Meaning-Making Coping Among Cancer Patients in Sweden and South Korea: A Comparative Perspective.
The present study compared meaning-making coping among cancer patients in Sweden and South Korea, with a focus on the sociocultural context. Semi-structured interviews were conducted with 51 Swedes and 33 Koreans. The results showed significant differences between the two countries as well as similarities in existential, spiritual, and religious coping. For example, Swedes primarily used meaning-making coping as a means of meditation or relaxation, whereas Koreans relied on coping with prayer and using healthy foods as a means to survive. The present study confirms the significance of investigating cultural context when we explore the use of meaning-making coping among people who have experienced cancer.


Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclast activity.
Most breast cancer patients with bone metastases will receive bisphosphonate treatment. This post hoc analysis investigated whether early normalization of urinary N-telopeptide of type I collagen (NTX) levels during bisphosphonate therapy correlates with a long-term reduction in skeletal-related event (SRE) risk and mortality in patients with breast cancer. This was a retrospective subset analysis of a phase III randomized trial comparing i.v. zoledronic acid with pamidronate treatment in patients with bone metastases from breast cancer or multiple myeloma. Patients with breast cancer who had NTX assessments at baseline and at months 1 and 3 (n = 342) were classified as normal (NTX < 64 nmol/mmol creatinine) or elevated (NTX > or = 64 nmol/mmol creatinine). The relative risk for an SRE or death was estimated with Cox regression models. Among the 328 evaluable patients treated with zoledronic acid, 196 patients (59.7%) had elevated baseline NTX, with 149 of those patients (76.0%) having normalized NTX levels and 31 patients (15.8%) having persistently elevated NTX levels at 3 months. The normalized NTX group had significantly lower risks for a first SRE, a first fracture or surgery to bone, or death than the group that had persistently elevated NTX levels. These results suggest that early normalization of elevated baseline NTX while receiving zoledronic acid is associated with longer event-free and overall survival times compared with persistently elevated NTX. Further analyses in cancer patients with elevated marker levels are warranted to confirm the implications of these findings.


Immunologic strategies for HIV-1 remission and eradication.
Antiretroviral therapy (ART) is able to suppress HIV-1 replication indefinitely in individuals who have access to these medications, are able to tolerate these drugs, and are motivated to take them daily for life. However, ART is not curative. HIV-1 persists indefinitely during ART as quiescent integrated DNA within memory CD4(+) T cells and perhaps other long-lived cellular reservoirs. In this Review, we discuss the role of the immune system in the establishment and maintenance of the latent HIV-1 reservoir. A detailed understanding of how the host immune system shapes the size and distribution of the viral reservoir should lead to the development of a new generation of immune-based therapeutics, which may eventually contribute to a curative intervention.


An Integrated Bioinformatics Approach for Identifying Genetic Markers that Predict Cerebrospinal Fluid Biomarker p-tau181/Aβ1-42 Ratio in ApoE4-Negative Mild Cognitive Impairment Patients.
Alzheimer's disease (AD) is the most common form of dementia, with no disease-modifying treatment yet available. Early detection of patients at risk of developing AD is of central importance. Blood-based genetic signatures can serve as early detection and as population-based screening tools. In this study, we aimed to identify genetic markers and gene signatures associated with cerebrospinal fluid (CSF) biomarkers levels of t-tau, p-tau181, and with the two ratios t-tau/Aβ1-42 and p-tau181/Aβ1-42 in the context of progression from mild cognitive impairment (MCI) to AD, and to identify a panel of genetic markers that can predict CSF biomarker p-tau181/Aβ1-42 ratio with consideration of APOE ε4 stratification. We analyzed genome-wide the Alzheimer's Disease Neuroimaging Initiative dataset with up to 48 months follow-up. In the first part of the analysis, the main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed for each of the four CSF biomarkers. In the second part of the analysis, we performed an integrated analysis of genome-wide association study results with pathway enrichment analysis, predictive modeling and network analysis in the subgroup of ApoE4-negative subjects. We identified a panel of five SNPs, rs6766238, rs1143960, rs1249963, rs11975968, and rs4836493, that are predictive for p-tau181/Aβ1-42 ratio (high/low) with a sensitivity of 66% and a specificity of 70% (AUC 0.74). These results suggest that a panel of SNPs is a potential prognostic biomarker in ApoE4-negative MCI patients.


Movement of Salmonella serovar Typhimurium and E. coli O157:H7 to Ripe Tomato Fruit Following Various Routes of Contamination.
Salmonella serovars have been associated with the majority of foodborne illness outbreaks involving tomatoes, and E. coli O157:H7 has caused outbreaks involving other fresh produce. Contamination by both pathogens has been thought to originate from all points of the growing and distribution process. To determine if Salmonella serovar Typhimurium and E. coli O157:H7 could move to the mature tomato fruit of different tomato cultivars following contamination, three different contamination scenarios (seed, leaf, and soil) were examined. Following contamination, each cultivar appeared to respond differently to the presence of the pathogens, with most producing few fruit and having overall poor health. The Micro-Tom cultivar, however, produced relatively more fruit and E. coli O157:H7 was detected in the ripe tomatoes for both the seed- and leaf- contaminated plants, but not following soil contamination. The Roma cultivar produced fewer fruit, but was the only cultivar in which E. coli O157:H7 was detected via all three routes of contamination. Only two of the five cultivars produced tomatoes following seed-, leaf-, and soil- contamination with Salmonella Typhimurium, and no Salmonella was found in any of the tomatoes. Together these results show that different tomato cultivars respond differently to the presence of a human pathogen, and for E. coli O157:H7, in particular, tomato plants that are either contaminated as seeds or have a natural opening or a wound, that allows bacteria to enter the leaves can result in plants that have the potential to produce tomatoes that harbor internalized pathogenic bacteria.


Energy expenditure at age 73 and 78--a five year follow-up.
There is limited knowledge concerning the energy turnover and energy requirements of the elderly. The aim of this study was to measure resting metabolic rate (RMR) and total energy expenditure (TEE), and to define activity energy expenditure (AEE) and physical activity level (PAL) in 11 78-year-old individuals. A further aim was to compare these measures with the same measures taken from the 11 subjects at age 73 years. Total body water (TBW) averaged 30.8 kg (SD 3.2) at age 73 and 28.8 kg (SD 3.5) at age 78 years ( p<0.01). RMR was measured with a ventilated-hood system and averaged 5.60 MJ/day (SD 0.66) at age 73 and 4.77 MJ/day (SD 0.32) at 78 years ( p<0.001). TEE, measured using the doubly labeled water method, averaged 9.64 MJ/day (SD 1.10) at age 73 and 8.30 MJ/day (SD 1.45) at 78 years ( p<0.05). AEE averaged 4.04 MJ/day (SD 0.44) at age 73 and 3.53 MJ/day (1.13) at 78 years (ns). PAL averaged 1.74 at both ages. TBW, TEE, and RMR decreased, whereas AEE and PAL did not change substantially during the 5-year follow-up. The PAL values indicated a physically active lifestyle for the age group.


Motivation and Retention of Physicians in Primary Healthcare Facilities: A Qualitative Study From Abbottabad, Pakistan.
Workforce motivation and retention is important for the functionality and quality of service delivery in health systems of developing countries. Despite huge primary healthcare (PHC) infrastructure, Pakistan's health indicators are not impressive; mainly because of under-utilization of facilities and low patient satisfaction. One of the major underlying issues is staff absenteeism. The study aimed to identify factors affecting retention and motivation of doctors working in PHC facilities of Pakistan. An exploratory study was conducted in a rural district in Khyber Puktunkhwa (KP) province, in Pakistan. A conceptual framework was developed comprising of three organizational, individual, and external environmental factors. Qualitative research methods comprising of semi-structured interviews with doctors working in basic health units (BHUs) and in-depth interviews with district and provincial government health managers were used. Document review of postings, rules of business and policy actions was also conducted. Triangulation of findings was carried out to arrive at the final synthesis. Inadequate remuneration, unreasonable facilities at residence, poor work environment, political interference, inadequate supplies and medical facilities contributed to lack of motivation among both male and female doctors. The physicians accepted government jobs in BHUs with a belief that these jobs were more secure, with convenient working hours. Male physicians seemed to be more motivated because they faced less challenges than their female counterparts in BHUs especially during relocations. Overall, the organizational factors emerged as the most significant whereby human resource policy, career growth structure, performance appraisal and monetary benefits played an important role. Gender and marital status of female doctors was regarded as most important individual factor affecting retention and motivation of female doctors in BHUs. Inadequate remuneration, unreasonable facilities at residence, poor work environment, political interference, inadequate supplies, and medical facilities contributed to lack of motivation in physicians in our study. Our study advocates that by addressing the retention and motivation challenges, service delivery can be made more responsive to the patients and communities in Pakistan and other similar settings.


Redundancy and cooperativity in the mechanics of compositely crosslinked filamentous networks.
The cytoskeleton of living cells contains many types of crosslinkers. Some crosslinkers allow energy-free rotations between filaments and others do not. The mechanical interplay between these different crosslinkers is an open issue in cytoskeletal mechanics. Therefore, we develop a theoretical framework based on rigidity percolation to study a generic filamentous system containing both stretching and bond-bending forces to address this issue. The framework involves both analytical calculations via effective medium theory and numerical simulations on a percolating triangular lattice with very good agreement between both. We find that the introduction of angle-constraining crosslinkers to a semiflexible filamentous network with freely rotating crosslinks can cooperatively lower the onset of rigidity to the connectivity percolation threshold-a result argued for years but never before obtained via effective medium theory. This allows the system to ultimately attain rigidity at the lowest concentration of material possible. We further demonstrate that introducing angle-constraining crosslinks results in mechanical behaviour similar to just freely rotating crosslinked semflexible filaments, indicating redundancy and universality. Our results also impact upon collagen and fibrin networks in biological and bio-engineered tissues.


Pulmonary cytochrome P-450 2J4 is reduced in a rat model of acute Pseudomonas pneumonia.
We previously reported that the levels of epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) are depressed in microsomes prepared from lungs of rats with acute Pseudomonas pneumonia. We also showed a potential role for cytochrome P-450 (CYP) metabolites of arachidonic acid (AA) in contractile responses of both normal pulmonary arteries and pulmonary arteries from rats with pneumonia. The CYP2J subfamily enzymes (endogenous source of EETs and HETEs) are constitutively expressed in human and rat lungs where they are localized in vascular smooth muscle and endothelium. The purpose of this study was to determine if CYP2J proteins are modified in pneumonia. Pseudomonas organisms were injected via a tracheostomy in the lungs of rats. Later (44 h), lungs were frozen, and microsomes were prepared from pneumonia and control rat lung homogenates. Lung microsomal proteins were then immunoblotted with anti-CYP2B1/2B2, anti-CYP4A, anti-CYP2J9pep2 (which reacts with rat CYP2J3), anti-CYP2J6pep1 (which reacts with rat CYP2J4), anti-CYP2J2pep4, or anti-CYP2J2pep3 (both of which react with all known CYP2J isozymes). Western blotting revealed a prominent 55-kDa band with anti-CYP2J2pep3, anti-CYP2J2pep4, and anti-CYP2J6pep1 (but not anti-CYP2J9pep2) that was reduced in pneumonia compared with control lung microsomes. The CYP2B bands (51-52 kDa) were less prominent and not different between pneumonia and control lungs. CYP4A proteins (20-HETE sources) were not detected in rat lung microsomes. Therefore, rat lung contains a protein with immunological characteristics similar to CYP2J4, and this CYP is reduced after pneumonia. We speculate that CYP2J (but not CYP2B) enzymes and their AA metabolic products (EETs) are involved in the modulation of pulmonary vascular tone in pneumonia in rats.


Sphingolipids in COPD.
Sphingolipids are a distinct class of lipid molecules widely found in nature, principally as cell membrane constituents. After initial uncertainty about their function, sphingolipids have been increasingly recognised to be metabolically active entities involved in many biological processes, including the control of inflammation. Their role as mediators of inflammation may have significant implications for a range of lung diseases in which inflammation is a central element of pathogenesis. Chronic obstructive pulmonary disease (COPD), a highly prevalent and morbid condition predominantly affecting cigarette smokers, is a prime example of a respiratory illness with an inflammatory component. Understandably, sphingolipids have received growing attention for their increasingly demonstrated role in the pathophysiology of COPD. The present review aims to be among the first to focus exclusively on the connection between sphingolipids and lung inflammation in COPD, providing the reader with a clinically oriented synopsis of this intriguing association.


Analysis of the bread wheat genome using whole-genome shotgun sequencing.
Bread wheat (Triticum aestivum) is a globally important crop, accounting for 20 per cent of the calories consumed by humans. Major efforts are underway worldwide to increase wheat production by extending genetic diversity and analysing key traits, and genomic resources can accelerate progress. But so far the very large size and polyploid complexity of the bread wheat genome have been substantial barriers to genome analysis. Here we report the sequencing of its large, 17-gigabase-pair, hexaploid genome using 454 pyrosequencing, and comparison of this with the sequences of diploid ancestral and progenitor genomes. We identified between 94,000 and 96,000 genes, and assigned two-thirds to the three component genomes (A, B and D) of hexaploid wheat. High-resolution synteny maps identified many small disruptions to conserved gene order. We show that the hexaploid genome is highly dynamic, with significant loss of gene family members on polyploidization and domestication, and an abundance of gene fragments. Several classes of genes involved in energy harvesting, metabolism and growth are among expanded gene families that could be associated with crop productivity. Our analyses, coupled with the identification of extensive genetic variation, provide a resource for accelerating gene discovery and improving this major crop.


Soluble lectin-like oxidized low-density lipoprotein receptor-1 as a novel biomarker for large-artery atherosclerotic stroke.
Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has been shown associated with the progression of atherosclerosis in endothelial cells. We sought to assess whether the baseline serum sLOX-1 levels are correlated with the presence and short-term functional outcome of large-artery atherosclerotic (LAA) stroke. The study recruited 241 subjects, including 148 consecutive patients with acute ischemic stroke with the subtype of LAA and 93 non-stroke controls. Clinical and laboratory data, including serum concentration of sLOX-1, were collected within 24 h of admission, and the severity of LAA stroke patients was evaluated by National Institutes of Health Stroke Scale score. And functional outcome was assessed by modified Rankin Scale three months after stroke. The association between sLOX-1 level and the functional outcome at three months was analyzed by multiple logistic regression models. Serum levels of sLOX-1 in the LAA stroke patients were significantly higher as compared to normal controls (2.48 ± 0.93 ng/ml vs. 2.22 ± 0.79 ng/ml in the controls, t = 2.301, p = 0.022). The levels of serum sLOX-1 in patients with good outcome were significantly lower than those with poor outcome (2.39 ± 0.94 ng/ml vs. 2.77 ± 0.84 ng/ml, p = 0.032). After adjusting for potential confounders, sLOX-1 was still an independent predictor for the function outcome with an adjusted OR of 3.39 (95% CI, 1.61-7.11, p = 0.001). The serum sLOX-1 level was higher in patients with LAA stroke, and it was an independent predictor of functional outcome in patients with LAA ischemic stroke.


Changes in antimicrobial susceptibility in a population of Escherichia coli isolated from feedlot cattle administered ceftiofur crystalline-free acid.
To determine effects of administration of ceftiofur crystalline-free acid (CCFA) on antimicrobial susceptibility of Escherichia coli in feedlot cattle. 61 feedlot steers. A cohort study was conducted. Steers were housed in pens (5 pens with 10 steers and 1 pen with 11 steers). Five steers in each pen were administered CCFA, and 5 served as control steers (1 pen had 6 control steers). The CCFA administration included a single-dose regimen (6.6 mg/kg, SC, on day 0), two-thirds-dose regimen (4.4 mg/kg, SC, on day 0), and 3-dose regimen (6.6 mg/kg, SC, on days 0, 6, and 13). Fecal samples were collected on days 0, 2, 6, 9, 13, 16, 20, and 28. Fecal samples were collected immediately before CCFA administration. Minimum inhibitory concentrations of 15 antimicrobials were determined for 3 E coli isolates/fecal sample. Escherichia coli were enumerated by use of direct-plating techniques. Resistance to 1 or more antimicrobials was detected in 986 of 1,441 (68.4%) isolates recovered. Administration of CCFA was associated with a transient increase in the population of ceftiofur-resistant isolates. Susceptibility returned to day 0 values (ie, samples collected immediately before CCFA administration) approximately 2 weeks after completion of CCFA administration. Agreement between ceftiofur resistance and co-resistance to ampicillin, chloramphenicol, streptomycin, sulfisoxazole, and tetracycline was almost perfect (kappa 0.97). We did not detect variation in susceptibility of E coli recovered from commingled control steers. Administration of CCFA provided selection pressure that favored transient expansion of multiple-resistant variants.


Mitochondrial Morphology, Function and Homeostasis Are Impaired by Expression of an N-terminal Calpain Cleavage Fragment of Ataxin-3.
Alterations in mitochondrial morphology and function have been linked to neurodegenerative diseases, including Parkinson disease, Alzheimer disease and Huntington disease. Metabolic defects, resulting from dysfunctional mitochondria, have been reported in patients and respective animal models of all those diseases. Spinocerebellar Ataxia Type 3 (SCA3), another neurodegenerative disorder, also presents with metabolic defects and loss of body weight in early disease stages although the possible role of mitochondrial dysfunction in SCA3 pathology is still to be determined. Interestingly, the SCA3 disease protein ataxin-3, which is predominantly localized in cytoplasm and nucleus, has also been associated with mitochondria in both its mutant and wildtype form. This observation provides an interesting link to a potential mitochondrial involvement of mutant ataxin-3 in SCA3 pathogenesis. Furthermore, proteolytic cleavage of ataxin-3 has been shown to produce toxic fragments and even overexpression of artificially truncated forms of ataxin-3 resulted in mitochondria deficits. Therefore, we analyzed the repercussions of expressing a naturally occurring N-terminal cleavage fragment of ataxin-3 and the influence of an endogenous expression of the S256 cleavage fragment in vitro and in vivo. In our study, expression of a fragment derived from calpain cleavage induced mitochondrial fragmentation and cristae alterations leading to a significantly decreased capacity of mitochondrial respiration and contributing to an increased susceptibility to apoptosis. Furthermore, analyzing mitophagy revealed activation of autophagy in the early pathogenesis with reduced lysosomal activity. In conclusion, our findings indicate that cleavage of ataxin-3 by calpains results in fragments which interfere with mitochondrial function and mitochondrial degradation processes.


Revision interposition arthroplasty of the elbow.
Between 1996 and 2008, nine patients with severe post-traumatic arthritis underwent revision of a failed interposition arthroplasty of the elbow with a further interposition procedure using an allograft of tendo Achillis at a mean of 5.6 years (0.7 to 13.1) after the initial procedure. There were eight men and one woman with a mean age of 47 years (36 to 56). The mean follow-up was 4.7 years (2 to 8). The mean Mayo Elbow Performance score improved from 49 (15 to 65) pre-operatively to 73 (55 to 95) (p = 0.04). The mean Disability of the Arm, Shoulder and Hand score was 26 (7 to 42). One patient was unavailable for clinical follow-up and one underwent total elbow replacement three months post-operatively. Of the remaining patients, one had an excellent, two had good, three fair and one a poor result. Subjectively, five of the nine patients were satisfied. Four continued manual labour. Revision interposition arthroplasty is an option for young, active patients with severe post-traumatic arthritis who require both mobility and durability of the elbow.


A B2 SINE insertion in the Comt1 gene (Comt1(B2i)) results in an overexpressing, behavior modifying allele present in classical inbred mouse strains.
Catechol-O-methyltransferase (COMT) is a key enzyme for dopamine catabolism and COMT is a candidate gene for human psychiatric disorders. In mouse it is located on chromosome 16 in a large genomic region of extremely low variation among the classical inbred strains, with no confirmed single nucleotide polymorphisms (SNPs) between strains C57BL/6J and DBA/2J within a 600-kB window. We found a B2 SINE in the 3' untranslated region (UTR) of Comt1 which is present in C57BL/6J (Comt1(B2i)) and other strains including 129 (multiple sublines), but is not found in DBA/2J (Comt1(+)) and many other strains including wild-derived Mus domesticus, M. musculus, M. molossinus, M.castaneus and M. spretus. Comt1(B2i) is absent in strains closely related to C57BL/6, such as C57L and C57BR, indicating that it was polymorphic in the cross that gave rise to these strains. The strain distribution of Comt1(B2i) indicates a likely origin of the allele in the parental Lathrop stock. A stringent association test, using 670 highly outbred mice (Boulder Heterogeneous Stock), indicates that this insertion allele may be responsible for a difference in behavior related to exploration. Gene expression differences at the mRNA and enzyme activity level (1.7-fold relative to wild type) indicate a mechanism for this behavioral effect. Taken together, these findings show that Comt1(B2i) (a B2 SINE insertion) results in a relatively modest difference in Comt1 expression and enzyme activity (comparable to the human Val-Met polymorphism) which has a demonstrable behavioral phenotype across a variety of outbred genetic backgrounds.


Definitions for Loss of Domain: An International Delphi Consensus of Expert Surgeons.
No standardized written or volumetric definition exists for 'loss of domain' (LOD). This limits the utility of LOD as a morphological descriptor and as a predictor of peri- and postoperative outcomes. Consequently, our aim was to establish definitions for LOD via consensus of expert abdominal wall surgeons. A Delphi study involving 20 internationally recognized abdominal wall reconstruction (AWR) surgeons was performed. Four written and two volumetric definitions of LOD were identified via systematic review. Panelists completed a questionnaire that suggested these definitions as standardized definitions of LOD. Consensus on a preferred term was pre-defined as achieved when selected by ≥80% of panelists. Terms scoring <20% were removed. Voting commenced August 2018 and was completed in January 2019. Written definition: During Round 1, two definitions were removed and seven new definitions were suggested, leaving nine definitions for consideration. For Round 2, panelists were asked to select all appealing definitions. Thereafter, common concepts were identified during analysis, from which the facilitators advanced a new written definition. This received 100% agreement in Round 3. Volumetric definition: Initially, panelists were evenly split, but consensus for the Sabbagh method was achieved. Panelists could not reach consensus regarding a threshold LOD value that would preclude surgery. Consensus for written and volumetric definitions of LOD was achieved from 20 internationally recognized AWR surgeons. Adoption of these definitions will help standardize the use of LOD for both clinical and academic activities.


In vitro amplification of ovine prions from scrapie-infected sheep from Great Britain reveals distinct patterns of propagation.
Protein misfolding cyclic amplification (PMCA) is a method that facilitates the detection of prions from many sources of transmissible spongiform encephalopathy (TSE). Sheep scrapie represents a unique diversity of prion disease agents in a range of susceptible PRNP genotypes. In this study PMCA was assessed on a range of Great Britain (GB) sheep scrapie isolates to determine the applicability to veterinary diagnosis of ovine TSE. PrPSc amplification by protein misfolding cyclic amplification (PMCA) was assessed as a diagnostic tool for field cases of scrapie. The technique was initially applied to thirty-seven isolates of scrapie from diverse geographical locations around GB, and involved sheep of various breeds and PRNP genotypes. All samples were amplified in either VRQ and/or ARQ PrPC substrate. For PrPSc from sheep with at least one VRQ allele, all samples amplified efficiently in VRQ PrPC but only PrPSc from ARH/VRQ sheep amplified in both substrates. PrPSc from ARQ/ARQ sheep displayed two amplification patterns, one that amplified in both substrates and one that only amplified in ARQ PrPC. These amplification patterns were consistent for a further 14/15 flock/farm mates of these sheep. Furthermore experimental scrapie strains SSBP1, Dawson, CH1641 and MRI were analysed. SSBP1 and Dawson (from VRQ/VRQ sheep) amplified in VRQ but not ARQ substrate. MRI scrapie (from ARQ/ARQ sheep) nor CH1641 did not amplify in ARQ or VRQ substrate; these strains required an enhanced PMCA method incorporating polyadenylic acid (poly(A)) to achieve amplification. PrPsc from 52 classical scrapie GB field isolates amplified in VRQ or ARQ or both substrates and supports the use of PMCA as a rapid assay for the detection of a wide range of ovine classical scrapie infections involving multiple PRNP genotypes and scrapie strains.


In vivo vulnerability grading system of plaques causing acute coronary syndromes: An intravascular imaging study.
Autopsy studies shed light on the interplay between fatal acute coronary syndromes (ACS) and features of plaque vulnerability. This is a prospective pilot study designed for generating a new in vivo imaging grading system of plaque vulnerability. We studied 87 coronary vessels in 63 consecutive patients: 48 with Acute Coronary Syndrome (ACS) and 15 with stable coronary artery disease using IntraVascular-Ultrasound Near-Infrared-Spectroscopy (IVUS-NIRS) and Optical Coherence Tomography (OCT). We identified 99 lesions: 21 were the ACS culprit lesions (18 ulcerations and 3 with intact fibrous cap), 78 were non-culprit lesions including plaques located in the same ACS culprit vessel (N12), plaques located in a non-culprit vessel in patients with ACS (28) and target lesions of stable patients (N 38). A second analysis focused on lipid plaques, comparing the 18 ACS culprit ulcerated lesions and the 55 non-culprit lesions. The co-presence of the following three features of vulnerability [Minimal Luminal Area (MLA) <4 mm2, Fibrous Cap Thickness (FCT) < 75 μm and superficial macrophages] was by far more frequent in ACS culprit lesions than in controls (OR 40.6 for all lesions and OR 45.7 for ulcerated culprit lesions only). The triple-feature OCT grading identified vulnerable plaques with a much higher accuracy than that obtained applying each single feature of vulnerability. The co-presence of the 3 OCT features of vulnerability (MLA < 4 mm2, FCT < 75 μm and superficial macrophages) identifies culprit ACS lesions with a very high odd ratio. This finding could set the basis for a new OCT vulnerability grading system including superficial macrophages.


Preoperative β-blocker use in coronary artery bypass grafting surgery: national database analysis.
Use of preoperative β-blockers has been associated with a reduction in perioperative mortality for patients undergoing coronary artery bypass grafting (CABG) surgery in observational research studies, which led to the adoption of preoperative β-blocker therapy as a national quality standard. To determine whether preoperative β-blocker use within 24 hours of CABG surgery is associated with reduced perioperative mortality in a contemporary sample of patients. Retrospective analysis of the Society of Thoracic Surgeons National Adult Cardiac database for 1107 hospitals performing cardiac surgery in the United States from January 1, 2008, through December 31, 2012. Participants included 506,110 patients 18 years and older undergoing nonemergent CABG surgery who had not experienced a myocardial infarction in the prior 21 days or any other high-risk presenting symptom. We used logistic regression and propensity matching with a greedy 5-to-1 digit-matching algorithm to examine the association between β-blocker use and the main outcomes of interest. Preoperative β-blocker use. Incidence of perioperative mortality, permanent stroke, prolonged ventilation, any reoperation, renal failure, deep sternal wound infection, and atrial fibrillation. Among the 506,110 patients undergoing CABG surgery who met the inclusion criteria, 86.24% received preoperative β-blockers within 24 hours of surgery. In propensity-matched analyses that included 138,542 patients, we found no significant difference between patients who did and did not receive preoperative β-blockers in rates of operative mortality (1.12% vs 1.17%; odds ratio [OR], 0.96 [95% CI, 0.87-1.06]; P = .38), permanent stroke (0.97% vs 0.98%; OR, 0.99 [95% CI, 0.89-1.10]; P = .81), prolonged ventilation (7.01% vs 6.86%; OR, 1.02 [95% CI, 0.98-1.07]; P = .26), any reoperation (3.60% vs 3.69%; OR, 0.97 [95% CI, 0.92-1.03]; P = .35), renal failure (2.33% vs 2.24%; OR, 1.04 [95% CI, 0.97-1.11]; P = .30), and deep sternal wound infection (0.29% vs 0.34%; OR, 0.86 [95% CI, 0.71-1.04]; P = .12). However, patients who received preoperative β-blockers within 24 hours of surgery had higher rates of new-onset atrial fibrillation when compared with patients who did not (21.50% vs 20.10%; OR, 1.09 [95% CI, 1.06-1.12]; P < .001). Results of logistic regression analyses were broadly consistent. Preoperative β-blocker use among patients undergoing nonemergent CABG surgery who have not had a recent myocardial infarction was not associated with improved perioperative outcomes.


Lenalidomide-bendamustine-rituximab in patients older than 65 years with untreated mantle cell lymphoma.
For elderly patients with mantle cell lymphoma (MCL), there is no defined standard therapy. In this multicenter, open-label phase 1/2 trial, we evaluated the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment for elderly patients with MCL. Patients >65 years with untreated MCL, stages II-IV were eligible for inclusion. Primary end points were maximally tolerable dose (MTD) of LEN and progression-free survival (PFS). Patients received 6 cycles every four weeks of L-B-R (L D1-14, B 90 mg/m2 IV, days 1-2 and R 375 mg/m2 IV, day 1) followed by single LEN (days 1-21, every four weeks, cycles 7-13). Fifty-one patients (median age 71 years) were enrolled from 2009 to 2013. In phase 1, the MTD of LEN was defined as 10 mg in cycles 2 through 6, and omitted in cycle 1. After 6 cycles, the complete remission rate (CRR) was 64%, and 36% were MRD negative. At a median follow-up time of 31 months, median PFS was 42 months and 3-year overall survival was 73%. Infection was the most common nonhematologic grade 3 to 5 event and occurred in 21 (42%) patients. Opportunistic infections occurred in 3 patients: 2 Pneumocystis carinii pneumonia and 1 cytomegalovirus retinitis. Second primary malignancies (SPM) were observed in 8 patients (16%). LEN could safely be combined with R-B when added from the second cycle in patients with MCL, and was associated with a high rate of CR and molecular remission. However, we observed a high degree of severe infections and an unexpected high number of SPMs, which may limit its use. This trial is registered at www.Clinicaltrials.gov as #NCT00963534.


Why Do People Exercise in Natural Environments? Norwegian Adults' Motives for Nature-, Gym-, and Sports-Based Exercise.
Exercise in natural environments ("green exercise") confers numerous health benefits, but little is known about why people engage in green exercise. This study examined the importance of nature experiences as a motive for physical activity and the motivational profile of people who engage in green exercise compared to gym- and sports-based exercise. Physical activity motives and typical times spent in different domains of physical activity were reported by 2168 Norwegian adults in a survey. Experiencing nature was generally rated as the second-most important physical activity motive, exceeded only by convenience motives, and it was especially important for older adults and those who engage in greater amounts of instrumental physical activity. Green exercisers reported stronger motives concerning convenience and experiencing nature, whereas gym- or sports-based exercisers reported stronger motives for physical health and sociability. The motives associated with different leisure-time exercise domains may assist in understanding optimal promotion of green exercise.


The National Cancer Institute best case series program: a summary of cases of cancer patients treated with unconventional therapies in India.
The National Cancer Institute (NCI) Best Case Series (BCS) Program provides an independent review of medical records, imaging, and pathology of cancer patients treated with unconventional therapies. The goal of the NCI BCS Program is to identify preliminary evidence of tumor regression and assess whether there is sufficient evidence to move forward with NCI-initiated research. The objective was to review case reports submitted by 4 practitioners from India who used ayurvedic and homeopathic therapies to treat cancer. Retrospective review of case reports of 4 practitioners from India who used ayurvedic and homeopathic therapies to treat cancer. A total of 68 cases were submitted to the NCI BCS Program. Fifty-one percent of the cases represented homeopathy and 49% ayurveda. Of the 68 cases, 32 (47%) of the cases were collectively designated as "persuasive" (P) or "supportive"(S), and 36 (53%) as "not evaluable." Forty-one (60%) patients did not have any prior conventional treatment. The challenge for submitters rests in their ability to supply sufficient documentation for the NCI BCS Program. The NCI BCS Program represents a unique avenue for the rigorous evaluation of "best cases" to identify complementary and alternative medicine modalities that are promising for prospective preclinical evaluation or prospective research.


Ancient DNA analysis of the extinct North American flat-headed peccary (Platygonus compressus).
The geographical range of extant peccaries extends from the southwestern United States through Central America and into northern Argentina. However, from the Miocene until the Pleistocene now-extinct peccary species inhabited the entirety of North America. Relationships among the living and extinct species have long been contentious. Similarly, how and when peccaries moved from North to South America is unclear. The North American flat-headed peccary (Platygonus compressus) became extinct at the end of the Pleistocene and is one of the most abundant subfossil taxa found in North America, yet despite this extensive fossil record its phylogenetic position has not been resolved. This study is the first to present DNA data from the flat-headed peccary and full mitochondrial genome sequences of all the extant peccary species. We performed a molecular phylogenetic analysis to determine the relationships among ancient and extant peccary species. Our results suggested that the flat-headed peccary is sister-taxon to a clade comprising the extant peccary species. Divergence date estimates from our molecular dating analyses suggest that if extant peccary diversification occurred in South America then their common ancestor must have dispersed from North America to South America well before the establishment of the Isthmus of Panama. We also investigated the genetic diversity of the flat-headed peccary by performing a preliminary population study on specimens from Sheriden Cave, Ohio. Flat-headed peccaries from Sheriden Cave appear to be genetically diverse and show no signature of population decline prior to extinction. Including additional extinct Pleistocene peccary species in future phylogenetic analyses will further clarify peccary evolution.


Effect of picibanil (OK432) on neutrophil-mediated antitumor activity: implication of monocyte-derived neutrophil-activating factors.
Picibanil (OK432), an extract from streptococci, has been widely utilized to treat malignant ascites and pleural effusions. The antitumor mechanism is believed to include complement-mediated neutrophil activation. Employing a flow-cytometric analysis of actin polymerization as an indicator of cell activation as well as a tumor proliferation assay, we have found that monocyte-derived neutrophil-activating factors were involved in OK432-induced neutrophil activation as well as antitumor activity. OK432-stimulated (0.1 KE/ml; 0.01 mg/ml) monocyte supernatants (OKMS) induced neutrophil actin polymerization and chemotaxis. OKMS were responsible for neutrophil-mediated inhibition of human leukemic (CEM) cell proliferation and stimulated neutrophils to produce superoxide in the presence of CEM leukemic cells at an effector/target ratio higher than 20/1. In contrast, OK432 alone, OK432-stimulated lymphocyte supernatants, or OK432-stimulated neutrophil supernatants had no effect on neutrophil activation or suppression of tumor cell proliferation. OK432 in combination with mononuclear cells also had no effect on the inhibition of CEM cell proliferation. Pretreatment of OKMS at 56 degrees C for 30 min did not affect its ability to activate neutrophils, implying that complement activation is not responsible for the neutrophil activation. Supernatants from OK432-stimulated mononuclear cells, as determined by enzyme-linked immunosorbent assays and radioimmunoassays, contained high levels of interleukin-8 (IL-8; 1567 +/- 145 pg/ml) and tumor necrosis factor (TNF alpha; 2105 +/- 152 pg/ml), low levels of leukotriene B4 (800 +/- 45 pg/ml) and IL-1 beta (180 +/- 22 pg/ml), but interferon gamma was not detectable. IL-1 beta, IL-8, and TNF alpha transcripts, undetectable in untreated monocytes, increased significantly after 30-60 min exposure to OK432. These results suggest that neutrophil-activating factors from monocytes or resident macrophages may play an important role in the OK432-induced neutrophil activation and antitumor activity.


Extensive reproductive disruption, ovarian masculinization and aromatase suppression in Atlantic croaker in the northern Gulf of Mexico hypoxic zone.
The long-term impacts on marine ecosystems of the recent dramatic worldwide increase in the incidence of coastal hypoxia are unknown. Here, we show widespread reproductive disruption in Atlantic croakers collected from hypoxic sites approximately 120 km apart in the extensive northern Gulf of Mexico continental shelf hypoxic zone. Gonadal growth and gamete production were impaired in croakers from hypoxic sites compared with fish from reference normoxic sites east of the Mississippi River Delta. Male germ cells were detected in approximately 19 per cent of croaker ovaries collected in the hypoxic region, but were absent in ovaries from normoxic sites. In addition, the sex ratio was skewed towards males at the hypoxic sites. The masculinization and other reproductive disruptions were associated with declines in neuroendocrine function, as well as ovarian and brain expression of aromatase (the enzyme that converts androgens to oestrogens). A similar incidence of ovarian masculinization and decline in ovarian aromatase expression were observed in croaker after chronic laboratory hypoxia exposure, indicating that ovarian masculinization is a specific hypoxia response and is due to decreased aromatase activity. The results suggest severe reproductive impairment can occur over large coastal regions in marine fish populations exposed to seasonal hypoxia, with potential long-term impacts on population abundance.


The Global Nutrition Report 2014: actions and accountability to accelerate the world's progress on nutrition.
In 2013, the Nutrition for Growth Summit called for a Global Nutrition Report (GNR) to strengthen accountability in nutrition so that progress in reducing malnutrition could be accelerated. This article summarizes the results of the first GNR. By focusing on undernutrition and overweight, the GNR puts malnutrition in a new light. Nearly every country in the world is affected by malnutrition, and multiple malnutrition burdens are the "new normal." Unfortunately, the world is off track to meet the 2025 World Health Assembly (WHA) targets for nutrition. Many countries are, however, making good progress on WHA indicators, providing inspiration and guidance for others. Beyond the WHA goals, nutrition needs to be more strongly represented in the Sustainable Development Goal (SDG) framework. At present, it is only explicitly mentioned in 1 of 169 SDG targets despite the many contributions improved nutritional status will make to their attainment. To achieve improvements in nutrition status, it is vital to scale up nutrition programs. We identify bottlenecks in the scale-up of nutrition-specific and nutrition-sensitive approaches and highlight actions to accelerate coverage and reach. Holding stakeholders to account for delivery on nutrition actions requires a well-functioning accountability infrastructure, which is lacking in nutrition. New accountability mechanisms need piloting and evaluation, financial resource flows to nutrition need to be made explicit, nutrition spending targets should be established, and some key data gaps need to be filled. For example, many UN member states cannot report on their WHA progress and those that can often rely on data >5 y old. The world can accelerate malnutrition reduction substantially, but this will require stronger accountability mechanisms to hold all stakeholders to account.


The effect of calnexin deletion on the expression level of binding protein (BiP) under heat stress conditions in Saccharomyces cerevisiae.
In order to investigate the effect of calnexin deletion on the induction of the main ER molecular chaperone BiP, we cultured the wild-type and calnexin-disrupted Saccharomyces cerevisiae strains under normal and stressed conditions. The growth rate of the calnexin-disrupted yeast was almost the same as that of the wild-type yeast under those conditions. However, the induced level of BiP mRNA in the ER was evidently higher in calnexin-disrupted S. cerevisiae than in the wild-type at 37 degrees C, but was almost the same in the two strains under normal conditions. The Western blot analysis results for BiP protein expression in the ER showed a parallel in the mRNA levels in the two strains. It is suggested that under heat stress conditions, the induction of BiP in the ER might recover part of the function of calnexin in calnexin-disrupted yeast, and result in the same growth rate as in wild-type yeast.


Spectrum of Benign Articular and Periarticular Findings at FDG PET/CT.
Whole-body fluorine 18 fluorodeoxyglucose (FDG) positron-emission tomography (PET)/computed tomography (CT) is performed primarily for oncologic indications; however, FDG uptake is not specific for malignancy. Herein we focus on causes of increased FDG uptake in and around joints, as lesions in these locations are commonly benign. A combination of primary intra-articular processes and osseous processes that may occur near the joint space will be discussed. Causes of intra-articular and periarticular increased FDG activity can be broadly divided into infectious, inflammatory, degenerative, and benign neoplastic categories. A familiarity with the full range of these processes is important to avoid misinterpretation, in turn decreasing unnecessary follow-up studies, procedures, and treatments. Differentiation from malignancy is often possible on the basis of a different level of FDG activity, divergent response to therapy, or differing changes over time, in comparison with a patient's known primary cancer. Recognizing an intra-articular lesion location can also be critical, as intra-articular metastases are rare. In some cases, benign FDG-avid articular and periarticular entities have a specific appearance at FDG PET/CT and a correct diagnosis may be made without any additional workup. In most other cases, comparison with prior studies and/or additional imaging can afford an accurate diagnosis. This review is meant to introduce the reader to a spectrum of benign FDG-avid articular and periarticular processes that may be encountered at oncologic FDG PET/CT to increase confidence and diagnostic accuracy. (©)RSNA, 2016.


Quantifying the total and bioavailable polycyclic aromatic hydrocarbons and dioxins in biochars.
Biochar soil amendment is advocated to mitigate climate change and improve soil fertility. A concern though, is that during biochar preparation PAHs and dioxins are likely formed. These contaminants can possibly be present in the biochar matrix and even bioavailable to exposed organisms. Here we quantify total and bioavailable PAHs and dioxins in a suite of over 50 biochars produced via slow pyrolysis between 250 and 900 °C, using various methods and biomass from tropical, boreal, and temperate areas. These slow pyrolysis biochars, which can be produced locally on farms with minimum resources, are also compared to biochar produced using the industrial methods of fast pyrolysis and gasification. Total concentrations were measured with a Soxhlet extraction and bioavailable concentrations were measured with polyoxymethylene passive samplers. Total PAH concentrations ranged from 0.07 μg g(-1) to 3.27 μg g(-1) for the slow pyrolysis biochars and were dependent on biomass source, pyrolysis temperature, and time. With increasing pyrolysis time and temperature, PAH concentrations generally decreased. These total concentrations were below existing environmental quality standards for concentrations of PAHs in soils. Total PAH concentrations in the fast pyrolysis and gasification biochar were 0.3 μg g(-1) and 45 μg g(-1), respectively, with maximum levels exceeding some quality standards. Concentrations of bioavailable PAHs in slow pyrolysis biochars ranged from 0.17 ng L(-1) to 10.0 ng L(-1)which is lower than concentrations reported for relatively clean urban sediments. The gasification produced biochar sample had the highest bioavailable concentration (162 ± 71 ng L(-1)). Total dioxin concentrations were low (up to 92 pg g(-1)) and bioavailable concentrations were below the analytical limit of detection. No clear pattern of how strongly PAHs were bound to different biochars was found based on the biochars' physicochemical properties.


A game-theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways.
Aggregation of amyloid-β (Aβ) peptides is a significant event that underpins Alzheimer's disease (AD). Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and behaviour. In this paper, we use our previously established results on heterotypic interactions between Aβ and fatty acids (FAs) to investigate off-pathway aggregation under the control of FA concentrations to develop a mathematical framework that captures the mechanism. Our framework to define and simulate the competing on- and off-pathways of Aβ aggregation is based on the principles of game theory. Together with detailed simulations and biophysical experiments, our models describe the dynamics involved in the mechanisms of Aβ aggregation in the presence of FAs to adopt multiple pathways. Specifically, our reduced-order computations indicate that the emergence of off- or on-pathway aggregates are tightly controlled by a narrow set of rate constants, and one could alter such parameters to populate a particular oligomeric species. These models agree with the detailed simulations and experimental data on using FA as a heterotypic partner to modulate the temporal parameters. Predicting spatio-temporal landscape along competing pathways for a given heterotypic partner such as lipids is a first step towards simulating scenarios in which the generation of specific 'conformer strains' of Aβ could be predicted. This approach could be significant in deciphering the mechanisms of amyloid aggregation and strain generation, which are ubiquitously observed in many neurodegenerative diseases.


Neural Circuits of Sexual Behavior in Caenorhabditis elegans.
The recently determined connectome of the Caenorhabditis elegans adult male, together with the known connectome of the hermaphrodite, opens up the possibility for a comprehensive description of sexual dimorphism in this species and the identification and study of the neural circuits underlying sexual behaviors. The C. elegans nervous system consists of 294 neurons shared by both sexes plus neurons unique to each sex, 8 in the hermaphrodite and 91 in the male. The sex-specific neurons are well integrated within the remainder of the nervous system; in the male, 16% of the input to the shared component comes from male-specific neurons. Although sex-specific neurons are involved primarily, but not exclusively, in controlling sex-unique behavior-egg-laying in the hermaphrodite and copulation in the male-these neurons act together with shared neurons to make navigational choices that optimize reproductive success. Sex differences in general behaviors are underlain by considerable dimorphism within the shared component of the nervous system itself, including dimorphism in synaptic connectivity.


Rehabilitation Predictors of Clinical Outcome Following Revision ACL Reconstruction in the MARS Cohort.
Revision anterior cruciate ligament (ACL) reconstruction has been documented to have worse outcomes than primary ACL reconstruction. The reasons remain varied and not completely understood. Patients undergoing revision ACL reconstruction were prospectively enrolled. Data collected included baseline demographics, surgical technique and pathological condition, prescribed rehabilitation instructions, and a series of validated patient-reported outcome instruments. Patients were followed for 2 years and asked to complete a set of outcome instruments identical to those completed at baseline. Subsequent surgical procedures on the ipsilateral knee were recorded. Regression analysis was used to control for age, sex, activity level, baseline outcome scores, and the above-mentioned rehabilitation-related variables in order to assess the factors affecting clinical outcomes 2 years after revision ACL reconstruction. A total of 843 patients met the inclusion criteria and were successfully enrolled, and 82% (695) were followed for 2 years. Two rehabilitation-related factors were found to influence outcome. First, patients who were prescribed an ACL brace for their return to sports had a significantly better Knee injury and Osteoarthritis Outcome Score (KOOS) for sports and recreational activities at 2 years (odds ratio [OR] =1.50, 95% confidence interval [CI] = 1.07 to 2.11; p = 0.019). Second, patients prescribed an ACL brace for the postoperative rehabilitation period were 2.3 times more likely to have subsequent surgery by 2 years (OR = 2.26, 95% CI = 1.11 to 4.60; p = 0.024). The odds of a graft rerupture were not affected by any type of brace wear. Rehabilitation-related factors that the physician can control at the time of an ACL reconstruction have the ability to influence clinical outcomes at 2 years. Weight-bearing and motion can be initiated immediately postoperatively. Bracing during the early postoperative period is not helpful. Use of a functional brace early in the postoperative period was associated with an increased risk of a reoperation. Use of a functional brace for a return to sports improved the KOOS on the sports/recreation subscale. Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.


Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment.
New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.


Unraveling psychomotor slowing in bipolar disorder.
In addition to affective and cognitive symptomatology, psychomotor deficits are known to be present in bipolar disorder (BD). Psychomotor functioning includes all of the processes necessary for completing a movement, from planning to initiation and execution. While these psychomotor symptoms have been studied extensively in schizophrenia and major depressive disorder, only simple measures have been conducted in BD. The present study examines psychomotor functioning in BD. Twenty-two euthymic BD patients and 21 healthy controls performed three computerized copying tasks varying in cognitive load. Movement times (MT), reflecting fine motor processing, and initiation times (IT), reflecting cognitive processing of visual-spatial information, were separately measured in each group. The BD patients had longer IT but not MT in the simplest task and the opposite pattern of longer MT but not IT in the complex task. However, when controlling for residual mood symptoms, the MT were no longer significantly slower in the BD group. The longer MT and IT in BD reflect overall psychomotor slowing. Specifically, the results provide evidence for cognitive slowing in BD. In addition, the longer MT in the complex task reflect a slowed motor component of movement when the cognitive load is high and when depressive symptoms are present. These findings extend the current knowledge of the nature of psychomotor slowing in BD and may have important prognostic implications for patients.


Behavior- and Modality-General Representation of Confidence in Orbitofrontal Cortex.
Every decision we make is accompanied by a sense of confidence about its likely outcome. This sense informs subsequent behavior, such as investing more-whether time, effort, or money-when reward is more certain. A neural representation of confidence should originate from a statistical computation and predict confidence-guided behavior. An additional requirement for confidence representations to support metacognition is abstraction: they should emerge irrespective of the source of information and inform multiple confidence-guided behaviors. It is unknown whether neural confidence signals meet these criteria. Here, we show that single orbitofrontal cortex neurons in rats encode statistical decision confidence irrespective of the sensory modality, olfactory or auditory, used to make a choice. The activity of these neurons also predicts two confidence-guided behaviors: trial-by-trial time investment and cross-trial choice strategy updating. Orbitofrontal cortex thus represents decision confidence consistent with a metacognitive process that is useful for mediating confidence-guided economic decisions.


Modeling enzymatic hydrolysis of lignocellulosic substrates using confocal fluorescence microscopy I: filter paper cellulose.
Enzymatic hydrolysis is one of the critical steps in depolymerizing lignocellulosic biomass into fermentable sugars for further upgrading into fuels and/or chemicals. However, many studies still rely on empirical trends to optimize enzymatic reactions. An improved understanding of enzymatic hydrolysis could allow research efforts to follow a rational design guided by an appropriate theoretical framework. In this study, we present a method to image cellulosic substrates with complex three-dimensional structure, such as filter paper, undergoing hydrolysis under conditions relevant to industrial saccharification processes (i.e., temperature of 50°C, using commercial cellulolytic cocktails). Fluorescence intensities resulting from confocal images were used to estimate parameters for a diffusion and reaction model. Furthermore, the observation of a relatively constant bound enzyme fluorescence signal throughout hydrolysis supported our modeling assumption regarding the structure of biomass during hydrolysis. The observed behavior suggests that pore evolution can be modeled as widening of infinitely long slits. The resulting model accurately predicts the concentrations of soluble carbohydrates obtained from independent saccharification experiments conducted in bulk, demonstrating its relevance to biomass conversion work.


Divergence-tolerant resonant bandpass filters.
Bandpass filters based on subwavelength dielectric gratings are grounded in physical principles that are totally distinct from their thin-film counterparts. Ease in fabrication, design scalability, material sparsity, and on-chip integration compatibility makes them a promising alternative especially for long-wavelength applications. Here we demonstrate the interesting attribute of resonant bandpass filters of high angular stability for fully conical light incidence. Fashioning an experimental bandpass filter with a subwavelength silicon grating on a quartz substrate, we show that fully conical incidence provides an angular full width at half-maximum linewidth of ∼9.5° compared to a linewidth of ∼0.1° for classical incidence. Slow angular variation of the central wavelength with full conical incidence arises via a corresponding slow angular variation of the resonant second diffraction orders driving the pertinent leaky modes. Moreover, full conical incidence maintains a profile with a single passband as opposed to the formation of two passbands characteristic of resonant subwavelength gratings under classical incidence. Our experimental results demonstrate excellent stability in angle, spectral profile, linewidth, and efficiency.


Replication of a holographic ion-etched spherical blazed grating for use at extreme-ultraviolet wavelengths: topography.
We have measured the topography of a holographic ion-etched spherical blazed grating and three of its replicas using an atomic force microscope. The master grating had a roughness of less than 5 angstroms rms, a blaze angle of 2.5 degrees, and an antiblaze angle of 3.3 degrees. Thus the groove profile was more triangular than sawtooth. We find that the replication process did not significantly change the master grating. Moreover, we find no significant difference in roughness, blaze angle, or antiblaze angle between the master and its replicas before or after multilayer coating. However, bumps were observed on the gratings after coating, the cause of which is not understood. Although widespread, they occupy a relatively small fraction of the total area.


Transient synchrony among populations of five foliage-feeding Lepidoptera.
Studies of transient population dynamics have largely focused on temporal changes in dynamical behaviour, such as the transition between periods of stability and instability. This study explores a related dynamic pattern, namely transient synchrony during a 49-year period among populations of five sympatric species of forest insects that share host tree resources. The long time series allows a more comprehensive exploration of transient synchrony patterns than most previous studies. Considerable variation existed in the dynamics of individual species, ranging from periodic to aperiodic. We used time-averaged methods to investigate long-term patterns of synchrony and time-localized methods to detect transient synchrony. We investigated transient patterns of synchrony between species and related these to the species' varying density dependence structures; even species with very different density dependence exhibited at least temporary periods of synchrony. Observed periods of interspecific synchrony may arise from interactions with host trees (e.g., induced host defences), interactions with shared natural enemies or shared impacts of environmental stochasticity. The transient nature of synchrony observed here raises questions both about the identity of synchronizing mechanisms and how these mechanisms interact with the endogenous dynamics of each species. We conclude that these patterns are the result of interspecific interactions that act only temporarily to synchronize populations, after which differences in the endogenous population dynamics among the species acts to desynchronize their dynamics.


The use of carbon monoxide as a probe molecule in spectroscopic studies for determination of exposed gold sites on TiO2.
The sol immobilisation technique, in which a stabilising ligand (such as polyvinyl alcohol or polyvinyl pyridine) can be used to tune metal particle size and composition, has become a valuable method of making supported nanoparticle catalysts. An unfortunate consequence of the stabilising ligand is that often access of reactant molecules to the metal nanoparticle surface is impeded. Several methods have been proposed for the removal of these ligands, though determination of the degree of their success is difficult. Here, we demonstrate the use of in situ infrared and UV-Vis spectroscopy to elucidate the access of carbon monoxide to the surface of Au/TiO2 catalysts before and after various ligand removal treatments. These were contrasted with a catalyst prepared by deposition precipitation prepared in the absence of stabilising ligand as a control. Changes were observed in the infrared spectrum, with the wavenumber of carbon monoxide linearly bonded to Au for catalysts shifting before and after ligand removal, which correlated well with the activity of the catalyst for carbon monoxide oxidation. Also the extent of shifting of the Au surface resonance plasmon band on the addition of carbon monoxide, observed by UV-Vis, also correlated well with catalyst activity. These simple methods can be used to determine the quantity of exposed metal sites after a ligand removal treatment and so determine the treatments effectiveness.


Obesity, Diabetes, Coffee, Tea, and Cannabis Use Alter Risk for Alcohol-Related Cirrhosis in 2 Large Cohorts of High-Risk Drinkers.
Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk. We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank. The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10-18) and higher premorbid body mass index (26.37 ± 0.16 kg/m2) than controls (24.44 ± 0.18 kg/m2, P = 5.77 × 10-15). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption. If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.


The silver lining of induced pluripotent stem cell variation.
Induced pluripotent stem cells (iPSCs) are being generated using various reprogramming methods and from different cell sources. Hence, a lot of effort has been devoted to evaluating the differences among iPSC lines, in particular with respect to their differentiation capacity. While line-to-line variability should mainly reflect the genetic diversity within the human population, here we review some studies that have brought attention to additional variation caused by genomic and epigenomic alterations. We discuss strategies to evaluate aberrant changes and to minimize technical and culture-induced noise, in order to generate safe cells for clinical applications. We focus on the findings from a recent study, which compared the differentiation capacity of several iPSC lines committed to the hematopoietic lineage and correlated the differential maturation capacity with aberrant DNA methylations. Although iPSC variation represents a challenge for the field, we embrace the authors' perspective that iPSC variations should be used to our advantage for predicting and selecting the best performing iPSC lines, depending on the desired application.


An extensive and diverse gene family of nicotinic acetylcholine receptor alpha subunits in Caenorhabditis elegans.
Using reverse transcription-polymerase chain reactions the transcription of eight novel candidate nicotinic acetylcholine receptor (nAChR) alpha subunit genes has been demonstrated in the nematode Caenorhabditis elegans. Together with five other alpha subunit genes described elsewhere by ourselves (unc-38) and other workers (deg-3, acr-4, Ce21 and acr-6), this is now the largest known family of nAChR alpha subunit genes in a single species. By homology we have identified four groups of alpha subunits: DEG-3-like; ACR-16[Ce21]-like; UNC-38-like and ACR-8-like. Five C. elegans nAChR alpha subunits contain a modification in loop C of the ACh binding site in which the normally conserved Tyr-x-Cys-Cys, is replaced by a distinct motif (Tyr-x-x-Cys-Cys). Variation is also found in the channel lining M2 regions, including the replacement in four subunits of the highly conserved leucine at the 9' position by valine and most notably, the replacement in all ACR-8-like subunits of the highly conserved glutamic acid at the -1' position by histidine. Restrained molecular dynamics simulations have been used to generate homo-pentameric M2 helix bundle models for alpha subunits and possible functional implications examined. The calculated electrostatic potential energy profile for the M2 region of ACR-8 differs strikingly from that of ACR-16[Ce21] largely due to the presence of histidine at the -1' position, suggesting a possible perturbation of nAChR channel action permeability in the presence of this subunit type.


Complications of alloderm and dermamatrix for parotidectomy reconstruction.
AlloDerm and DermaMatrix are 2 acellular dermal implants currently used by reconstructive surgeons at our institution for reconstruction of parotidectomy defects. We looked at the postoperative complication rates following subcutaneous implantation of these acellular dermal implants for parotid bed reconstruction. A retrospective analysis was conducted following approval by the Institutional Review Board at Vanderbilt University Medical Center. All parotid and reconstructive operations were performed between 2001 and 2009 by 1 of 4 surgeons in the Department of Otolaryngology-Head and Neck Surgery. Data were collected to determine operative variables and postoperative course. Operative variables assessed were tumor type, type of implant used, type of parotidectomy (total or subtotal), and duration of Jackson Pratt (JP) drain placement. One hundred patients were analyzed. Sixty-nine AlloDerm implants were associated with 5 complications (7%), whereas 31 DermaMatrix implants were associated with 8 complications (26%) (p = .0107). When comparing total parotidectomies, the complication rate was 1 of 20 for AlloDerm (5%) and 1 of 12 for DermaMatrix (8%) (p = .7061). When looking at subtotal parotidectomies, the incidence of complications was found to be 4 of 49 for AlloDerm (8%) and 7 of 19 for DermaMatrix (37%) (p = .004). Our study suggests that DermaMatrix was associated with increased postoperative complications compared to AlloDerm, especially in the subset of patients undergoing subtotal parotidectomy.


A comparison of a similarity-based and a feature-based 2-D-3-D registration method for neurointerventional use.
Two-dimensional (2-D)-to-three-dimensional (3-D) registration can improve visualization which may aid minimally invasive neurointerventions. Using clinical and phantom studies, two state-of-the-art approaches to rigid registration are compared quantitatively: an intensity-based algorithm using the gradient difference similarity measure; and an iterative closest point (ICP)-based algorithm. The gradient difference approach was found to be more accurate, with an average registration accuracy of 1.7 mm for clinical data, compared to the ICP-based algorithm with an average accuracy of 2.8 mm. In phantom studies, the ICP-based algorithm proved more reliable, but with more complicated clinical data, the gradient difference algorithm was more robust. Average computation time for the ICP-based algorithm was 20 s per registration, compared with 14 min and 50 s for the gradient difference algorithm.


Characterization of the cysJIH regions of Salmonella typhimurium and Escherichia coli B. DNA sequences of cysI and cysH and a model for the siroheme-Fe4S4 active center of sulfite reductase hemoprotein based on amino acid homology with spinach nitrite reductase.
The hemoprotein component of Salmonella typhimurium sulfite reductase (NADPH) (EC 18.104.22.168) was purified to homogeneity from cysJ266, a mutant strain lacking sulfite reductase flavoprotein. The siroheme- and Fe4S4-containing enzyme was isolated as a monomeric 63-kDa polypeptide and consisted of a mixture of unligated enzyme and a complex with sulfite. Following reduction with 5'-deazaflavin-EDTA and reoxidation, the complex was converted to the uncomplexed, high spin ferri-siroheme state seen previously with Escherichia coli sulfite reductase hemoprotein preparations. The S. typhimurium hemoprotein exhibited catalytic and physical properties identical to the hemoprotein prepared by urea dissociation of E. coli sulfite reductase holoenzyme and was fully competent in reconstituting NADPH-sulfite reductase activity when combined with excess purified sulfite reductase flavoprotein. The DNA sequences of cysI and cysH from S. typhimurium and E. coli B were determined and, together with previously reported data, confirmed the organization of this region as promoter-cysJ-cysI-cysH with all three genes oriented in the same direction from the promoter. Molecular weights deduced for the cysI-encoded sulfite reductase hemoprotein and for the cysH-encoded 3'-phosphoadenosine 5'-phosphosulfate sulfotransferase were approximately 64,000 and 28,000, respectively. Comparison of the deduced amino acid sequence of sulfite reductase hemoprotein with that of spinach nitrite reductase (Back, E., Burkhart, W., Moyer, M., Privalle, L., and Rothstein, S. (1988) Mol. Gen. Genet. 212, 20-26), which also contains siroheme and an Fe4S4 cluster, showed two groups of cysteine-containing sequences with the structures Cys-(X)3-Cys and Cys-(X)5-Cys, which are homologous in the two enzymes and are postulated to provide the ligands of the Fe4S4 cluster in both proteins. From these sequences and from crystallographic (McRee, D. E., Richardson, D. C., Richardson, J. S., and Siegel, L. M. (1986) J. Biol. Chem. 261, 10277-10281) and spectroscopic data in the literature, a model is proposed for the structure of the active center of these two enzymes.


SmedGD 2.0: The Schmidtea mediterranea genome database.
Planarians have emerged as excellent models for the study of key biological processes such as stem cell function and regulation, axial polarity specification, regeneration, and tissue homeostasis among others. The most widely used organism for these studies is the free-living flatworm Schmidtea mediterranea. In 2007, the Schmidtea mediterranea Genome Database (SmedGD) was first released to provide a much needed resource for the small, but growing planarian community. SmedGD 1.0 has been a depository for genome sequence, a draft assembly, and related experimental data (e.g., RNAi phenotypes, in situ hybridization images, and differential gene expression results). We report here a comprehensive update to SmedGD (SmedGD 2.0) that aims to expand its role as an interactive community resource. The new database includes more recent, and up-to-date transcription data, provides tools that enhance interconnectivity between different genome assemblies and transcriptomes, including next-generation assemblies for both the sexual and asexual biotypes of S. mediterranea. SmedGD 2.0 (http://smedgd.stowers.org) not only provides significantly improved gene annotations, but also tools for data sharing, attributes that will help both the planarian and biomedical communities to more efficiently mine the genomics and transcriptomics of S. mediterranea.


Effect of Solid Biological Waste Compost on the Metabolite Profile of Brassica rapa ssp. chinensis.
Large quantities of biological waste are generated at various steps within the food production chain and a great utilization potential for this solid biological waste exists apart from the current main usage for the feedstuff sector. It remains unclear how the usage of biological waste as compost modulates plant metabolites. We investigated the effect of biological waste of the processing of coffee, aronia, and hop added to soil on the plant metabolite profile by means of liquid chromatography in pak choi sprouts. Here we demonstrate that the solid biological waste composts induced specific changes in the metabolite profiles and the changes are depending on the type of the organic residues and its concentration in soil. The targeted analysis of selected plant metabolites, associated with health beneficial properties of the Brassicaceae family, revealed increased concentrations of carotenoids (up to 3.2-fold) and decreased amounts of glucosinolates (up to 4.7-fold) as well as phenolic compounds (up to 1.5-fold).


Motivation toward Physical Exercise and Subjective Wellbeing: The Mediating Role of Trait Self-Control.
Motivation toward physical exercise (MPE) and trait self-control (TSC) were identified as key predictors of subjective wellbeing (SWB). However, there has not been any research designed to examine the mediating role of TSC in the relationship between MPE and SWB. The present study utilizes self-determination theory, control-process theory of self-regulation, and theory of multiple pathways of TSC in order to examine whether TSC mediates the relationships of autonomous MPE (A-MPE), controlled MPE (C-MPE), and impersonal MPE (NO-MPE) with SWB using structural equation modeling (XLSTAT PLS). Three hundred seventeen adult American individuals (Mage = 32.97, SDage = 11.30), who reported to be regular exercisers, voluntarily answered questionnaires assessing MPE, TSC, and SWB. Correlational analyses revealed positive relationships between A-MPE, TSC, and SWB, and negative relationships of C-MPE and NO-MPE with TSC and SWB. Mediation analyses revealed that TSC mediated the relationships of A-MPE (partial mediation) and C-MPE (full mediation) with SWB, but did not mediate the relationship between NO-MPE and SWB. The estimates of the quality of the hypothesized model were acceptable (outer model GoF = 0.935; absolute GoF = 0.330; relative GoF = 0.942; inner model GoF = 1.008; R2 = 36.947%). Finally, this study supports the view that MPE can influence SWB through TSC, and incites to pursue the examination of the relationships between self-determined motivation, self-regulation mechanisms, and health-related outcomes.


Could work be a source of behavioural disorders? A study in horses.
Stress at work, as shown by a number of human studies, may lead to a variety of negative and durable effects, such as impaired psychological functioning (anxiety, depression...). Horses share with humans this characteristic of working on a daily basis and are submitted then to work stressors related to physical constraints and/or more "psychological" conflicts, such as potential controversial orders from the riders or the requirement to suppress emotions. On another hand, horses may perform abnormal repetitive behaviour ("stereotypies") in response to adverse life conditions. In the present study, we investigated whether the type of work the horses are used for may have an impact on their tendency to show stereotypic behaviour (and its type) outside work. Observations in their box of 76 horses all living in the same conditions, belonging to one breed and one sex, revealed that the prevalence and types of stereotypies performed strongly depended upon the type of work they were used for. The stereotypies observed involved mostly mouth movements and head tossing/nodding. Work constraints probably added to unfavourable living conditions, favouring the emergence of chronic abnormal behaviours. This is especially remarkable as the 23 hours spent in the box were influenced by the one hour work performed every day. To our knowledge, this is the first evidence of potential effects of work stressors on the emergence of abnormal behaviours in an animal species. It raises an important line of thought on the chronic impact of the work situation on the daily life of individuals.


Transgenic mdx mice expressing dystrophin with a deletion in the actin-binding domain display a "mild Becker" phenotype.
The functional significance of the actin-binding domain of dystrophin, the protein lacking in patients with Duchenne muscular dystrophy, has remained elusive. Patients with deletions of this domain (domain I) typically express low levels of the truncated protein. Whether the moderate to severe phenotypes associated with such deletions result from loss of an essential function, or from reduced levels of a functional protein, is unclear. To address this question, we have generated transgenic mice that express wild-type levels of a dystrophin deleted for the majority of the actin-binding domain. The transgene derived protein lacks amino acids 45-273, removing 2 of 3 in vitro identified actin interacting sites and part of hinge 1. Examination of the effect of this deletion in mice lacking wild-type dystrophin (mdx) suggests that a functional domain I is not essential for prevention of a dystrophic phenotype. However, in contrast to deletions in the central rod domain and to full-length dystrophin, both of which are functional at only 20% of wild-type levels, proteins with a deletion in domain I must be expressed at high levels to prevent a severe dystrophy. These results are also in contrast to the severe dystrophy resulting from truncation of the COOH-terminal domain that links dystrophin to the extracellular matrix. The mild phenotype observed in mice with domain I-deletions indicates that an intact actin-binding domain is not essential, although it does contribute to an important function of dystrophin. These studies also suggest the link between dystrophin and the subsarcolemmal cytoskeleton involves more than a simple attachment of domain I to actin filaments.


Circulating microRNAs as biomarkers for detection of autologous blood transfusion.
MicroRNAs (miRNAs) are small non-coding RNAs that regulate various biological processes. Cell-free miRNAs measured in blood plasma have emerged as specific and sensitive markers of physiological processes and disease. In this study, we investigated whether circulating miRNAs can serve as biomarkers for the detection of autologous blood transfusion, a major doping technique that is still undetectable. Plasma miRNA levels were analyzed using high-throughput quantitative real-time PCR. Plasma samples were obtained before and at several time points after autologous blood transfusion (blood bag storage time 42 days) in 10 healthy subjects and 10 controls without transfusion. Other serum markers of erythropoiesis were determined in the same samples. Our results revealed a distinct change in the pattern of circulating miRNAs. Ten miRNAs were upregulated in transfusion samples compared with control samples. Among these, miR-30b, miR-30c, and miR-26b increased significantly and showed a 3.9-, 4.0-, and 3.0-fold change, respectively. The origin of these miRNAs was related to pulmonary and liver tissues. Erythropoietin (EPO) concentration decreased after blood reinfusion. A combination of miRNAs and EPO measurement in a mathematical model enhanced the efficiency of autologous transfusion detection through miRNA analysis. Therefore, our results lay the foundation for the development of miRNAs as novel blood-based biomarkers to detect autologous transfusion.


Predicting suicides after psychiatric hospitalization in US Army soldiers: the Army Study To Assess Risk and rEsilience in Servicemembers (Army STARRS).
The US Army experienced a sharp increase in soldier suicides beginning in 2004. Administrative data reveal that among those at highest risk are soldiers in the 12 months after inpatient treatment of a psychiatric disorder. To develop an actuarial risk algorithm predicting suicide in the 12 months after US Army soldier inpatient treatment of a psychiatric disorder to target expanded posthospitalization care. There were 53,769 hospitalizations of active duty soldiers from January 1, 2004, through December 31, 2009, with International Classification of Diseases, Ninth Revision, Clinical Modification psychiatric admission diagnoses. Administrative data available before hospital discharge abstracted from a wide range of data systems (sociodemographic, US Army career, criminal justice, and medical or pharmacy) were used to predict suicides in the subsequent 12 months using machine learning methods (regression trees and penalized regressions) designed to evaluate cross-validated linear, nonlinear, and interactive predictive associations. Suicides of soldiers hospitalized with psychiatric disorders in the 12 months after hospital discharge. Sixty-eight soldiers died by suicide within 12 months of hospital discharge (12.0% of all US Army suicides), equivalent to 263.9 suicides per 100,000 person-years compared with 18.5 suicides per 100,000 person-years in the total US Army. The strongest predictors included sociodemographics (male sex [odds ratio (OR), 7.9; 95% CI, 1.9-32.6] and late age of enlistment [OR, 1.9; 95% CI, 1.0-3.5]), criminal offenses (verbal violence [OR, 2.2; 95% CI, 1.2-4.0] and weapons possession [OR, 5.6; 95% CI, 1.7-18.3]), prior suicidality [OR, 2.9; 95% CI, 1.7-4.9], aspects of prior psychiatric inpatient and outpatient treatment (eg, number of antidepressant prescriptions filled in the past 12 months [OR, 1.3; 95% CI, 1.1-1.7]), and disorders diagnosed during the focal hospitalizations (eg, nonaffective psychosis [OR, 2.9; 95% CI, 1.2-7.0]). A total of 52.9% of posthospitalization suicides occurred after the 5% of hospitalizations with highest predicted suicide risk (3824.1 suicides per 100,000 person-years). These highest-risk hospitalizations also accounted for significantly elevated proportions of several other adverse posthospitalization outcomes (unintentional injury deaths, suicide attempts, and subsequent hospitalizations). The high concentration of risk of suicide and other adverse outcomes might justify targeting expanded posthospitalization interventions to soldiers classified as having highest posthospitalization suicide risk, although final determination requires careful consideration of intervention costs, comparative effectiveness, and possible adverse effects.


Factors Influencing Expression of Antixenosis in Soybean to Anticarsia gemmatalis and Spodoptera frugiperda (Lepidoptera: Noctuidae).
This study aimed to evaluate some factors that influence the expression of antixenosis in soybean genotypes against Anticarsia gemmatalis Hübner and Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae). Free-choice and no-choice feeding assays were performed with the resistant soybean genotype IAC 100 and the susceptible genotype BRSGO 8360 using A. gemmatalis and S. frugiperda larvae. The following factors that may affect expression of resistance were evaluated: one larva versus two larvae per leaf disc; use of larvae without prior feeding suspension versus larvae starved for 3 h prior to the assay; leaf discs versus entire leaflets; upper part versus lower part of the plant; and, vegetative versus reproductive growth stages. The level of resistance exhibited by the genotype IAC 100 was high enough to not be obscured by the effects of all factors assayed in the present study upon the feeding preference of A. gemmatalis and S. frugiperda larvae. However, our results demonstrate the importance of knowing the optimal conditions for conducting an assay for evaluating resistance of genotypes for specialist and generalist insect species. Utilization of two larvae of A. gemmatalis per leaf disc, not starved before the assays, with leaf discs from the upper part of plants at the reproductive growth stage provided better discrimination of differences in antixenosis expression in soybean genotypes. For S. frugiperda, use of one larva per leaf disc, not starved before the assays, with leaf discs from the lower part of plants at the reproductive growth stage gave more satisfactory results for feeding preference tests.


(-)Pentobarbital opens ion channels of long duration in cultured mouse spinal neurons.
Intracellular recordings from voltage-clamped mouse spinal neurons in tissue culture were used to study the membrane mechanisms underlying inhibitory responses to gamma-aminobutyric acid and the (-) isomer of pentobarbital. Fluctuation analysis suggested that both substances activated ion channels in the membranes. However, the channels activated by pentobarbital remained open five times longer than those activated by gamma-aminobutyric acid.


Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation.
Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATPase that alters the phasing of nucleosomes on DNA and has recently been implicated in DNA double-stranded break (DSB) repair. Here, we show that depletion of CHD4 in acute myeloid leukemia (AML) blasts induces a global relaxation of chromatin that renders cells more susceptible to DSB formation, while concurrently impeding their repair. Furthermore, CHD4 depletion renders AML blasts more sensitive both in vitro and in vivo to genotoxic agents used in clinical therapy: daunorubicin (DNR) and cytarabine (ara-C). Sensitization to DNR and ara-C is mediated in part by activation of the ataxia-telangiectasia mutated pathway, which is preliminarily activated by a Tip60-dependent mechanism in response to chromatin relaxation and further activated by genotoxic agent-induced DSBs. This sensitization preferentially affects AML cells, as CHD4 depletion in normal CD34(+) hematopoietic progenitors does not increase their susceptibility to DNR or ara-C. Unexpectedly, we found that CHD4 is necessary for maintaining the tumor-forming behavior of AML cells, as CHD4 depletion severely restricted the ability of AML cells to form xenografts in mice and colonies in soft agar. Taken together, these results provide evidence for CHD4 as a novel therapeutic target whose inhibition has the potential to enhance the effectiveness of genotoxic agents used in AML therapy.


Assessment of Rapid Response Teams at Top-Performing Hospitals for In-Hospital Cardiac Arrest.
Rapid response teams (RRTs) are foundational to hospital response to deteriorating conditions of patients. However, little is known about differences in RRT organization and function across top-performing and non-top-performing hospitals for in-hospital cardiac arrest (IHCA) care. To evaluate differences in design and implementation of RRTs at top-performing and non-top-performing sites for survival of IHCA, which is known to be associated with hospital performance on IHCA incidence. A qualitative analysis was performed of data from semistructured interviews of 158 hospital staff members (nurses, physicians, administrators, and staff) during site visits to 9 hospitals participating in the Get With The Guidelines-Resuscitation program and consistently ranked in the top, middle, and bottom quartiles for IHCA survival during 2012-2014. Site visits were conducted from April 19, 2016, to July 27, 2017. Data analysis was completed in January 2019. Semistructured in-depth interviews were performed and thematic analysis was conducted on strategies for IHCA prevention, including RRT roles and responsibilities. Of the 158 participants, 72 were nurses (45.6%), 27 physicians (17.1%), 27 clinical staff (17.1%), and 32 administrators (20.3%). Between 12 and 30 people at each hospital participated in interviews. Differences in RRTs at top-performing and non-top-performing sites were found in the following 4 domains: team design and composition, RRT engagement in surveillance of at-risk patients, empowerment of bedside nurses to activate the RRT, and collaboration with bedside nurses during and after a rapid response. At top-performing hospitals, RRTs were typically staffed with dedicated team members without competing clinical responsibilities, who provided expertise to bedside nurses in managing patients who were at risk for deterioration, and collaborated with nurses during and after a rapid response. Bedside nurses were empowered to activate RRTs based on their judgment and experience without fear of reprisal from physicians or hospital staff. In contrast, RRT members at non-top-performing hospitals had competing clinical responsibilities and were generally less engaged with bedside nurses. Nurses at non-top-performing hospitals reported concerns about potential consequences from activating the RRT. This qualitative study's findings suggest that top-performing hospitals feature RRTs with dedicated staff without competing clinical responsibilities, that work collaboratively with bedside nurses, and that can be activated without fear of reprisal. These findings provide unique insights into RRTs at hospitals with better IHCA outcomes.


The influence of the OPRM1 (A118G) polymorphism on behavioral and neural correlates of aggression in healthy males.
Current models of aggression suggest that in addition to personality traits and environmental factors, biological vulnerability associated with genetics substantially impacts aggressive behavior. In a functional imaging study, we investigated the influence of the single nucleotide polymorphism of the mu 1 subtype opioid receptor gene (OPRM1), implicated in sociability, on correlates of trait and state aggression to delineate the function of these influences in aggression. A key aim was further to differentiate different aspects of aggressive reactions - namely, the reaction to provocation and the decision to punish an opponent. 59 healthy males performed a modified Taylor Aggression Paradigm during functional magnetic resonance imaging. The implementation of the paradigm allowed for individual assessments of the decision to behave aggressively, the experience of provocation and the ramification of punishment for the participant or the opponent. The influence of variation in the OPRM1 gene was measured by the functional A118G polymorphism. G allele carriers showed lower levels of general aggression and self-reported physical aggression. Additionally, these participants exhibited increased activation in dorsolateral prefrontal, orbitofrontal, anterior cingulate and insular cortices when choosing higher punishments for the opponent. The OPRM1 polymorphism did not influence aggression in reaction to social provocation. Thus, we suggest that this genetic variant affects one's trait aggressiveness rather than actual behavioral reactivity to provocation. Investigating brain regions that are specifically linked to provocation yielded activation in cortico-limbic circuits which might mediate the evaluation of provocation and the experience of anger and thus shed light on neural processes underlying the risk for aggressive behavior. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.