noncommunicable diseases such as diabetes and heart disease. Furthermore, noncommunicable diseases are frequently encountered in patients with severe mental disorders such as schizophrenia. The pathways underlying the comorbidity of mental disorders and noncommunicable diseases are complex. For example, mental and physical noncommunicable diseases may have common environmental risk factors such as unhealthy lifestyles, and treatments for one condition may have side effects that increase the risk of another condition. Building on the robust evidence base for effective treatments for a range of mental disorders, there is now a growing evidence base for how such treatments can be integrated into the care of people with noncommunicable diseases. The best-established delivery model is a team approach that features a nonspecialist case manager who coordinates care with primary care physicians and specialists. This approach maximizes efficiencies in person-centered care, which are essential for achieving universal health coverage for both noncommunicable diseases and mental disorders. A number of research gaps remain, but there is sufficient evidence for policy makers to immediately implement measures to integrate mental health and noncommunicable disease care in primary care platforms.


Complex interaction of dendritic connectivity and hierarchical patch size on biodiversity in river-like landscapes.
Habitat fragmentation and land use changes are causing major biodiversity losses. Connectivity of the landscape or environmental conditions alone can shape biodiversity patterns. In nature, however, local habitat characteristics are often intrinsically linked to a specific connectivity. Such a link is evident in riverine ecosystems, where hierarchical dendritic structures command related scaling on habitat capacity. We experimentally disentangled the effect of local habitat capacity (i.e., the patch size) and dendritic connectivity on biodiversity in aquatic microcosm metacommunities by suitably arranging patch sizes within river-like networks. Overall, more connected communities that occupy a central position in the network exhibited higher species richness, irrespective of patch size arrangement. High regional evenness in community composition was found only in landscapes preserving geomorphological scaling properties of patch sizes. In these landscapes, some of the rarer species sustained regionally more abundant populations better tracking their own niche requirements compared to landscapes with homogeneous patch size or landscapes with spatially uncorrelated patch size. Our analysis suggests that altering the natural link between dendritic connectivity and patch size strongly affects community composition and population persistence at multiple scales. The experimental results are demonstrating a principle that can be tested in theoretical metacommunity models and eventually be projected to real riverine ecosystems.


Infection of polarized cultures of human intestinal epithelial cells with hepatitis A virus: vectorial release of progeny virions through apical cellular membranes.
Although hepatitis A virus (HAV) is typically transmitted by the fecal-oral route, little is known of its interactions with cells of the gastrointestinal tract. We studied the replication of HAV in polarized cultures of Caco-2 cells, a human cell line which retains many differentiated functions of small intestinal epithelial cells. Virus uptake was 30- to 40-fold more efficient when the inoculum was placed on the apical rather than the basolateral surface of these cells, suggesting a greater abundance of the cellular receptor for HAV on the apical surface. Infection proceeded without cytopathic effect and did not influence transepithelial resistance or the diffusion of inulin across cell monolayers. Nonetheless, there was extensive release of progeny virus, which occurred almost exclusively into apical supernatant fluids (36.4% +/- 12.5% of the total virus yield compared with 0.23% +/- 0.13% release into basolateral fluids). Brefeldin A caused a profound inhibition of HAV replication, but also selectively reduced apical release of virus. These results indicate that polarized human epithelial cell cultures undergo vectorial infection with HAV and that virus release is largely restricted to the apical membrane. Virus release occurs in the absence of cytopathic effect and may involve cellular vesicular transport mechanisms.


Morphology and phylogenetic position of Spongiochrysis hawaiiensis gen. et sp. nov., the first known terrestrial member of the order Cladophorales (Ulvophyceae, Chlorophyta).
Spongiochrysis hawaiiensis gen. et sp. nov. is described from material collected at two sites on O'ahu, Hawaiian Islands. This alga produced golden-yellow crusts on the bark of Casuarina trees and consisted of globular cells with an axial stellate chloroplast. The only form of reproduction was a specialized type of autosporulation in which a budding-like division of the mother cell produced daughter cells of different sizes. Phylogenetic analyses of the 18S rRNA gene showed that Spongiochrysis hawaiiensis is a member of the freshwater clade of the Cladophorales/Siphonocladales lineage in the green algal class Ulvophyceae. On the basis of its unicellular habit and terrestrial habitat, this species is well differentiated from all other members of the same lineage and can be considered as the first known successful step of a member of the order Cladophorales into terrestrial habitats. The implications of the description of this species with regard to both green algal evolution and conservation of little-known tropical habitats are discussed. The holotype specimen of Spongiochrysis hawaiiensis is GALW015489 and isotype specimens have also been deposited in the BISH and BM herbaria.


Modulation of spontaneous locomotor and respiratory drives to hindlimb motoneurons temporally related to sympathetic drives as revealed by Mayer waves.
In this study we investigated how the networks mediating respiratory and locomotor drives to lumbar motoneurons interact and how this interaction is modulated in relation to periodic variations in blood pressure (Mayer waves). Seven decerebrate cats, under neuromuscular blockade, were used to study central respiratory drive potentials (CRDPs, usually enhanced by added CO2) and spontaneously occurring locomotor drive potentials (LDPs) in hindlimb motoneurons, together with hindlimb and phrenic nerve discharges. In four of the cats both drives and their voltage-dependent amplification were absent or modest, but in the other three, one or other of these drives was common and the voltage-dependent amplification was frequently strong. Moreover, in these three cats the blood pressure showed marked periodic variation (Mayer waves), with a slow rate (periods 9-104 s, mean 39 ± 17 SD). Profound modulation, synchronized with the Mayer waves was seen in the occurrence and/or in the amplification of the CRDPs or LDPs. In one animal, where CRDPs were present in most cells and the amplification was strong, the CRDP consistently triggered sustained plateaux at one phase of the Mayer wave cycle. In the other two animals, LDPs were common, and the occurrence of the locomotor drive was gated by the Mayer wave cycle, sometimes in alternation with the respiratory drive. Other interactions between the two drives involved respiration providing leading events, including co-activation of flexors and extensors during post-inspiration or a locomotor drive gated or sometimes entrained by respiration. We conclude that the respiratory drive in hindlimb motoneurons is transmitted via elements of the locomotor central pattern generator. The rapid modulation related to Mayer waves suggests the existence of a more direct and specific descending modulatory control than has previously been demonstrated.


Prime time for minor subunits of the type II secretion and type IV pilus systems.
The type II secretion system (T2SS) exports folded proteins from the periplasms of Gram-negative bacteria. The type IV pilus system (T4PS) is a multifunctional machine used for adherence, motility and DNA transfer in bacteria and archaea. Partial sequence identity between the two systems suggests that they are related and might function via a similar mechanism, the dynamic assembly and disassembly of pseudopilus (T2SS) or pilus (T4PS) filaments. The major subunit in each system is thought to form the bulk of the (pseudo)pilus, while minor (low-abundance) subunits have proposed roles in assembly initiation, antagonism of disassembly, or modulation of (pseudo)pilus functional properties. In this issue, Cisneros et al. () extend their previous finding that pseudopilus assembly is primed by the minor pseudopilins, showing that the same proteins can initiate assembly of Escherichia coli T4P. Similarly, they show that the E. coli minor pilins prime the polymerization of T2S pseudopili, although unlike genuine pseudopili, the chimeric filaments did not support secretion. This work reinforces the notion of a common assembly mechanism for the T2S and T4P systems.


Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma.
Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non-coding regions. In total, 5 individual MSP assays (located in CCDC177, NXPH1, lnc-MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) also predict overall survival. Furthermore, a robust 58-marker methylation signature predicting overall and event-free survival was established. In conclusion, this study encompasses the largest DNA methylation biomarker study in neuroblastoma so far. We identified and independently validated several novel prognostic biomarkers, as well as a prognostic 58-marker methylation signature.


A 12-Year Experience With Chimney and Periscope Grafts for Treatment of Type I Endoleaks.
To evaluate the midterm outcomes of chimney and/or periscope grafts (CPGs) in patients presenting type I endoleak after a previous endovascular aneurysm repair (EVAR). Between June 2002 and April 2014, 24 consecutive patients (mean age 73.9±9.2 years; 23 men) presenting a type I endoleak were addressed with CPGs to extend the proximal and/or distal landing zone and to maintain side branch perfusion. Indication for treatment was a type Ia endoleak in 23 (96%) patients and a type Ib endoleak in one. Median interval from the previous EVAR to endoleak treatment with CPGs was 52.2±48.9 months (range 0.2-179). All patients had proximal/distal landing zones precluding any standard endovascular reintervention. Measured outcomes included technical success and perioperative mortality and morbidity. Technical success was defined as a procedure completed as intended, with no secondary procedures within 30 days. Midterm outcomes included survival, CPG patency, endoleaks, and freedom from reintervention. Technical success was 96%; a single patient required an additional procedure to seal a recurrent type Ia endoleak. Intraoperative revascularization of all 55 target vessels (2.3/patient) with CPGs was successful. One (4%) patient died within 30 days. Estimated survival at 12, 24, and 36 months was 83%; estimated CPG patency at the same intervals was 94%. Over a mean follow-up of 23.4±29 months, 6 (25%) reinterventions were performed; of these, 4 were secondary to type I endoleak. Aneurysm diameters reduced from 88.3±26 to 85.5±33 mm (p=0.49) over the mean follow-up. The CPG technique is a safe and effective tool for treatment of type I endoleak after previous EVAR. The CPG technique is feasible even in nonelective patients, with excellent outcomes in terms of patency. Close imaging follow-up is warranted to rule out recurrent or de novo endoleaks.


Omega-3 fatty acids and inflammatory processes: from molecules to man.
Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor κB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti-inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance.


Resistance to discontinuing breast cancer screening in older women: A qualitative study.
Screening mammography is associated with reduced breast cancer-specific mortality; however, among older women, evidence suggests that the potential harms of screening may outweigh the benefits. We used a qualitative approach to examine the willingness of older women from different racial/ethnic groups to discontinue breast cancer screening. Women ≥70 years of age who reported having a screening mammogram in the past 3 years and/or reported that they intended to continue screening in the future were recruited for in-depth interviews. Participants who intended to continue screening were asked to describe how the following hypothetical scenarios would impact a decision to discontinue screening: health concerns or limited life expectancy, a physician's recommendation to discontinue, reluctance to undergo treatment, and recommendations from experts or governmental panels to stop screening. Semi-structured, face-to-face interviews were audio-recorded. Data coding and analysis followed inductive and deductive approaches. Regardless of the scenario, participants (n = 29) expressed a strong intention to continue screening. Based on the hypothetical physician recommendations, intentions to continue screening appeared to remain strong. They did not envision a change in their health status that would lead them to discontinue screening and were skeptical of expert/government recommendations. There were no differences observed according to age, race/ethnicity, or education. Among older women who planned to continue screening, intentions to continue breast cancer screening appear to be highly resilient and resistant to recommendations from physicians or expert/government panels.


Γδ T Cell-Based Immunotherapy in Melanoma: State of the Art.
Metastatic melanoma is still associated with a poor prognosis, and there is increasing interest in immunotherapy alone or in combination with other adjuvant therapies. Γδ T lymphocytes play a pivot role in the immune response against cancer, but while γδ-based immunotherapy is already a clinical reality for several solid tumors, data on melanoma are still limited and fragmented. This systematic review presents preclinical and clinical evidence for a role of γδ T lymphocytes in immunotherapeutic strategies for advanced melanoma and discusses research state of the art and future perspectives. Current strategies focus on in vivo stimulation, and ex vivo adoptive therapy and vaccination; results are promising, but further studies are needed to better investigate the interactions in tumoral microenvironment and to improve clinical efficacy of immunotherapeutic protocols.


Postoperative management of pulmonary endarterectomy and outcome.
Pulmonary artery thromboendarterectomy (PTE) has been regarded as a promising, potentially curative surgical procedure. However, PTE is associated with specific postoperative complications, such as reperfusion pulmonary edema and right heart failure leading to a considerable mortality of 7-24%. Despite its limitations PTE is a better surgical alternative to lung transplantation which carries high morbidity and mortality. The aim of the study is to analyze the efficacy, safety, morbidity and survival associated in the postoperative period and quality of life after six months of PTE in Indian patients. Forty-one patients with surgically correctable chronic thromboembolic pulmonary hypertension underwent pulmonary endarterectomy. All patients were in New York Heart Association (NYHA) Class II, III or IV. Preoperative mean pulmonary artery pressure was 40.98 +/- 9.29 mmHg and mean pulmonary vascular resistance was 418.39 +/- 95.88 dynes/sec/cm(-5). All patients were followed up to six months and a telephonic survey was conducted using a standard questionnaire. They were assessed and classified as per NYHA grading. There was a significant reduction in the mean pulmonary artery pressure (from 40.98 +/- 9.29 mmHg to 24.13 +/- 7.36 mmHg, P < 0.001) and pulmonary vascular resistance (from 418.39 +/- 95.88 dynes/sec/cm(-5) to 142.45 +/- 36.27 dynes/sec/cm(-5), P < 0.001) with a concomitant increase in the cardiac index (from 1.99 +/- 0.20 L/min/m 2 to 3.28 +/- 0.56 L/min/m 2 , P < 0.001) during the postoperative period. The mortality rate in our study was 12.19% (five patients). Ninety per cent of the patients reported a significant improvement in the quality of life and exercise tolerance after surgery compared to the preoperative state. Pulmonary endarterectomy is an effective and potentially curative surgical treatment for patients with severe chronic thromboembolic pulmonary hypertension. The current techniques of operation make the procedure relatively safe and long-term survival, NYHA functional status and exercise capacity improve significantly.


Ferroelectric Oxides for Solar Energy Conversion, Multi-Source Energy Harvesting/Sensing, and Opto-Ferroelectric Applications.
Photoferroelectrics belong to a unique material family that exhibits both photovoltaic and ferroelectric effects simultaneously. The photovoltaic effect is the only known direct method of converting light into electricity and is the basis of solar cells. The ferroelectric effect can induce piezoelectric and pyroelectric effects, which are the working principles of widely used kinetic and thermal sensors, transducers, actuators, and energy harvesters. For a long time, photoferroelectric research was restricted to theoretical investigations only because of either the wide band gap (Eg ), which is not able to effectively absorb visible light, or to the weak ferroelectricity caused by a narrow Eg . Recent scientific breakthroughs, however, have opened doors for the development of practical applications. In this article, emerging concepts of creating balanced photovoltaic and ferroelectric properties for photoferroelectrics, as well as those of novel applications in future devices, are presented.


Smooth model surfaces from lignin derivatives. I. Preparation and characterization.
Lignin model surfaces were prepared from aqueous alkaline solutions by spin-coating on silica wafers. Films of thicknesses between 20 and 140 nm were easily made by variations in the spinning rate or in the lignin concentration. The roughnesses of the lignin surfaces were relatively low, approximately 1.1 nm (rms) on an area of 25 microm2, as determined by atomic force microscopy imaging. The stability of the lignin films in aqueous solutions was found to be excellent. No changes in the thickness of model surfaces immersed in slightly alkaline solutions (pH 9.2) could be detected even after 5 h soaking. A 10 percent reduction in the thickness of the lignin film was observed after 5 h of exposure to a solution containing 0.1 M NaCl. This novel preparation method opens great possibilities for further fundamental studies, where interactions between lignin and other substances are of interest to investigate.


Geographic and temporal trends in antimicrobial nonsusceptibility in Streptococcus pneumoniae in the post-vaccine era in the United States.
We examined whether observed increases in antibiotic nonsusceptible nonvaccine serotypes after introduction of pneumococcal conjugate vaccine in the United States in 2000 were driven primarily by vaccine or antibiotic use. Using active surveillance data, we evaluated geographic and temporal differences in serotype distribution and within-serotype differences during 2000-2009. We compared nonsusceptibility to penicillin and erythromycin by geography after standardizing differences across time, place, and serotype by regressing standardized versus crude proportions. A regression slope (RS) approaching zero indicates greater importance of the standardizing factor. Through 2000-2006, geographic differences in nonsusceptibility were better explained by within-serotype prevalence of nonsusceptibility (RS 0.32, 95% confidence interval [CI], .08-.55 for penicillin) than by geographic differences in serotype distribution (RS 0.71, 95% CI, .44-.97). From 2007-2009, serotype distribution differences became more important for penicillin (within-serotype RS 0.52, 95% CI, .11-.93; serotype distribution RS 0.57, 95% CI, .14-1.0). Differential nonsusceptibility, within individual serotypes, accounts for most geographic variation in nonsusceptibility, suggesting selective pressure from antibiotic use, rather than differences in serotype distribution, mainly determines nonsusceptibility patterns. Recent trends suggest geographic differences in serotype distribution may be affecting the prevalence of nonsusceptibility, possibly due to decreases in the number of nonsusceptible serotypes.


Micro-shear bond strengths of adhesive resins to coronal dentin versus the floor of the pulp chamber.
To evaluate the micro-shear bond strengths to superficial coronal dentin and the floor of the pulp chamber using two dentin bonding systems and to compare the ultrastructure of the resin-dentin interface of the two regions. 30 non-carious molars were used to obtain 2 mm thick slabs of coronal dentin and dentin at the pulp chamber. The specimens in each region were divided into three sub-groups to be bonded as follows; Clearfil SE Bond was used according to the manufacturer's instructions, Single Bond was applied to either wet dentin (Blot dry Group) or air-dried dentin (Dry Group) after phosphoric acid etching. A resin composite cylinder 0.5 mm high and 0.75 mm in diameter formed using a vinyl tube was bonded to the dentin. Specimens were stored at 37 degrees C for 24 hours in water and then stressed in shear at a crosshead speed of 1 mm/minute. The data were analyzed with one-way ANOVA and Fisher's PLSD test at the 5% level of significance. In addition, the ultrastructure of cross-sectioned dentin surfaces, the conditioned dentin surface and the resin dentin interfaces were observed by SEM. The bond strengths of Clearfil SE Bond and the Single Bond Blot dry group were approximately 40 MPa in coronal dentin and 30 MPa in the dentin at the floor of the pulp chamber respectively. However, the bond strengths of Single Bond were significantly lower in the Dry condition (MPa) (P < 0.05). SEM observations revealed the thickness of the hybrid layer created by Clearfil SE Bond in coronal dentin and at the floor of the pulp chamber were less than 1.0 microm thick. For Single Bond, a 3-4 microm hybrid layer was created in coronal dentin, while a thinner hybrid layer was observed in the floor of the pulp chamber. Morphological and structural variations in dentin may have influenced the bond strengths of the bonding systems to the floor of the pulp chamber.


Relative risk of mortality after traumatic brain injury: a population-based study of the role of age and injury severity.
To test if observed vs. expected mortality differs by age among traumatic brain injury (TBI) cases, a population-based, historical cohort study was conducted in Olmsted County, Minnesota. From all residents with any diagnosis suggestive of TBI 1985-1999, we randomly sampled 7,800 and reviewed their medical records to confirm the event. Confirmed incident cases were categorized by age in years (<16 = pediatric, 16-65 = adult, > 65 elderly) and severity (moderate/severe vs. mild) and followed for vital status through 6/30/2004. We compared observed 6-month and 10-year mortality with expected and tested if the differences varied by age. Of 1,433 confirmed incident cases, 35% were pediatric; 55% were adult; only 9% were elderly; 11.2% of all cases were moderate/severe; the proportions by increasing age group were 11.4%, 8.5%, 26.7%. The proportions who died within 6 months increased with increasing age group, both for moderate/severe (10.3%, 40.3%, 50.0%) and mild cases (0%, 0%, 9.1%); mortality for moderate/severe cases was nearly 40 times that for mild cases, independent of age. Among 6-month survivors, 10-year mortality differed from expected only for adult cases. For all cases, after adjusting for sex, year of TBI, and severity, the difference between observed and expected 10-year mortality was greater for adult cases than for pediatric cases and similar for adult and elderly cases. Elderly individuals account for <10% of TBI cases and >50% of 10-year mortality, yet much of this discrepancy reflects age-associated mortality in general. Findings have implications for (1) reducing the number of excess deaths following TBI and (2) caring for survivors.


Campylobacter jejuni inhibits the absorptive transport functions of Caco-2 cells and disrupts cellular tight junctions.
Caco-2 cells are models of absorptive enterocytes. The net transport of fluid from apical to basolateral surfaces results in 'domes' forming in differentiated monolayers. Here, the effect of Campylobacter jejuni on this process has been examined. C. jejuni caused no changes in short-circuit current upon infection of Caco-2 cell monolayers in Ussing chambers. Thus, no active secretory events could be demonstrated using this model. It was therefore hypothesized that C. jejuni could inhibit the absorptive function of enterocytes and that this may contribute to diarrhoeal disease. C. jejuni infection of fluid-transporting ('doming') Caco-2 cells resulted in a significant reduction in dome number, which correlated with a decrease in tight junction integrity in infected monolayers, when measured as transepithelial electrical resistance. Defined mutants of C. jejuni also reduced dome numbers in infected monolayers. C. jejuni also altered the distribution of the tight junction protein occludin within cell monolayers. The addition to monolayers of extracellular gentamicin prevented these changes, indicating the contribution of extracellular bacteria to this process. Thus, tight junction integrity is required for fluid transport in Caco-2 cell monolayers as leaky tight junctions cannot maintain support of transported fluid at the basolateral surface of infected cell monolayers. Inhibition of absorptive cell function, changes in epithelial resistance and rearrangement of tight junctional proteins such as occludin represent a potential diarrhoeal mechanism of C. jejuni.


Atrophy, hypometabolism and clinical trajectories in patients with amyloid-negative Alzheimer's disease.
See O'Sullivan and Vann (doi:10.1093/aww166) for a scientific commentary on this article.About 15% of patients clinically diagnosed with Alzheimer's disease do not show high tracer retention on amyloid positon emission tomography imaging. The present study investigates clinical and demographic features, patterns of brain atrophy and hypometabolism and longitudinal clinical trajectories of these patients. Forty amyloid-negative patients carrying a pre-scan diagnosis of Alzheimer's disease dementia from four centres were included (11/29 females/males; mean age = 67 ± 9). Detailed clinical histories, including the clinical diagnoses before and after the amyloid scan and at follow-up, were collected. Patients were classified according to their pre-scan clinical phenotype as amnestic (memory predominant), non-amnestic (predominant language, visuospatial or frontal symptoms), or non-specific (diffuse cognitive deficits). Demographic, clinical, neuropsychological, magnetic resonance imaging and (18)F-fluorodeoxyglucose positon emission tomography data were compared to 27 amyloid-positive typical Alzheimer's disease cases (14/13 females/males; mean age = 71 ± 10) and 29 amyloid-negative controls (15/14 females/males; mean age = 69 ± 12) matched for age, gender and education. There were 21 amnestic, 12 non-amnestic, and seven non-specific amyloid-negative Alzheimer's disease cases. Amyloid-negative subgroups did not differ in age, gender or education. After the amyloid scan, clinicians altered the diagnosis in 68% of amyloid-negative patients including 48% of amnestic versus 94% of non-amnestic and non-specific cases. Amnestic amyloid-negative cases were most often reclassified as frontotemporal dementia, non-amnestic as frontotemporal dementia or corticobasal degeneration, and non-specific as dementia with Lewy bodies or unknown diagnosis. The longer-term clinical follow-up was consistent with the post-scan diagnosis in most cases (90%), including in amnestic amyloid-negative cases whose post-positon emission tomography diagnosis remained Alzheimer's disease. While the non-amnestic and non-specific amyloid-negative cases usually showed patterns of atrophy and hypometabolism suggestive of another degenerative disorder, the amnestic amyloid-negative cases had subtle atrophy and hypometabolism, restricted to the retrosplenial/posterior cingulate cortex. Patients with a negative amyloid positon emission tomography scan following an initial clinical diagnosis of Alzheimer's disease have heterogeneous clinical presentations and neuroimaging profiles; a majority showed a clinical progression that was consistent with a neurodegenerative condition. In contrast, in the subgroup of amnestic amyloid-negative cases, the clinical presentation and follow-up usually remained consistent with Alzheimer's disease. An alternative diagnosis was not made in about half of the amnestic amyloid-negative cases, highlighting the need for a clinical framework and terminology to define these patients, who may have underlying limbic-predominant, non-amyloid-related pathologies.


The Promiscuous sumA Missense Suppressor from Salmonella enterica Has an Intriguing Mechanism of Action.
While most missense suppressors have very narrow specificities and only suppress the allele against which they were isolated, the sumA missense suppressor from Salmonella enterica serovar Typhimurium is a promiscuous or broad-acting missense suppressor that suppresses numerous missense mutants. The sumA missense suppressor was identified as a glyV tRNA Gly3(GAU/C) missense suppressor that can recognize GAU or GAC aspartic acid codons and insert a glycine amino acid instead of aspartic acid. In addition to rescuing missense mutants caused by glycine to aspartic acid changes as expected, sumA could also rescue a number of other missense mutants as well by changing a neighboring (contacting) aspartic acid to glycine, which compensated for the other amino acid change. Thus the ability of sumA to rescue numerous missense mutants was due in part to the large number of glycine codons in genes that can be mutated to an aspartic acid codon and in part to the general tolerability and/or preference for glycine amino acids in proteins. Because the glyV tRNA Gly3(GAU/C) missense suppressor has also been extensively characterized in Escherichia coli as the mutA mutator, we demonstrated that all gain-of-function mutants isolated in a glyV tRNA Gly3(GAU/C) missense suppressor are transferable to a wild-type background and thus the increased mutation rates, which occur in glyV tRNA Gly3(GAU/C) missense suppressors, are not due to the suppression of these mutants.


Positive patch-test reactions to mixed dialkyl thioureas: cross-sectional data from the North American Contact Dermatitis Group, 1994 to 2004.
Allergic contact dermatitis from thioureas is uncommon but may result from exposure to rubber, especially neoprene. To (1) describe the population with positive patch-test reactions to mixed dialkyl thioureas (MDTU) (ie, diethylthiourea and dibutylthiourea); (2) determine clinical and occupational relevance associated with reactions to MDTU and identify the most commonly related sources and occupations; and (3) examine the frequency of co-reacting allergens in MDTU-positive patients. A retrospective analysis of cross-sectional data of 22,025 patients patch-tested by the North American Contact Dermatitis Group between 1994 and 2004. Of 21,898 patients tested with MDTU, 225 (1.0%) had positive reactions; of these, 173 (76.9%) were currently relevant and 29 (17.1%) were occupationally relevant. Patients positive to MDTU were 2.6 times more likely to have foot involvement than patients with positive reactions to other allergens (p < .0001). Footwear was the most commonly identified source overall (20.0%) whereas gloves were the most common occupational source. Of the 173 patients with currently relevant MDTU reactions, 24.9% also reacted to another rubber allergen. Current clinical relevance of reactions to MDTU was high; occupational relevance was less frequent. Patch tests with common rubber allergens (carbamates, thiurams, and mercaptobenzothiazole) may fail to detect many cases of thiourea-induced rubber allergic contact dermatitis.


[Medical education in Taegu (1890-1945)].
In Taegu, the Yaknyongshi was established as early as the 9th year of King Hyojong (1658) of the Chosen Dynasty, and in the 10th year of King Hyojong (1659) the "Tonguibogam" was published as a Yongyongbon edition by the Kyongsang Provincial Government. In fact, it may not be an exaggeration to say that Taegu was the base of the traditional medicine in Korea. In the meantime the general public began to become aware of the importance of Western medicine when Fr. Woodbridge O Johnson of the Northern Presbyerian Church introduced Western medicine by opening the "Miguk Yakpang" (American dispensary) and began to teach Western medicine to Korean youths. At that time, while constructing the Kyong for a war against Russia, Japanese began to establish hospitals in several majar cities and towns along the railway line and mobilized Tonginhae doctors. However, those medical facilities were solely for the benefit of Japanese people residing in Korea and had nothing to do with ordinary Koreans. The attached medical school of the Taegu Tonginuiwon failed, contrary to expectation, to turn out even a single Korean medical doctor. This hospital was later reorganized into Taegu Chahyeuiwon and was soon closed according to the policy of educational unification of the Government General Korea. ...


Spatial spectrum analysis of wave-front correction with a segmented mirror.
An expression is derived for the spatial power spectrum of wave-front errors after correction with a segmented mirror. This includes estimates of the spectral contributions of segment piston and tilt corrections and spatial aliasing by a regular array of segments. The approach allows rapid computation of wave-front error spectra in systems with highly segmented mirrors.


Motivational Climate Profiles, Pubertal Status, and Well-Being Among Female Adolescent Aesthetic Sport Athletes.
Girls participating in aesthetic sports may be at risk for disordered eating and low self-esteem. Informed by self-determination theory, the authors examined motivational climate profiles to understand how climate dimensions differentially relate to psychological needs satisfaction, self-esteem, and disordered eating. Female gymnasts, divers, and figure skaters (N = 183; mean age = 13.5) completed a survey to assess perceptions of the motivational climate, perceived sport competence, autonomy, relatedness, self-esteem, and dieting. Pubertal status was assessed to control for developmental differences. Three profiles emerged: High Important Role/Low Performance, High Effort and Cooperation/High Rivalry, and Low Mastery/High Unequal Recognition and Punishment. A 3 × 2 multivariate analysis of variance revealed profile groups significantly differed on perceived autonomy, coach relatedness, and teammate relatedness. In addition, perceived competence, self-esteem, and dieting significantly differed by pubertal status. For autonomy, the High Important Role/Low Performance group reported the highest scores. For coach and teammate relatedness, the Low Mastery/High Unequal Recognition and Punishment group reported significantly lower scores than the other 2 groups. Postpubertal girls reported lower sport ability and self-esteem and greater dieting. Physical maturity and social context were important in explaining girls' psychological needs satisfaction and well-being. Results add to the authors' understanding of the complex nature and influence of the motivational climate.


AML-1A and AML-1B regulation of MIP-1alpha expression in multiple myeloma.
Macrophage inflammatory protein-1alpha (MIP-1alpha) is produced in high concentration by multiple myeloma (MM) cells in about 70% of patients, and MIP-1alpha levels correlate with their disease activity. Patients who have high levels of MIP-1alpha have a poor prognosis. Furthermore, blocking MIP-1alpha expression in an in vivo model of human MM profoundly decreases both tumor burden and bone destruction, suggesting that MIP-1alpha is an important mediator of MM bone disease. Therefore, to analyze the regulation of MIP-1alpha production in MM, we cloned the human MIP-1alpha promoter and characterized the transcription factor (TF) motifs that control MIP-1alpha expression in MM cells. The proximal region of MIP-1alpha promoter was composed of 2 sets of identical transcription regulatory regions consisting of GATA-2(+) AML-1(+) C/EBPalpha motifs. Since 2 alternatively spliced variants of the acute myeloid leukemia-1 (AML-1) class of TFs can bind the AML-1 region, AML-1A and AML-1B, the relationship between the expression levels of AML-1A or AML-1B in MM cells and their capacity to express MIP-1alpha was examined. AML-1A mRNA was relatively overexpressed compared with AML-1B in MM cell lines that produced high levels of MIP-1alpha (> 1 ng/mL per 10(6) cells per 72 hours), but AML-1A was not increased in MM cell lines that expressed less than 200 pg/mL MIP-1alpha. More importantly, the ratio of AML-1A to AML-1B mRNA levels was also increased in 3 of 3 highly purified myeloma cells from patients with MM who expressed increased amounts of MIP-1alpha. The ratio of AML-1A to AML-1B mRNA in patients with MM was 8-fold higher than in healthy controls. Transduction of AML-1B into the MM-derived MM.1S and ARH-77 cells totally blocked MIP-1alpha production, while AML-1A did not further increase the already high levels of MIP-1alpha produced by these cells. Taken together, these data demonstrate that in patients with MM who produce increased concentrations of MIP-1alpha, the relative level of AML-1B is significantly decreased compared with healthy controls. The data suggest that strategies that enhance AML-1B expression or decrease AML-1A in MM cells may be beneficial therapeutically.


Comparison of inhibitory and binding characteristics of an antibody causing acquired von Willebrand syndrome: an assay for von Willebrand factor binding by antibody.
An acquired inhibitor of von Willebrand factor (vWF) activity occurring in a patient with benign gammopathy and von Willebrand syndrome (vWS) has been partially characterized. The inhibitor-induced syndrome resulted in low to undetectable plasma levels of vWF/ristocetin, vWF/botrocetin, FVIIIR:Ag, and FVIII:C with a normal to slightly prolonged bleeding time. Platelet vWF was normal. Intensive and continuous infusion of a heat-treated factor VIII concentrate (Hemofil-T, Hyland, Glendale, Calif) elevated the FVIII:C plasma levels to about 100%, with an increase in FVIIIR:Ag levels to about 340% and vWF/ristocetin levels to about 40%, much lower than expected based on the dose of Hemofil-T and its content of vWF and FVIII:C activities. The inhibitor bound to staphylococcal protein A (SpA) with high affinity, indicating an IgG antibody (Ab). An assay for the vWF-binding capacity was developed on the basis of absorption of the Ab from serially diluted plasma by SpA and removal of vWF and FVIII:C activities from normal plasma by the SpA-Ab complex. The Ab-binding site was on the vWF component of the factor VIII complex. The Ab was unable to bind isolated FVIII:C. The combined use of the new vWF-binding assay and a battery of tests for inhibition of vWF-dependent platelet aggregation with ristocetin (which detects high molecular weight vWF), with botrocetin (which detects high and low molecular weight vWF), and with platelet-aggregating factor (which detects high molecular weight vWF) provided a means of analysis of Ab effect on in vitro vWF function. Using these tests, a comparison was made of the effects of the vWS Ab with those of an Ab inhibitor occurring in homozygous von Willebrand's disease. The Ab of the vWS patient had weak inhibitory action on vWF/ristocetin without having an effect on vWF/botrocetin and platelet-aggregating factor, a high titer vWF-binding capacity, and no anamnestic response following concentrate therapy. These findings contrasted with those of the Ab occurring in inhibitor von Willebrand's disease in which vWF inhibitor and binding values were similar, with a strong anamnestic response. The findings indicate that the vWS Ab binds to an epitope on the molecular vWF in such a way that causes only limited inhibition of vWF/ristocetin function and no inhibition of vWF/botrocetin function, suggesting that these two functional domains are at separate sites.


Re-Thinking Anxiety: Using Inoculation Messages to Reduce and Reinterpret Public Speaking Fears.
Inoculation theory offers a framework for protecting individuals against challenges to an existing attitude, belief, or state. Despite the prevalence and damaging effects of public speaking anxiety, inoculation strategies have yet to be used to help individuals remain calm before and during public speaking. We aimed to test the effectiveness of an inoculation message for reducing the onset of public speaking anxiety, and helping presenters interpret their speech-related anxiety more positively. Participants (Mage = 20.14, SD = 2.72) received either an inoculation (n = 102) or control (n = 128) message prior to engaging a public speaking task and reported a range of anxiety-related perceptions. Accounting for personality characteristics and perceptions of task importance, and relative to control participants, those who received the inoculation message reported significantly lower pre-task anxiety, and following the task, reported that they had experienced lower somatic anxiety, and that the inoculation message had caused them to view their nerves in a less debilitating light. Inoculation messages may be an effective strategy for helping participants reframe and reduce their apprehension about public speaking, and investigating their efficacy in other stress-inducing contexts may be worthwhile.


Hysteroscopic myomectomy: our experience and review.
To analyze the results of hysteroscopic myomectomy in our center and to compare the results to those published in the literature. We performed a retrospective study of the clinical histories of patients who had undergone hysteroscopic myomectomy with a resectoscope between January 1992 and December 1999. Procedures were performed at a hysteroscopic clinic in the Department of Obstetrics and Gynecology at the University Public Hospital in Madrid's south zone. One hundred twenty pre-, peri-, and postmenopausal women with submucous myomas were included in the study. All patients underwent hysteroscopic resection with a monopolar loop. We performed 120 hysteroscopic myomectomies. The patients' median age was 44.8 years (23 to 74). Abnormal uterine bleeding (AUB) was the most frequent indication (84.1%). Inability to reproduce was the indication in 14 (11.6%) cases. GnRH analogue preparation was used in 60% of cases. We operated on 52 (43.3%) type 0, 51 (42.5%) type I, and 17 (14.1%) type II myomas, according to Wamsteker and Blok classification. A median of 32.5 (10 to 105) minutes was required for the interventions. The myomectomy was combined with another operation (12 polypectomies, 24 endometrial resections, and 1 laparoscopic ovarian cystectomy) in 32 patients. The median retention of glycemia was 281 cc (0 to 1300). We could not complete the resection in 22 patients. Twelve underwent reoperation (3 hysterectomies and 9 second myomectomies). No serious complications occurred, and the median hospital stay was 25.4 hours. The histological study confirmed leiomyoma in all the cases. The intervention results were satisfactory after a follow-up period of 12 months to 7 years, AUB being controlled in 88.5% of the patients. Hysteroscopic myomectomy is a reliable procedure that is effective in controlling abnormal uterine bleeding. It is a good alternative to hysterectomy and has an acceptable surgical time and minimum hospital stay. To reduce the need of reintervention, appropriate patient selection and improved technique are necessary. The technique also offers significant economic savings compared with the conventional surgical methods.


Risk and uncertainty: shifting decision making for aneuploidy screening to the first trimester of pregnancy.
The clinical introduction of first trimester aneuploidy screening uniquely challenges the informed consent process for both patients and providers. This study investigated key aspects of the decision-making process for this new form of prenatal genetic screening. Qualitative data were collected by nine focus groups that comprised women of different reproductive histories (N = 46 participants). Discussions explored themes regarding patient decision making for first trimester aneuploidy screening. Sessions were audio recorded, transcribed, coded, and analyzed to identify themes. Multiple levels of uncertainty characterize the decision-making process for first trimester aneuploidy screening. Baseline levels of uncertainty existed for participants in the context of an early pregnancy and the debate about the benefit of fetal genetic testing in general. Additional sources of uncertainty during the decision-making process were generated from weighing the advantages and disadvantages of initiating screening in the first trimester as opposed to waiting until the second. Questions of the quality and quantity of information and the perceived benefit of earlier access to fetal information were leading themes. Barriers to access prenatal care in early pregnancy presented participants with additional concerns about the ability to make informed decisions about prenatal genetic testing. The option of the first trimester aneuploidy screening test in early pregnancy generates decision-making uncertainty that can interfere with the informed consent process. Mechanisms must be developed to facilitate informed decision making for this new form of prenatal genetic screening.


From Detection of Individual Metastases to Classification of Lymph Node Status at the Patient Level: The CAMELYON17 Challenge.
Automated detection of cancer metastases in lymph nodes has the potential to improve the assessment of prognosis for patients. To enable fair comparison between the algorithms for this purpose, we set up the CAMELYON17 challenge in conjunction with the IEEE International Symposium on Biomedical Imaging 2017 Conference in Melbourne. Over 300 participants registered on the challenge website, of which 23 teams submitted a total of 37 algorithms before the initial deadline. Participants were provided with 899 whole-slide images (WSIs) for developing their algorithms. The developed algorithms were evaluated based on the test set encompassing 100 patients and 500 WSIs. The evaluation metric used was a quadratic weighted Cohen's kappa. We discuss the algorithmic details of the 10 best pre-conference and two post-conference submissions. All these participants used convolutional neural networks in combination with pre- and postprocessing steps. Algorithms differed mostly in neural network architecture, training strategy, and pre- and postprocessing methodology. Overall, the kappa metric ranged from 0.89 to -0.13 across all submissions. The best results were obtained with pre-trained architectures such as ResNet. Confusion matrix analysis revealed that all participants struggled with reliably identifying isolated tumor cells, the smallest type of metastasis, with detection rates below 40%. Qualitative inspection of the results of the top participants showed categories of false positives, such as nerves or contamination, which could be targeted for further optimization. Last, we show that simple combinations of the top algorithms result in higher kappa metric values than any algorithm individually, with 0.93 for the best combination.


Climate influences parasite-mediated competitive release.
Parasitism is believed to play an important role in maintaining species diversity, for instance by facilitating coexistence between competing host species. However, the possibility that environmental factors may govern the outcome of parasite-mediated competition has rarely been considered. The closely related amphipods Corophium volutator and Corophium arenarium both serve as second intermediate host for detrimental trematodes. Corophium volutator is the superior competitor of the two, but also suffers from higher mortality when exposed to infective trematode stages. Here, we report parasite-mediated competitive release of C. arenarium in an intertidal habitat, in part triggered by unusually high temperatures linked to the North Atlantic climate oscillation (NAO). The elevated temperatures accelerated the transmission of cercariae from sympatric first intermediate hosts (mud snails) to amphipods, causing a local collapse of the parasite-sensitive C. volutator population and concordant increase in the abundance of the competitively inferior C. arenarium.


Transcriptional response of Musca domestica larvae to bacterial infection.
The house fly Musca domestica, a cosmopolitan dipteran insect, is a significant vector for human and animal bacterial pathogens, but little is known about its immune response to these pathogens. To address this issue, we inoculated the larvae with a mixture of Escherichia coli and Staphylococcus aureus and profiled the transcriptome 6, 24, and 48 h thereafter. Many genes known to controlling innate immunity in insects were induced following infection, including genes encoding pattern recognition proteins (PGRPs), various components of the Toll and IMD signaling pathways and of the proPO-activating and redox systems, and multiple antimicrobial peptides. Interestingly, we also uncovered a large set of novel immune response genes including two broad-spectrum antimicrobial peptides (muscin and domesticin), which might have evolved to adapt to house-fly's unique ecological environments. Finally, genes mediating oxidative phosphorylation were repressed at 48 h post-infection, suggesting disruption of energy homeostasis and mitochondrial function at the late stages of infection. Collectively, our data reveal dynamic changes in gene expression following bacterial infection in the house fly, paving the way for future in-depth analysis of M. domestica's immune system.


Risk factors for perineal wound complications following abdominoperineal resection.
Perineal wound complications are common following abdominoperineal resection. This study investigates the factors contributing to these complications. Patients undergoing abdominoperineal resection at our institution from June 1997 to May 2003 were reviewed. Significant predictors associated with minor (separation <2 cm, stitch abscesses, or sinus tracts) or major (>2 cm of separation, reoperation required, or readmission) wound complications were ascertained. Of 153 patients, there were 22 major (14 percent) and 32 minor (24 percent) wound complications. Patients with anal cancer had a higher rate of major complications than those with rectal cancer or inflammatory bowel disease. Minor wound complications were more common in patients with anal cancer and inflammatory bowel disease than those with rectal cancer. Factors associated with a higher rate of major wound complications included flap closure, tumor size, body mass index, diabetes, and indication for the procedure. When the subset of patients with rectal cancer was considered, higher rates of major wounds were associated with increased body mass index, diabetes, and stage. Minor complications were associated with a two-team approach and increasing body mass index. This is currently the largest review of perineal wound complications following abdominoperineal resection. Patients with anal cancer and inflammatory bowel disease were at higher risk for perineal wound complications than those with rectal cancer. Preoperative radiation and primary closure were not associated with increased complications following abdominoperineal resection for rectal cancer.


Observation of non-odd order harmonics by sub-2-cycle laser pulses.
High order harmonics generation from argon gas was comprehensively investigated by using multi-cycle and few-cycle laser pulses. Non-odd order harmonics were observed for sub-5-fs pulses, compare to the normal odd-order harmonics in the multi-cycle case. Theoretic analysis shows that the new spectral structure origins from the asymmetry of laser field in few-cycle pulses. This asymmetry induced both amplitude and phase difference between attosecond pulses from consecutive half-cycle of the laser field, which change the interference property of attosecond pulses and result in complex spectrum.


Prehospital resuscitation practices: a survey of prehospital providers.
Numerous factors affect decision making in the prehospital provision of resuscitative care. This study was undertaken to determine current practices involved in the initiation, continuation and termination of resuscitative efforts, and the impact of advance directives, in the prehospital resuscitation setting. This cross-sectional mailed questionnaire surveyed 3807 members of the National Association of Emergency Medical Technicians. The study instrument included questions regarding the termination and withholding of resuscitative efforts in the prehospital setting, as well as survival rates, local protocols and compliance with advance directives. Of 1546 respondents (41% response rate), with a mean 9.0 years of experience, most (89%) indicated that they would withhold resuscitative efforts in the presence of an official state-approved advance directive. However, very few providers would withhold resuscitative efforts if only an unofficial document (4%) or verbal report of an advance directive (10%) were available. Providers with more than 10 years experience were more likely to withhold resuscitation attempts in the presence of only a verbal report of an advance directive (p = 0.02, Chi-square), and were more likely to withhold resuscitation attempts in situations they considered futile (p = 0.001, Chi-square). Most (77%) respondents have local EMS guidelines for termination of resuscitation in the prehospital setting, but 23% of those consider existing guidelines to be inadequate. The majority of prehospital providers stated that they honor official state-approved advance directives, but do not follow directives from unofficial documents or verbal reports of advance directives. More experienced providers stated that they withhold resuscitative efforts more often in futile situations, or in the presence of unofficial advance directives. Advance directives should be utilized more uniformly among patients who wish to forgo resuscitative efforts in the event of cardiac arrest. Because many local protocols are judged to be inadequate, we support the institution of improved clinical guidelines regarding the prehospital termination of resuscitative efforts.


Channels of change: contrasting network mechanisms in the use of interventions.
This study informs community science, and seeks to narrow the research-to-practice gap, by examining how the interpersonal networks within a setting influence individuals' use of interventions. More specifically, it explores the role of two network mechanisms-cohesion and structural similarity-in urban elementary school teachers' use of interventions designed to improve academic and behavioral outcomes for students. Lagged regression models examine how position in advice giving networks influenced weekly use of the daily report card and peer assisted learning by kindergarten through fourth grade teachers in three schools. Results indicate that intervention use spreads among teachers with similar patterns of advice-giving relationships (i.e., via structural similarity), rather than from teachers who are sources of advice (i.e., via cohesion). These results are consistent with findings in other settings, and suggest that researchers wishing to increase the use of an intervention should select change agents based on their patterns of their relationships, rather than on their direct connections.


Hepatic high-density lipoprotein receptors: roles in lipoprotein metabolism and potential for therapeutic modulation.
High-density lipoprotein (HDL) plays an important role in protection against atherosclerosis. A major part of HDL's antiatherogenic role is through mediating reverse cholesterol transport from peripheral cells, such as macrophages and other cells in the artery wall, to the liver. Hepatic HDL receptors should, therefore, play an important role in either mediating or modulating HDL-dependent reverse cholesterol transport. The scavenger receptor class B type I (SR-BI) was first identified as a hepatic HDL receptor almost 10 years ago and is well characterized at the molecular level. This review highlights recent studies that provide insight into the cellular pathways involved in SR-BI-mediated lipid transfer between bound lipoproteins and cells, supports a role for this receptor in reverse cholesterol transport and protection against experimental atherosclerosis in mice, and explores the consequences of sequence variations in the gene encoding SR-BI in humans.


Active inflammation increases the heterogeneity of MRI texture in mice with relapsing experimental allergic encephalomyelitis.
Inflammation modulates tissue damage in relapsing-remitting multiple sclerosis (MS) both acutely and chronically, but its severity is difficult to evaluate with conventional MRI analysis. In mice with experimental allergic encephalomyelitis (EAE, a model of MS), we administered ultra small particles of iron oxide to track macrophage-mediated inflammation during the onset (relapse) and recovery (remission) of disease activity using high field MRI. We performed MRI texture analysis, a sensitive measure of tissue regularity, and T2 assessment both in EAE lesions and the control tissue, and measured spinal cord volume. We found that inflammation was 3 times more remarkable at onset than at recovery of EAE in histology yet demyelination appeared similar across animals and disease course. In MRI, lesion texture was more heterogeneous; T2 was lower; and spinal cord volume was greater in EAE than in controls, but only MRI texture was worse at relapse than at remission of EAE. Moreover, MRI texture correlated with spinal cord volume and tended to correlate with the extent of disability in EAE. While subject to further confirmation, our findings may suggest the sensitivity of MRI texture analysis for accessing inflammation.


Implementation of EU discharge guidelines at IVAR's Regional Wastewater Treatment Plant of North Jaeren, Stavanger, Norway.
Norway is a leading country on wastewater treatment comprising chemical precipitation processes. This is because Norwegian effluent standards to the North Sea have traditionally focused on phosphorus removal. In most cases, chemical treatment therefore has been considered to give lower investment and operating costs than biological treatment. Norwegian wastewater policy and management is based on the EU guidelines resulting from the EEA (European Economic Area) Agreement. According to the 1991 Urban Wastewater Treatment Directive, this will in most cases require secondary treatment. However, primary treatment can be accepted for plants larger than 10,000 PT with effluents to less sensitive coastal areas, if no negative environmental impacts can be proved. The main objective of the Regional Water, Sewerage and Waste Company (IVAR) is to comply with the prevailing effluent limits at lowest possible cost. During the past four years, IVAR has therefore undertaken comprehensive optimising of the precipitation process including full-scale experiments with different coagulant dosing control systems and different types of coagulants. IVAR also accomplished a feasibility study of introducing biological treatment as an alternative to chemical treatment. Under the prevailing frame conditions of discharge requirements and sludge deposit costs, it is not economically feasible to change to organic coagulants or biological treatment. This conclusion might have to be altered resulting from the implementation of new EU regulations and increasing sludge deposit costs. This paper presents results from full-scale experiments, extracts from the feasibility study and a comparison of costs. Furthermore, the practical consequences of implementing the EU-guidelines are discussed.


Deletion of P58(IPK), the Cellular Inhibitor of the Protein Kinases PKR and PERK, Causes Bone Changes and Joint Degeneration in Mice.
Protein kinase-like endoplasmic reticulum kinase (PERK) and protein kinase R (PKR) are implicated in endoplasmic reticulum stress-induced arthritis and pro-inflammatory cytokine-mediated cartilage degradation in vitro, respectively. We determined whether knockout of the cellular inhibitor of PERK and PKR, P58(IPK) causes joint degeneration in vivo and whether these molecules are activated in human osteoarthritis (OA). Sections of knee joints from P58(IPK)-null and wild-type mice aged 12-13 and 23-25 months were stained with toluidine blue and scored for degeneration using the osteoarthritis research society international (OARSI) system. Bone changes were assessed by radiology and high-resolution micro-computed tomography of hind limbs. Sections from the medial tibial plateaus of two human knees, removed in total knee replacement surgery for OA, were immunolabelled for phosphorylated PERK and PKR and P58(IPK). Knockout mice exhibited narrower tibiae (p = 0.0031) and smaller epiphyses in tibiae (p = 0.0004) and femora (p = 0.0214). Older knockout mice had reduced total volume inside the femoral periosteal envelope (p = 0.023), reduced tibial (p = 0.03), and femoral (p = 0.0012) bone volumes (BV) and reduced femoral BV fraction (p = 0.025). Compared with wild-types, younger P58(IPK)-null mice had increased OARSI scores in medial femoral condyles (p = 0.035). Thirty four percent of null mice displayed severe joint degeneration with complete articular cartilage loss from the medial compartment and heterotopic chondro-osseous tissue in the medial joint capsule. Phosphorylated PERK and PKR were localized throughout human osteoarthritic tibial plateaus but, in particular, in areas exhibiting the most degeneration. There was limited expression of P58(IPK). This study is the first to reveal a critical role for P58(IPK) in maintaining joint integrity in vivo, implicating the PKR and PERK stress signaling pathways in bony changes underlying the pathogenesis of joint degeneration.


Relevance to self: A brief review and framework of neural systems underlying appraisal.
We argue that many similar findings observed in cognitive, affective, and social neuroimaging research may compose larger processes central to generating self-relevance. In support of this, recent findings from these research domains were reviewed to identify common systemic activation patterns. Superimposition of these patterns revealed evidence for large-scale supramodal processes, which are argued to mediate appraisal of self-relevant content irrespective of specific stimulus types (e.g. words, pictures) and task domains (e.g. induction of reward, fear, pain, etc.). Furthermore, we distinguish between two top-down sub-systems involved in appraisal of self-relevance, one that orients pre-attentive biasing information (e.g. anticipatory or mnemonic) to salient or explicitly self-relevant phenomena, and another that engages introspective processes (e.g. self-reflection, evaluation, recollection) either in conjunction with or independent of the former system. Based on aggregate patterns of activation derived from the reviewed studies, processes in a ventral medial prefrontal cortex (MPFC)-subcortical network appear to track with the former pathway, and processes in a dorsal MPFC-cortical-subcortical network with the latter. As a whole, the purpose of this framework is to re-conceive the functionality of these systems in terms of supramodal processes that more directly reflect the influences of relevance to the self.


The therapeutic potential of CXC chemokine blockade in acute inflammation in the brain.
Mammalian neurones of the central nervous system (CNS) are terminally differentiated, and there is little endogenous capacity of the CNS to repair itself. Peripheral tissue injury, disease or infection results in a stereotypical inflammatory response to protect the host from pathogens and to promote tissue repair. However, collateral or 'bystander' damage is characteristic of any inflammatory response. Thus, it is apparent that the CNS has evolved mechanisms to regulate tightly the acute inflammatory response, and in particular to restrict the recruitment of neutrophils, in an attempt to protect itself from the potentially damaging consequences of inflammation in the brain. However, neutrophils are not always excluded from the brain. Indeed, they are found in large numbers in the brain parenchyma following traumatic lesions, stroke lesions, and in rodents, during the 'window of susceptibility'. Therapy targeted at blocking excitotoxic cell death has not successfully transferred from rodent models of stroke to human stroke patients. Restricting leukocyte entry to the brain, thereby inhibiting the inflammatory response, may prove to be a more practical therapeutic approach. The evidence presented in this review suggests that antagonising the effects of CXC chemokines may represent one route to achieve this goal.


Cytogenetic heterogeneity and their serial dynamic changes during acquisition of cytogenetic aberrations in cultured mesenchymal stem cells.
To minimize the risk of tumorigenesis in mesenchymal stem cells (MSCs), G-banding analysis is widely used to detect chromosomal aberrations in MSCs. However, a critical limitation of G-banding is that it only reflects the status of metaphase cells, which can represent as few as 0.01% of tested cells. During routine cytogenetic testing in MSCs, we often detect chromosomal aberrations in minor cell populations. Therefore, we aimed to investigate whether such a minority of cells can expand over time or if they ultimately disappear during MSC passaging. We passaged MSCs serially while monitoring quantitative changes for each aberrant clone among heterogeneous MSCs. To investigate the cytogenetic status of interphase cells, which represent the main population, we also performed interphase FISH analysis, in combination with G-banding and telomere length determination. In human adipose tissue-derived MSCs, 4 types of chromosomal aberrations were found during culturing, and in umbilical cord MSCs, 2 types of chromosomal aberrations were observed. Sequential dynamic changes among heterogeneous aberrant clones during passaging were similar to the dynamic changes observed in cancer stem cells during disease progression. Throughout all passages, the quantitative G-banding results were inconsistent with those of the interphase FISH analysis. Interphase FISH revealed hidden aberrations in stem cell populations with normal karyotypes by G-banding analysis. We found that telomere length gradually decreased during passaging until the point at which cytogenetic aberrations appeared. The present study demonstrates that rare aberrant clones at earlier passages can become predominant clones during later passages. Considering the risk of tumorigenesis due to aberrant MSCs, we believe that our results will help to establish proper safety guidelines for MSC use. In particular, we believe it is critical to test for chromosomal aberrations using both G-banding and FISH to ensure the safety of human stem cells that are manufactured in vitro for clinical applications.


Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6.
Individuals with subtotal complement C6 deficiency possess a C6 molecule that is 14% shorter than normal C6 and present in low but detectable concentrations (1-2% of the normal mean). We now show that this dysmorphic C6 is bactericidally active and lacks an epitope that was mapped to the most carboxy-terminal part of C6 using C6 cDNA fragments expressed as fusion proteins in the pUEX expression system. We thus predicted that the abnormal C6 molecule might be carboxy-terminally truncated and sought a mutation in an area approximately 14% from the carboxy-terminal end of the coding sequence. By sequencing PCR-amplified products from this region, we found, in three individuals from two families, a mutation that might plausibly be responsible for the defect. All three have an abnormal 5' splice donor site of intron 15, which would probably prevent splicing. An in-frame stop codon is found 17 codons downstream from the intron boundary, which would lead to a truncated polypeptide 13.5% smaller than normal C6. This result was unexpected, as earlier studies mapped the C5b binding site, or a putative enzymatic region, to this part of C6. Interestingly, all three subjects were probably heterozygous for both subtotal C6 and complete C6 deficiency.


The Role of Autonomous and Controlled Motivation in Exercise Intentions of Participants in a Mass Cycling Event.
Purpose: This study used self-determination theory to examine the role of participants' autonomous and controlled motivation to exercise and to participate in a challenging mass cycling event and investigated whether the event enhanced intended and actual exercise behavior among the participants. Method: Two hundred and twenty-eight subjects, having participated in the cycling event, completed a questionnaire shortly after the event and again 4 months later. The questionnaire measured self-reported cycling and exercise activity, training in preparation of the event, motivation to participate in the event, motivation to exercise, and future exercise intentions due to the event. Results: Results showed that most participants were very active in cycling and other sports. The expected positive effect of autonomous motivation on exercise intentions and behavior could not be confirmed in our study. Multiple regression analyses revealed that the event had an enhancing effect on exercise intentions shortly after the event among participants that scored higher on controlled motivation to exercise (β = 0.15) and to participate (β = 0.15); also, participants were more satisfied with the event (β = 0.19) and had followed a preparation program before the event (β = 0.15). However, intentions and exercise behavior distinctively dropped 4 months after the event. Conclusions: Events aiming to enhance their participants' exercise behavior need to attract less active participants and need to make additional efforts to prevent relapse in intentions and exercise behavior.


Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors.
CD4+ type 1 T regulatory (Tr1) cells have a crucial role in inducing tolerance. Immune regulation by these cells is mainly mediated through the secretion of high amounts of IL-10. Several studies have suggested that this regulatory population may be involved in tumor-mediated immune-suppression. However, direct evidence of a role for Tr1 cells in human solid tumors is lacking. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC; n = 39) or liver metastases from colorectal cancer (LM-CRC; n = 60) we identify a CD4+FoxP3-IL-13-IL-10+ T cell population in tumors of individuals with primary or secondary liver cancer that is characterized as Tr1 cells by the expression of CD49b and the lymphocyte activation gene 3 (LAG-3) and strong suppression activity of T cell responses in an IL-10 dependent manner. Importantly, the presence of tumor-infiltrating Tr1 cells is correlated with tumor infiltration of plasmacytoid dendritic cells (pDCs). pDCs exposed to tumor-derived factors enhance IL-10 production by Tr1 cells through up-regulation of the inducible co-stimulatory ligand (ICOS-L). These findings suggest a role for pDCs and ICOS-L in promoting intra-tumoral immunosuppression by Tr1 cells in human liver cancer, which may foster tumor progression and which might interfere with attempts of immunotherapeutic intervention.


Enhanced plasmid DNA utilization in transiently transfected CHO-DG44 cells in the presence of polar solvents.
Although the protein yields from transient gene expression (TGE) with Chinese hamster ovary (CHO) cells have recently improved, the amount of plasmid DNA (pDNA) needed for transfection remains relatively high. We describe a strategy to reduce the pDNA amount by transfecting CHO-DG44 cells with 0.06 μg pDNA/10(6) cells (10% of the optimal amount) in the presence of nonspecific (filler) DNA and various polar solvents including dimethylsufoxide, dimethyl formamide, acetonitrile, dimethyl acetamide (DMA), and hexamethyl phosphoramide (HMP). All of the polar solvents with the exception of HMP increased the production of a recombinant antibody in comparison to the untreated control transfection. In the presence of 0.25% DMA, the antibody yield in a 7-day batch culture was 500 mg/L. This was fourfold higher than the yield from the untreated control transfection. Mechanistic studies revealed that the polar solvents did not affect polyethylenimine-mediated pDNA delivery into cells or nuclei. The steady-state transgene mRNA level was elevated in the presence of each of the polar solvents tested, while the transgene mRNA half-life remained the same. These results indicated that the polar solvents enhanced transgene transcription. When screening a panel of recombinant antibodies and Fc-fusion proteins for production in the presence of the polar solvents, the highest increase in yield was observed following DMA addition for 11 of the 12 proteins. These results are expected to enhance the applicability of high-yielding TGE processes with CHO-DG44 cells by decreasing the amount of pDNA required for transfection.


Skin involvement in systemic sclerosis.
Skin thickening is a characteristic feature of SSc. More extensive skin involvement coincides with more severe internal organ manifestation(s), poor prognosis and increased disability, at least in the early phase of the diffuse cutaneous scleroderma subset. The fully validated, feasible method ('gold standard') for measuring the dermal skin thickness is the modified Rodnan skin score (mRSS). The responsiveness of mRSS was somewhat modest in clinical trials, and a careful teaching process is necessary. Parallel method(s) for measuring skin thickness need to be used in the future. Ultrasound (US) measurement of the dermis with a 20-30 MHz probe is a valid, reproducible and responsive method in patients with dcSSc. However, US is time-consuming and requires a training process. Of the mechanical instruments available, only the durometer, which measures the hardness of skin, has been validated. The inter- and intra-observer reproducibility and sensitivity to change of durometry were good, and correlated with mRSS and US-measured skin thickness. Several further mechanical instruments exist including the elastometer, twistometer, cutometer and plicometer. They seem to distinguish between involved and non-involved skin, and therefore merit further evaluation. The measurement of late-stage, irreversible skin damage/atrophy should be resolved in the future through the development and validation of new instruments.


Anti-proliferation effect of 5,5-diphenyl-2-thiohydantoin (DPTH) in human vascular endothelial cells.
The aim of this study was to examine the anti-proliferation effect of 5,5-diphenyl-2-thiohydantoin (DPTH), an analogue of antiepileptic drug phenytoin (5,5-diphenylhydantoin), on human umbilical vein endothelial cells (HUVEC) and its possible molecular mechanism underlying. Here we demonstrated that DPTH at a range of concentrations (12.5-50 microM) dose- and time-dependently inhibited DNA synthesis and decreased cell number in cultured HUVEC, but not human fibroblasts. DPTH was not cytotoxic at these concentrations. [3H]Thymidine incorporation and flow cytometry analyses demonstrated that treatment of HUVEC with DPTH arrested the cell at the G0/G1 phase of the cell cycle. Western blot analysis revealed that the protein level of p21 increased after DPTH treated. In contrast, the protein levels of p27, p53, cyclins A, D1, D3 and E, cyclin-dependent kinase (CDK)2, and CDK4 in HUVEC were not changed significantly after DPTH treatment. Immunoprecipitation showed that the formations of the CDK2-p21 and CDK4-p21 complex, but not the CDK2-p27 and CDK4-p27 complex, were increased in the DPTH-treated HUVEC. Kinase assay further demonstrated that both CDK2 and CDK4 kinase activities were decreased in the DPTH-treated HUVEC. Pretreatment of HUVEC with a p21 antisense oligonucleotide reversed the DPTH-induced inhibition of [3H]thymidine incorporation into HUVEC. In conclusion, these data suggest that DPTH inhibits HUVEC proliferation by increasing the level of p21 protein, which in turn inhibits CDK2 and CDK4 kinase activities, and finally interrupts the cell cycle. The findings from the present study suggest that DPTH might have the potential to inhibit the occurrence of angiogenesis.


Awareness of cervix cancer risk factors in educated youth: a cross-sectional, questionnaire based survey in India, Nepal, and Sri Lanka.
The main aim of this study was to evaluate the awareness of cervix cancer risk factors among Educated Youth with respect to socio demographic factors. A cross-sectional questionnaire survey was carried out among 1268 female undergraduate students in Delhi, Mangalore (India), Pokhara (Nepal) and Kandy (Srilanka) between 25 April 2010 and 20 August 2010 using structured questionnaire containing details of awareness of cervix cancer risk factors and socio demographic details. Descriptive statistics and testing of hypothesis were used for the analysis. Data analyzed using EPI INFO and SPSS 16 software. In the 1,268 subjects, the mean age of Indian (528, 41.6%), Nepalese (480, 37.9%) and Srilankan (260, 20.5%) were 18.3 ± SD 0.7, 18.6 ± SD 0.8 and 18.0 ± SD 1.5 years, respectively. Distribution of students according to religion varied across the countries. Majority of the students were Hindus in India (61.4%) and Nepal (89.6%) while in Srilanka the majority (53.8%) were Buddhist. Relationships could be established between nationality and risk factors viz. awareness regarding cervix cancer (p= 0.024), sexual activity at an early age (before 16) can cause cervix cancer (p=0.0001), multiple sex partners can cause cervix cancer (p=0.001), condom/other birth control measures cant prevent HPV infection (p=0.0001), smoking as a risk factor(p=0.0001), hereditary risk factor (p=0.015), and first degree relative (p=0.0001). These results indicate that there is an urgent need for a reinvigorated and tailored approach to cervix cancer prevention among the educated youth in India, Nepal and Srilanka. Prevention efforts should be focused on improving social awareness, enforcing education strategies to reduce risk factors and improving the strength and quality of counselling.


Competitive female runners with a history of iliotibial band syndrome demonstrate atypical hip and knee kinematics.
Cross-sectional experimental laboratory study. To examine differences in running mechanics between runners who had previously sustained iliotibial band syndrome (ITBS) and runners with no knee-related running injuries. ITBS is the second leading cause of knee pain in runners and the most common cause of lateral knee pain. Despite its prevalence, few biomechanical studies have been conducted to better understand its aetiology. Because the iliotibial band has both femoral and tibial attachments, it is possible that atypical hip and foot mechanics could result in the development of ITBS. The running mechanics of 35 females who had previously sustained ITBS were compared to 35 healthy age-matched and running distance-matched healthy females. Comparisons of hip, knee, and ankle 3-dimensional kinematics and internal moments during the stance phase of running gait were measured. The ITBS group exhibited significantly greater peak rearfoot invertor moment, peak knee internal rotation angle, and peak hip adduction angle compared to controls. No significant differences in peak rearfoot eversion angle, peak knee flexion angle, peak knee external rotator moment, or peak hip abductor moments were observed between groups. Females with a previous history of ITBS demonstrate a kinematic profile that is suggestive of increased stress on the iliotibial band. These results were generally similar to those reported for a prospective study conducted within the same laboratory environment.


Linkage analysis of diabetes status among hypertensive families: the Hypertension Genetic Epidemiology Network study.
Type 2 diabetes susceptibility is determined by multiple genetic and environmental factors. Genome-wide linkage scans have localized common regions, possibly harboring susceptibility genes on chromosomes 1, 2, 12, and 20. Variability in linkage findings underscores the probable genetic heterogeneity of type 2 diabetes. Thus, we conducted a genome scan of diabetes status using maximum likelihood methods that model affection status by a liability threshold model. Hypertensive sibships and their offspring and/or parents in the Hypertension Genetic Epidemiology Network study were recruited from five field centers. The diabetes phenotype was derived using the World Health Organization criteria and adjusted for race/study center, age, age2, sex, and with and without percent body fat. In total, 567 diabetic participants were identified in 437 families. Variance component linkage analysis was performed among 1,545 Caucasians and 1,608 African Americans using race-specific marker allele frequencies. We detected a quantitative trait loci (QTLs) influencing diabetes variance (logarithm of odds = 3.4) on chromosome 22, which overlaps a positive type 2 diabetes finding among Canadian Oji-Cree Indians. We also observed suggestive evidence for linkage on chromosomes 1, 2, 5, 8, 14, 17, and 19. The identification and replication of type 2 diabetes QTLs will bring us closer to the detection of functional genes that influence diabetes susceptibility.


Boron uptake, localization, and speciation in marine brown algae.
In contrast to the generally boron-poor terrestrial environment, the concentration of boron in the marine environment is relatively high (0.4 mM) and while there has been extensive interest in its use as a surrogate of pH in paleoclimate studies in the context of climate change-related questions, the relatively depth independent, and the generally non-nutrient-like concentration profile of this element have led to boron being neglected as a potentially biologically relevant element in the ocean. Among the marine plant-like organisms the brown algae (Phaeophyta) are one of only five lineages of photosynthetic eukaryotes to have evolved complex multicellularity. Many of unusual and often unique features of brown algae are attributable to this singular evolutionary history. These adaptations are a reflection of the marine coastal environment which brown algae dominate in terms of biomass. Consequently, brown algae are of fundamental importance to oceanic ecology, geochemistry, and coastal industry. Our results indicate that boron is taken up by a facilitated diffusion mechanism against a considerable concentration gradient. Furthermore, in both Ectocarpus and Macrocystis some boron is most likely bound to cell wall constituent alginate and the photoassimilate mannitol located in sieve cells. Herein, we describe boron uptake, speciation, localization and possible biological function in two species of brown algae, Macrocystis pyrifera and Ectocarpus siliculosus.


Human influence on sub-regional surface air temperature change over India.
Human activities have been implicated in the observed increase in Global Mean Surface Temperature. Over regional scales where climatic changes determine societal impacts and drive adaptation related decisions, detection and attribution (D&A) of climate change can be challenging due to the greater contribution of internal variability, greater uncertainty in regionally important forcings, greater errors in climate models, and larger observational uncertainty in many regions of the world. We examine the causes of annual and seasonal surface air temperature (TAS) changes over sub-regions (based on a demarcation of homogeneous temperature zones) of India using two observational datasets together with results from a multimodel archive of forced and unforced simulations. Our D&A analysis examines sensitivity of the results to a variety of optimal fingerprint methods and temporal-averaging choices. We can robustly attribute TAS changes over India between 1956-2005 to anthropogenic forcing mostly by greenhouse gases and partially offset by other anthropogenic forcings including aerosols and land use land cover change.


Technique for studying arthropod and microbial communities within tree tissues.
Phloem tissues of pine are habitats for many thousands of organisms. Arthropods and microbes use phloem and cambium tissues to seek mates, lay eggs, rear young, feed, or hide from natural enemies or harsh environmental conditions outside of the tree. Organisms that persist within the phloem habitat are difficult to observe given their location under bark. We provide a technique to preserve intact phloem and prepare it for experimentation with invertebrates and microorganisms. The apparatus is called a 'phloem sandwich' and allows for the introduction and observation of arthropods, microbes, and other organisms. This technique has resulted in a better understanding of the feeding behaviors, life-history traits, reproduction, development, and interactions of organisms within tree phloem. The strengths of this technique include the use of inexpensive materials, variability in sandwich size, flexibility to re-open the sandwich or introduce multiple organisms through drilled holes, and the preservation and maintenance of phloem integrity. The phloem sandwich is an excellent educational tool for scientific discovery in both K-12 science courses and university research laboratories.


Action understanding within and outside the motor system: the role of task difficulty.
When we observe actions, we activate parietal and premotor areas that are also recruited when we perform actions ourselves. It has been suggested that this action mirroring is causally involved in the process of action understanding. Alternatively, it might reflect the outcome of action understanding, with the underlying cognitive processes taking place elsewhere. To identify and characterize areas involved in action understanding, we presented participants with point-light displays depicting human actions and engaged them in tasks that required identifying the effector (arm/leg) or the goal of an action. We observed a stronger blood oxygen level-dependent signal during the Goal in comparison to the Effector Task not only in premotor areas, but also in the middle temporal gyrus (MTG) and the anterior ventrolateral prefrontal cortex. In the MTG, the Goal Task led to a signal higher than the Effector Task only when actions were easy to understand, whereas frontal areas showed this difference also when the task was difficult, a finding that is not caused by a ceiling effect. Our results suggest an interplay between temporal and frontal areas that is modulated by task difficulty and thus provide important constraints for biologically plausible models of action understanding.


Immune reconstitution inflammatory syndrome in natalizumab-associated PML.
To study the outcome of patients with multiple sclerosis (MS) and with natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution inflammatory syndrome (IRIS). MedWatch reports from Biogen-Idec (manufacturer of natalizumab, Tysabri(®)) were reviewed which comprised all 42 cases of natalizumab-related PML cases since its reintroduction until March 2010. All except 2 patients with natalizumab-related PML were managed by discontinuation of natalizumab and plasmapheresis/immunoadsorption (PLEX/IA). Seventeen patients had contrast enhancement of PML lesions on neuroimaging at the time of diagnosis before withdrawal/removal of natalizumab (early-PML-IRIS) and 23 patients developed contrast enhancement only after withdrawal/removal of natalizumab (late-PML-IRIS). All patients developed IRIS. IRIS was defined as worsening of neurologic deficits during the immune reconstitution following discontinuation of natalizumab, corroborated by inflammatory changes on neuroimaging. Following PLEX/IA, JC viral load in CSF increased by >10 fold in those with early-PML-IRIS but <2 fold in late-PML-IRIS. IRIS developed earlier and was more severe in early-PML-IRIS (p < 0.05). At the last follow-up, all patients had worse EDSS scores but this was higher in patients with early-PML-IRIS compared to those with late-PML-IRIS (p > 0.05). Mortality was comparable between the 2 groups, 29.4 ± 11% vs 21.7 ± 8.8%. Corticosteroid therapy during IRIS was associated with better Expanded Disability Status Scale outcome, p < 0.05. Early immunologic rebound in natalizumab-associated PML has worse survival and neurologic outcome. PLEX/IA may accelerate IRIS and its impact on the final outcome is unclear. Corticosteroid therapy provides a modest benefit and needs to be systemically studied in a controlled manner in the management of natalizumab-associated PML-IRIS.


Nitrification inhibition by silver nanoparticles.
Nitrification inhibition by silver nanoparticles (nanosilver) was evaluated by extant respirometry using enriched nitrifying bacteria isolated from wastewater treatment plants. Silver nanoparticles were more toxic than silver ions or silver chloride colloids, all of which did not disrupt cell membrane integrity at 1 mg/L Ag. The toxicity of silver nanoparticles was reduced in the presence of various anions, especially sulfide. The results suggest that silver nanoparticles have the same behaviour of surface complexation as silver ions, and inhibition by nanosilver in wastewater treatment may be removed by reaction of silver nanoparticles with soluble sulfide species.


Chimpanzee adenovirus- and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults.
Respiratory syncytial virus (RSV) causes respiratory infection in annual epidemics, with infants and the elderly at particular risk of developing severe disease and death. However, despite its importance, no vaccine exists. The chimpanzee adenovirus, PanAd3-RSV, and modified vaccinia virus Ankara, MVA-RSV, are replication-defective viral vectors encoding the RSV fusion (F), nucleocapsid (N), and matrix (M2-1) proteins for the induction of humoral and cellular responses. We performed an open-label, dose escalation, phase 1 clinical trial in 42 healthy adults in which four different combinations of prime/boost vaccinations were investigated for safety and immunogenicity, including both intramuscular (IM) and intranasal (IN) administration of the adenovirus-vectored vaccine. The vaccines were safe and well tolerated, with the most common reported adverse events being mild injection site reactions. No vaccine-related serious adverse events occurred. RSV neutralizing antibody titers rose in response to IM prime with PanAd3-RSV and after IM boost for individuals primed by the IN route. Circulating anti-F immunoglobulin G (IgG) and IgA antibody-secreting cells (ASCs) were observed after the IM prime and IM boost. RSV-specific T cell responses were increased after the IM PanAd3-RSV prime and were most efficiently boosted by IM MVA-RSV. Interferon-γ (IFN-γ) secretion after boost was from both CD4(+) and CD8(+) T cells, without detectable T helper cell 2 (TH2) cytokines that have been previously associated with immune pathogenesis following exposure to RSV after the formalin-inactivated RSV vaccine. In conclusion, PanAd3-RSV and MVA-RSV are safe and immunogenic in healthy adults. These vaccine candidates warrant further clinical evaluation of efficacy to assess their potential to reduce the burden of RSV disease.


In vivo performance of a novel fluorinated magnetic resonance imaging agent for functional analysis of bile acid transport.
A novel trifluorinated cholic acid derivative, CA-lys-TFA, was designed and synthesized for use as a tool to measure bile acid transport noninvasively using magnetic resonance imaging (MRI). In the present study, the in vivo performance of CA-lys-TFA for measuring bile acid transport by MRI was investigated in mice. Gallbladder CA-lys-TFA content was quantified using MRI and liquid chromatography/tandem mass spectrometry. Results in wild-type (WT) C57BL/6J mice were compared to those in mice lacking expression of Asbt, the ileal bile acid transporter. (19)F signals emanating from the gallbladders of WT mice 7 h after oral gavage with 150 mg/kg CA-lys-TFA were reproducibly detected by MRI. Asbt-deficient mice administered the same dose had undetectable (19)F signals by MRI, and gallbladder bile CA-lys-TFA levels were 30-fold lower compared to WT animals. To our knowledge, this represents the first report of in vivo imaging of an orally absorbed drug using (19)F MRI. Fluorinated bile acid analogues have potential as tools to measure and detect abnormal bile acid transport by MRI.