Vectors for RNAi technology in poplar.
The potential of double-stranded RNA interference (RNAi) technology was studied for down-regulation of gene expression in poplar. A set of vectors was constructed generating RNAs capable of duplex formation of sequences specific for the beta-glucuronidase (GUS) reporter gene system. These gene cassettes are driven by the CaMV-35S promoter. To address the question of gene silencing, we tested the functionality of these vectors, both in transient assays by transforming protoplasts with the RNAi constructs, and in stably transformed GUSexpressing poplar plants. Agrobacterium-mediated transformation of those GUS-expressing plants with a GUS-specific RNAi construct showed a strong down-regulation of the reporter gene. From these results we conclude that RNAi is also functional in poplar.


MicroRNAs: markers of β-cell stress and autoimmunity.
We discuss current knowledge about microRNAs (miRNAs) in type 1 diabetes (T1D), an autoimmune disease leading to severe loss of pancreatic β-cells. We describe: the role of cellular miRNAs in regulating immune functions and pathways impacting insulin secretion and β-cell survival; circulating miRNAs as disease biomarkers. Studies examined miRNAs in experimental models and patients, including analysis of tissues from organ donors, peripheral blood cells, and circulating miRNAs in serum, plasma, and exosomes. Studies employed diverse designs and methodologies to detect miRNAs and measure their levels. Selected miRNAs have been linked to the regulation of key biological pathways and disease pathogenesis; several circulating miRNAs are associated with having T1D, islet autoimmunity, disease progression, and immune and metabolic functions, for example, C-peptide secretion, in multiple studies. A growing literature reveals multiple roles of miRNAs in T1D, provide new clues into the regulation of disease mechanisms, and identify reproducible associations. Yet challenges remain, and the field will benefit from joint efforts to analyze results, compare methodologies, formally test the robustness of miRNA associations, and ultimately move towards validating robust miRNA biomarkers.


Dietary linoleic and α-linolenic acids affect anxiety-related responses and exploratory activity in growing pigs.
Growing evidence suggests that the dietary ratio of linoleic acid (LA) to α-linolenic acid (ALA), the precursors of arachidonic acid (AA) and docosahexaenoic acid (DHA), respectively, may affect behavior in mammals. This study aimed at evaluating the impact of dietary LA and ALA intake on behaviors of growing pigs, a pertinent model for human nutrition. At 7 wk of age, 32 pigs were allocated to 4 dietary treatments varying in daily intake of LA (1.3 and 2.6 g · kg body weight(-0.75) · d(-1) for low- and high-LA groups, respectively) and ALA (0.15 and 1.5 g · kg body weight(-0.75) · d(-1) for low- and high-ALA groups, respectively) for 4 wk. Between days 12 and 18, general behavior in the home pen was observed and pigs were subjected to an open field and novel object test. At 11 wk of age, brain fatty acid composition was analyzed. Compared with high LA intake, low LA intake increased the time spent on exploration, particularly nosing in the home pen (P < 0.05) and the open field (P < 0.05), and tended to reduce the time spent lying with eyes open in the home pen (P = 0.09). Time spent lying with eyes open also tended to be affected by the interaction between LA and ALA (P = 0.08). A high-LA/high-ALA intake (ratio of 2; P < 0.05) and a low-LA/high-ALA intake (ratio of 1; P = 0.06) decreased the latency to approach the novel object compared with a low-LA/low-ALA intake (ratio of 9). DHA in the frontal cortex was positively correlated with exploratory behaviors in the home pen (rs = 0.56, P < 0.01), whereas AA was negatively correlated with time spent lying with eyes closed (rs = -0.48, P < 0.01). Low LA intake and a low dietary LA:ALA ratio increased exploration and decreased anxiety-related behaviors in pigs. It is suggested that changes in brain DHA and AA induced by dietary LA and ALA intake mediate these behavioral changes.


[Ultrasonic integrated backscatter analysis in patients with dilated cardiomyopathy: comparison with healthy individuals].
Ultrasonic tissue characterization, based on the measurements of integrated backscatter (IBS) analysis, has the potential to provide quantitative information which could characterize the functional and structural state of cardiac muscle. In this study we aimed to determine whether the integrated backscatter is measurable and quantifiable in left ventricular walls in patients with dilated cardiomyopathy (DCMP) and can be used to identify changes in myocardial structure and contractility. We studied 32 subjects: 16 patients with idiopathic dilated cardiomyopathy who were free of atrial fibrillation, bundle branch block and valvular heart disease (12 male, 4 female, mean age 48 +/- 18) and 16 healthy volunteers (10 male, 6 female, mean age 46 +/- 8). Left ventricular diastolic and systolic diameters, septum and posterior wall (PW) systolic and diastolic thickness were measured in the parasternal long axis view with M-mode echocardiography. Ejection fraction (EF), fractional shortening (FS), septum and posterior percent wall thickening (WT%) were calculated in the parasternal long axis view with M-mode echocardiography. Real time IBS was measured from the parasternal long axis view of the left ventricle at the level of basal posterior and septal walls. Mean IBS was expressed as averaged IBS values and cyclic variation of IBS (CVIBS) was expressed as the difference between end-diastolic (peak) and end-systolic (nadir) IBS values averaged over all cardiac cycles. CVIBS values obtained from septum and PW in idiopathic DCMP group were statistically different from control group (p = 0.003, p < 0.001, respectively). Septal and PW mean IBS values in idiopathic DCMP group were greater and statistically different from control group (p < 0.05). Septum and PW CVIBS values correlated with WT%, EF and FS positively. But, septum and PW mean IBS values did not correlate with WT%, EF and FS. CVIBS and mean IBS values which were obtained with IBS method may be useful to determine myocardial contractile performance and myocardial structural properties, respectively.


Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats.
In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development's (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security.


Influence of epidermal thickness, pigmentation and redness on skin autofluorescence.
Detection of autofluorescence at the skin surface is highly influenced by melanin and hemoglobin. Epidermal absorption and scattering may also be an influencing factor and is represented in this article as a quantitative parameter, epidermal thickness. To examine this parameter we measured the 370 nm fluorescence in vivo after excitation with 330 nm and the 455 nm fluorescence after excitation with 330 and 370 nm. Measurements were performed on sun-exposed skin at the dorsal aspect of the forearm and shoulder and on nonexposed buttock skin. Skin pigmentation and redness of the same body sites were measured by reflectance spectroscopy. The thickness of the stratum corneum and the cellular part of epidermis was quantified by light microscopy of skin biopsies. Multiple regression analysis was used to find correlations between autofluorescence and the potential influencing factors. We found a highly significant correlation of skin autofluorescence with pigmentation and redness for both emission wavelengths (Em). A small but significant correlation to epidermal thickness was found only for excitation wavelength (Ex) 370 nm and Em455 nm if body site was included in the analysis. No correlation between Ex330:Em370 and Ex330:Em455 and thickness of epidermis was found. For practical use, correction of skin autofluorescence for pigmentation is essential, correction for redness is of less importance and correction for epidermal thickness is unnecessary.


Indomethacin reduces glomerular and tubular damage markers but not renal inflammation in chronic kidney disease patients: a post-hoc analysis.
Under specific conditions non-steroidal anti-inflammatory drugs (NSAIDs) may be used to lower therapy-resistant proteinuria. The potentially beneficial anti-proteinuric, tubulo-protective, and anti-inflammatory effects of NSAIDs may be offset by an increased risk of (renal) side effects. We investigated the effect of indomethacin on urinary markers of glomerular and tubular damage and renal inflammation. We performed a post-hoc analysis of a prospective open-label crossover study in chronic kidney disease patients (n = 12) with mild renal function impairment and stable residual proteinuria of 4.7±4.1 g/d. After a wash-out period of six wks without any RAAS blocking agents or other therapy to lower proteinuria (untreated proteinuria (UP)), patients subsequently received indomethacin 75 mg BID for 4 wks (NSAID). Healthy subjects (n = 10) screened for kidney donation served as controls. Urine and plasma levels of total IgG, IgG4, KIM-1, beta-2-microglobulin, H-FABP, MCP-1 and NGAL were determined using ELISA. Following NSAID treatment, 24 h -urinary excretion of glomerular and proximal tubular damage markers was reduced in comparison with the period without anti-proteinuric treatment (total IgG: UP 131[38-513] vs NSAID 38[17-218] mg/24 h, p<0.01; IgG4: 50[16-68] vs 10[1-38] mg/24 h, p<0.001; beta-2-microglobulin: 200[55-404] vs 50[28-110] ug/24 h, p = 0.03; KIM-1: 9[5]-[14] vs 5[2]-[9] ug/24 h, p = 0.01). Fractional excretions of these damage markers were also reduced by NSAID. The distal tubular marker H-FABP showed a trend to reduction following NSAID treatment. Surprisingly, NSAID treatment did not reduce urinary excretion of the inflammation markers MCP-1 and NGAL, but did reduce plasma MCP-1 levels, resulting in an increased fractional MCP-1 excretion. In conclusion, the anti-proteinuric effect of indomethacin is associated with reduced urinary excretion of glomerular and tubular damage markers, but not with reduced excretion of renal inflammation markers. Future studies should address whether the short term glomerulo- and tubulo-protective effects as observed outweigh the possible side-effects of NSAID treatment on the long term.


Rapid intravenous loading of levodopa for human research: clinical results.
Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition of peripheral metabolism levodopa does not change mean cerebral blood flow. For neuroimaging studies of Parkinson disease (PD) and Tourette syndrome, we sought to rapidly produce a biologically relevant steady-state levodopa concentration and then maintain that concentration for at least an hour. We also wished to minimize side effects, even in individuals without prior levodopa treatment. We designed a two-stage intravenous infusion protocol based on published levodopa pharmacokinetic data. We report results of 125 infusions in 106 subjects, including healthy volunteers, PD patients, and people with chronic tics. At higher doses (target steady-state levodopa concentrations of 2,169 and 1,200 ng/ml), treatment-naive volunteers had unacceptably frequent side effects. The final infusion protocol, with a target steady-state concentration of 600 ng/ml, was well-tolerated (mild nausea in 11% of subjects was the only side effect occurring significantly more than in single-blind saline infusions), produced the desired plasma levodopa concentration (612+/-187 ng/ml, mean+/-S.D.), and produced statistically significant antiparkinsonian benefit (16% mean reduction in a standard rating of parkinsonian motor signs, P<0.0005).


[Psychotherapy of adjustment disorders].
The purpose of the present study was to investigate the long-term effects of outpatient client-centered psychotherapy limited to 12 sessions on patients with adjustment disorder (ICD-10 F43.2). The patients in the follow-up study (n = 25) had been diagnosed to be suffering from an adjustment disorder in response to one of the following stressful events: the loss of an important person or a severe negative experience at work or university with lasting negative consequences. Two years after completion of treatment they were examined in regard to their levels of anxiety, depression and satisfaction with life by applying standardized measures. According to self-ratings lasting significant improvements in comparison to the initial symptom severity and no impairment in comparison to the results immediately after the end of the therapy could be observed. Subsequently the symptom decrease gained in the short-term therapy period is clearly maintained over the post-therapy period. Post-treatment gains after two years in the meaning of subsequent improvements - as often discovered in client-centered psychotherapies - could, however, not be demonstrated for patients with this type of disorder.


Retransplantation Outcomes at a Large Lung Transplantation Program.
With the increase of primary lung transplantation across major centers worldwide, over the last several years the need of lung retransplant (ReTX) is likely to increase. Therefore, characterization of ReTX patients is prudent and necessary. Our study aimed to investigate and characterize the covariates and outcomes associated with lung ReTX survival in a single large U.S. transplant center. Demographic, clinical diagnoses, and comorbidities were analyzed. Kaplan-Meier statistics were used to calculate and predict survival for 30 days and up to 3 years. Cox proportional modeling was used to determine the variables associated with mortality. Of included 684 lung transplants performed at the Houston Methodist Hospital between January 2009 and December 2015, 49 were lung ReTX. Median age of primary lung transplant (non-ReTX) and ReTx recipients was 62 and 49 years, respectively. Chronic graft rejection in the form of restrictive chronic lung allograft dysfunction and bronchiolitis obliterans syndrome was the main indications for ReTX. Compared with non-ReTX patients, ReTX patients had higher median lung allocation score (46.2 vs 37.0, respectively) and higher mortality after 6 months posttransplant. ReTX, older age, female sex, hospitalization 15 days or longer, estimated glomerular filtration rate less than 60, 6-minute walk distance less than 400 ft, and donor/recipient height ratio less than 1 were significantly associated with decreased 1-year patient and graft survival. Chronic graft rejection was still the major cause of death in the long-term follow-up recipients. Our findings suggested that lung ReTX recipients have poor long-term survival outcomes. Lung ReTX should only be offered to carefully selected patients.


Insulin-like growth factor-1 is an endogenous mediator of focal ischemia-induced neural progenitor proliferation.
The adult mammalian brain contains resident neural progenitors in the subgranular zone of the dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricles. The proliferation of neural progenitors increases after focal cerebral ischemia in both of these regions, but the mechanisms that promote ischemia-induced neural progenitor proliferation are not yet understood. We hypothesize that diffusible factors from the ischemic area play a role in this process as the DG is remote from the area of infarction. In this study, we observed that the peak of neural progenitor proliferation in the ipsilateral DG was between day 2 and day 4 of reperfusion after transient middle cerebral artery occlusion in adult spontaneously hypertensive rats. GeneChip and real-time PCR analysis showed a three- to 102-fold increase in the expression of 15 diffusible, mitogenic factors in the ischemic cortex at 3 days of reperfusion. Of these, insulin-like growth factor-1 (IGF-1) showed increased protein expression in the activated astrocytes in the ischemic penumbra. In addition, the progenitors in both the SVZ and DG showed IGF-1 receptor expression. Inhibiting IGF-1 activity by introcerebroventricular infusion of IGF-1 antibody significantly prevented the ischemia-induced neural progenitor proliferation. These results indicate that IGF-1 formed in the ischemic penumbra might be one of the diffusible factors that mediate post-ischemic neural progenitor proliferation.


Melting of Duplex DNA in the Absence of ATP by the NS3 Helicase Domain through Specific Interaction with a Single-Strand/Double-Strand Junction.
Helicases unwind double-stranded nucleic acids, remove secondary structures from single-stranded nucleic acids, and remove proteins bound to nucleic acids. For many helicases, the mechanisms for these different functions share the ability to translocate with a directional bias as a result of ATP binding and hydrolysis. Nonstructural protein 3 (NS3) is an essential enzyme expressed by the hepatitis C virus (HCV) and is known to catalyze the unwinding of both DNA and RNA substrates in a 3'-to-5' direction. We investigated the role of nucleic acid binding in the unwinding mechanism by examining ATP-independent unwinding. We observed that even in the absence of ATP, the NS3 helicase domain (NS3h) unwound duplexes only when they contained a 3'-tail (i.e., 3'-to-5' directionality). Blunt-ended duplexes and 5'-tailed duplexes were not melted even in the presence of a large excess concentration of the protein. NS3h was found to diffuse rapidly along single-stranded DNA at a rate of 30 nucleotides(2) s(-1). Upon encountering an appropriate single-strand/double-strand (ss/ds) junction, NS3h slowly melted the duplex under conditions with an excess protein concentration relative to DNA concentration. When a biotin-streptavidin block was placed into the ssDNA region, no melting of DNA was observed, suggesting that NS3h must diffuse along the ssDNA, and that the streptavidin blocked the diffusion. We conclude that the specific interaction between NS3h and the ss/dsDNA junction, coupled with diffusion, allows binding energy to melt duplex DNA with a directional bias. Alternatively, we found that the full-length NS3 protein did not exhibit strict directionality and was dependent on duplex DNA length. NS3 was able to unwind the duplex even in the presence of the biotin-streptavidin block. We propose a noncanonical model of unwinding for NS3 in which the enzyme binds directly to the duplex via protein-protein interactions to melt the substrate.


Surface EMG in Clinical Assessment and Neurorehabilitation: Barriers Limiting Its Use.
This article addresses the potential clinical value of techniques based on surface electromyography (sEMG) in rehabilitation medicine with specific focus on neurorehabilitation. Applications in exercise and sport pathophysiology, in movement analysis, in ergonomics and occupational medicine, and in a number of related fields are also considered. The contrast between the extensive scientific literature in these fields and the limited clinical applications is discussed. The "barriers" between research findings and their application are very broad, and are longstanding, cultural, educational, and technical. Cultural barriers relate to the general acceptance and use of the concept of objective measurement in a clinical setting and its role in promoting Evidence Based Medicine. Wide differences between countries exist in appropriate training in the use of such quantitative measurements in general, and in electrical measurements in particular. These differences are manifest in training programs, in degrees granted, and in academic/research career opportunities. Educational barriers are related to the background in mathematics and physics for rehabilitation clinicians, leading to insufficient basic concepts of signal interpretation, as well as to the lack of a common language with rehabilitation engineers. Technical barriers are being overcome progressively, but progress is still impacted by the lack of user-friendly equipment, insufficient market demand, gadget-like devices, relatively high equipment price and a pervasive lack of interest by manufacturers. Despite the recommendations provided by the 20-year old EU project on "Surface EMG for Non-Invasive Assessment of Muscles (SENIAM)," real international standards are still missing and there is minimal international pressure for developing and applying such standards. The need for change in training and teaching is increasingly felt in the academic world, but is much less perceived in the health delivery system and clinical environments. The rapid technological progress in the fields of sensor and measurement technology (including sEMG), assistive devices, and robotic rehabilitation, has not been driven by clinical demands. Our assertion is that the most important and urgent interventions concern enhanced education, more effective technology transfer, and increased academic opportunities for physiotherapists, occupational therapists, and kinesiologists.


Assessing intern handover processes.
New standards for resident work hours set in 2011 changed the landscape of patient care in teaching hospitals, and resulted in new challenges for US residency training programmes to overcome. One such challenge was a dramatic increase in the number of patient handovers performed by residents. As a result, there is a renewed focus for clinical teachers to develop educational strategies to optimise the patient handover process and improve the quality of patient care and safety. In order to investigate current gaps in resident handovers, we examined the handover processes performed by medicine interns at two academic medical centres in Baltimore, Maryland, USA. We used trained observers to collect data on whether handovers were conducted face to face, with questions asked, in private locations, with written documentation, and without distractions or interruptions. Results were analysed using chi-square tests, and adjusted for clustering at the observer and intern levels. Interns successfully conducted handovers face to face (99.5%), asked questions (85.3%), used private locations (91%), included written handover documentation (95.8%) and did not experience distractions for the majority of the time (87.7%); however, interruptions were pervasive, occurring 41.3 per cent of the time. In order to investigate current gaps in resident handovers, we examined the handover processes performed by medicine interns Interns conducted patient handovers face to face, with questions asked, in private locations, with written documentation and without distractions the majority of the time; however, interruptions during the handover process were common. Exploring gaps at the individual programme level is a critical first step to develop effective teaching strategies to optimise handovers in residency.


Photochemotherapy induces the apoptosis of monocytes without impairing their function.
Extracorporeal photopheresis (ECP) is a powerful therapy currently used to treat various hematological disorders as in graft versus host disease. Clinical data clearly demonstrate its efficacy and immunomodulation toward the pathogenic T cells. However, ECP mechanism of action is still poorly understood. Monocytes represent up to 30% of the total amount of treated cells and are known to play an important role in adaptive immunity. However, data from previous reports analyzing the effect of psoralen and UV-A irradiation (PUVA) on their functions are heterogeneous. In this study, we focused on the effect of PUVA on human monocytes functions in adaptive immunity. Purified human monocytes were treated in vitro by PUVA. We measured their kinetic of apoptosis after the treatment. We also determine whether their phenotype and functionalities were modified. Finally, we assessed the functionalities of PUVA-treated monocytes-derived dendritic cells (DC). PUVA treatment sentenced purified monocytes to die in 6 days and immediately altered their migratory capacities without impairing their ability of endocytosis. It also up-regulated co-stimulatory molecules and production of inflammatory cytokines on activation and consequently stimulated allogeneic or autologous T cells as efficiently as untreated monocytes. Moreover, PUVA-treated monocytes retained their ability to differentiate into fully functional DC that maturated and stimulated T cells as well as normal DC. Our data demonstrate that monocytes undergo apoptosis and loose a part of their migratory capacity after ECP and the surviving cell functionalities are not impaired, suggesting that monocytes have a minor effect on ECP-mediated immunomodulation.


Exploration of temporal stability and prognostic power of radiomic features based on electronic portal imaging device images.
We aimed to explore the temporal stability of radiomic features in the presence of tumor motion and the prognostic powers of temporally stable features. We selected single fraction dynamic electronic portal imaging device (EPID) (n = 275 frames) and static digitally reconstructed radiographs (DRRs) of 11 lung cancer patients, who received stereotactic body radiation therapy (SBRT) under free breathing. Forty-seven statistical radiomic features, which consisted of 14 histogram-based features and 33 texture features derived from the graylevel co-occurrence and graylevel run-length matrices, were computed. The temporal stability was assessed by using a multiplication of the intra-class correlation coefficients (ICCs) between features derived from the EPID and DRR images at three quantization levels. The prognostic powers of the features were investigated using a different database of lung cancer patients (n = 221) based on a Kaplan-Meier survival analysis. Fifteen radiomic features were found to be temporally stable for various quantization levels. Among these features, seven features have shown potentials for prognostic prediction in lung cancer patients. This study suggests a novel approach to select temporally stable radiomic features, which could hold prognostic powers in lung cancer patients.


Influence of cooling on curing temperature distribution during cementing of modular cobalt-chromium and monoblock polyethylene acetabular cups.
Total hip replacements for older patients are usually cemented to ensure high postoperative primary stability. Curing temperatures vary with implant material and cement thickness (30°C to 70°C), whereas limits for the initiation of thermal bone damage are reported at 45°C to 55°C. Thus, optimizing surgical treatment and the implant material are possible approaches to lower the temperature. The aim of this study was to investigate the influence of water cooling on the temperature magnitude at the acetabulum cement interface during curing of a modular cobalt-chromium cup and a monoblock polyethylene acetabular cup. The curing temperature was measured for SAWBONE and human acetabuli at the cement-bone interface using thermocouples. Peak temperature for the uncooled condition reached 70°C for both cup materials but was reduced to below 50°C in the cooled condition for the cobalt-chromium cup (P = .027). Cooling is an effective method to reduce curing temperature with metal implants, thereby avoiding the risk of thermal bone damage.


A case control series for the effect of photobiomodulation in patients with low back pain and concurrent depression.
To present incidental findings in patients with low back pain (LBP) who received photobiomodulation (PBM) administered to the back and thighs as an adjunct to physical therapy (PT) and then experienced improvement in concurrent depression. Five outpatients with LBP and concurrent self-reported depression were treated for LBP over five weeks with PT (5-sessions) and concurrent PBM (final 3-sessions), and retrospectively matched to five control patients treated with PT alone (5-sessions). The PBM device emitted light at 850nm and 660 nm with an irradiance of 100 mW/cm2 and fluence of 3 J/cm2 on 12 symmetrical posterior sites (thoracic, lumbar and thighs) for 30 sec/site. Both groups had non-significant differences in all baseline scores, except for higher functional status (ARGS) in the PBM-group (33.6 ± 12.2 vs.18.6 ± 3.6, t(8) = 2.638, p = 0.030). After treatment, the mean decrease in depression scores (OMSQ-12 item #6) was significantly larger in the PBM-group (43.0 ± 22.0 vs. 8.0 ± 5.7, t(8) = 3.449, p = 0.009). Improvement in functional status (ARGS) in the PBM-group was similar to that in the controls (42.0 ± 13.5 vs. 43.4 ± 11.1, t(8) = 0.179, p = 0.862), suggesting group differences in antidepressant effect were independent of functional status improvement. This preliminary investigation suggests that an antidepressant effect may result from PBM to the back and thighs in patients with LBP and concurrent depression.


Combined irradiation and three-drug chemotherapy in inoperable colorectal carcinoma.
Forty patients with inoperable or not radically resected tumours in the rectum or rectosigmoideum were treated with irradiation combined with 5-fluorouracil, methotrexate and cyclophosphamide. The acute toxicity was moderate, but 3 patients developed late complications such as fibrosis and fistulation in the irradiated area. Twenty-one patients had a measurable tumour within the radiation fields and were included in the evaluation of the tumour response. Of these patients 8 achieved complete and 5 partial tumour remission. Nevertheless, it is emphasized that this treatment cannot be recommended because of severe complications observed in a following randomized series of patients receiving irradiation combined with 5-fluorouracil and methotrexate.


Leukemic stem cell phenotype is associated with mutational profile in acute myeloid leukemia.
Understanding leukemic stem cell (LSC) is important for acute myeloid leukemia (AML) treatment. However, association of LSC with patient prognosis and genetic information in AML patients is unclear. Here we investigated the associations between genetic information and the various LSC phenotypes, namely multipotent progenitor (MPP)-like, lymphoid primed multipotent progenitor (LMPP)-like and granulocyte-macrophage progenitors (GMP)-like LSC in 52 AML patients. In secondary AML patients, MPP-like LSC was significantly higher than de novo AML (p = 0.0037). The proportion of MPP-like LSC was especially high in post-myeloproliferative neoplasm AML (p = 0.0485). There was no correlation between age and LSC phenotype. Mutations of KRAS and NRAS were observed in MPP-like LSC dominant patients, TP53 and ASXL1 mutations in LMPP-like LSC dominant patients, and CEBPA, DNMT3A and IDH1 mutations in GMP-like LSC dominant patients. Furthermore, KRAS mutation was significantly associated with MPP-like LSC expression (p = 0.0540), and TP53 mutation with LMPP-like LSC expression (p = 0.0276). When the patients were separated according to the combined risk including next generation sequencing data, the poorer the prognosis, the higher the LMPP-like LSC expression (p = 0.0052). This suggests that the dominant phenotype of LSC is one of the important factors in predicting the prognosis and treatment of AML. LSC phenotype in AML is closely associated with the recurrent mutations which has prognostic implication. Further research to confirm the meaning of LSC phenotype in the context of genetic aberration is warranted.


Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy.
Acute kidney injury (AKI) is associated with significant mortality, which increases further when combined with acute lung injury. Experiments in rodents have shown that kidney ischemia-reperfusion injury (IRI) facilitates lung injury and inflammation. To identify potential ischemia-specific lung molecular pathways involved, we conducted global gene expression profiling of lung 6 or 36 h following 1) bilateral kidney IRI, 2) bilateral nephrectomy (BNx), and 3) sham laparotomy in C57BL/6J mice. Bronchoalveolar lavage fluid analysis revealed increased total protein, and lung histology revealed increased cellular inflammation following IRI, but not BNx, compared with sham controls. Total RNA from whole lung was isolated and hybridized to 430MOEA (22,626 genes) GeneChips (n = 3/group), which were analyzed by robust multichip average and significance analysis of microarrays and linked to gene ontology (GO) terms using MAPPFinder. The microarray power analysis predicted that the false discovery rate (q < 1%) and > or =50%-fold change compared with sham would represent significant changes in gene expression. Analysis identified 266 and 455 ischemia-specific, AKI-associated lung genes with increased expression and 615 and 204 with decreased expression at 6 and 36 h, respectively, compared with sham controls. Real-time PCR analysis validated select array changes in lung serum amyloid A3 and endothelin-1. GO analysis revealed significant activation (Z > 1.95) of several proinflammatory and proapoptotic biological processes. Ischemic AKI induces functional and transcriptional changes in the lung distinct from those induced by uremia alone. Further investigation using this lung molecular signature induced by kidney IRI will provide mechanistic insights and new therapies for critically ill patients with AKI.


Secondary bruxism: A valid diagnosis or just a coincidental finding of additional masticatory muscle activity? A narrative review of literature.
Bruxism is defined as a repetitive masticatory muscle activity that can manifest it upon awakening (awake bruxism-AB) or during sleep (sleep bruxism-SB). Some forms of both, AB and SB can be associated to many other coexistent factors, considered of risk for the initiation and maintenance of the bruxism. Although controversial, the term 'secondary bruxism' has frequently been used to label these cases. The absence of an adequate definition of bruxism, the non-distinction between the circadian manifestations and the report of many different measurement techniques, however, are important factors to be considered when judging the literature findings. The use (and abuse) of drugs, caffeine, nicotine, alcohol and psychoactive substances, the presence of respiratory disorders during sleep, gastroesophageal reflux disorders and movement, neurological and psychiatric disorders are among these factors. The scarcity of controlled studies and the complexity and interactions among all aforementioned factors, unfortunately, does not allow to establish any causality or temporal association with SB and AB. The supposition that variables are related depends on different parameters, not clearly demonstrated in the available studies. This narrative review aims at providing oral health care professionals with an update on the co-risk factors and disorders possibly associated with bruxism. In addition, the authors discuss the appropriateness of the term 'secondary bruxism' as a valid diagnostic category based on the available evidence. The absence of an adequate definition of bruxism, the non-distinction between the circadian manifestations and the report of many different measurement techniques found in many studies preclude any solid and convincing conclusion on the existence of the 'secondary' bruxism.


46,XY Disorder of Sex Development Caused by 17α-Hydroxylase/17,20-Lyase Deficiency due to Homozygous Mutation of CYP17A1 Gene: Consequences of Late Diagnosis.
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease due to specific enzyme deficiencies in the adrenal steroidogenesis pathway. A 40-year-old Chinese woman was referred to the Endocrine Unit for the work-up of a syndrome characterized by long-lasting and multidrug resistant high blood pressure, severe hypokalemia with metabolic alkalosis, and primary amenorrhea. The patient presented with sexual infantilism, lack of breast development, absence of axillary and pubic hair, tall stature, and slenderness. CT scan revealed enlarged adrenal glands bilaterally and the absence of the uterus, the ovaries, and the Fallopian tubes. Furthermore, diffuse osteopenia and osteoporosis and incomplete ossification of the growth plate cartilages were demonstrated. Chromosomal analysis showed a normal male 46,XY, karyotype, and on molecular analysis of the CYP17A1 gene she resulted homozygous for the g.4869T>A; g.4871delC (p.Y329Kfs?) mutation in exon 6. Hydrocortisone and ethinyl-estradiol supplementation therapy led to incomplete withdrawal of antihypertensive drug and breast development progression to Tanner stage B2 and slight height increase, respectively. We describe a late-discovered case of CAH with 46,XY disorder of sex development. Deficiency of 17α-hydroxylase/17,20-lyase due to a homozygous CYP17A1 gene mutation was the underlying cause. Laboratory, imaging, and genetic features are herein reported and discussed.


Peculiarities of the embryonic development of Polypodium hydriforme Ussov (Coelenterata), a parasite of acipenserid oocytes.
"Unicellular" stages (107 specimens) and multicellular stages (64 specimens) of embryogenesis of Polypodium, found in 14 sterlet (Acipenser ruthenus L.) females, have been studied with light microscopy, cytophotometry, and autoradiography following incubation with 3H-uridine. All stages of the embryonic development occur inside host oocytes. The "unicellular" stage includes a binucleate cell with unequally sized nuclei; separation inside it of a small cell around the smaller nucleus, i.e. transformation of the single cell into a complex of 2 cells, the larger one enveloping the smaller; formation of a cavity inside the nucleus of the large (outer) cell, and migration of the small cell into it, and "cell-in-a-cell" stage, the small (generative) cell being inside the cavity formed by the nucleus of the large (trophic) cell. The latter gives rise to a hypertrophied but still unicellular envelope around the embryo, the trophamnion. The multicellular stages start with segmentation of the generative cell into blastomeres. These form a morula lying inside the cavity of the trophamnion. Gastrulation occurs by morular delamination. The inversion of the germ layers, typical of parasitic Polypodium stages, apparently arises during gastrulation. Both the generative cell ("egg") and the blastomeres are haploid, at least until the morula stage. The eggs of Polypodium are the smallest ones among coelenterates; they lack yolk and develop without fertilization. Diploidy seems to be restored during segmentation. The trophamnion cell grows, its nucleus becomes highly polypoid, and its cytoplasm accumulates mucoprotein inclusions. Both the blastomere nuclei and the trophamnion nucleus have large nucleoli and actively synthesize RNA. The stages of embryogenesis of Polypodium closely correspond to stages of the host oogenesis. The embryonic development of Polypodium lasts several years and is the slowest among coelenterates. However, it has some features typical of the class Hydrozoa.


Public awareness of childhood, teenager and young adult cancer signs and symptoms in Great Britain: a cross-sectional survey.
To assess public awareness of the risks and symptoms of cancer in children, teenagers, and young adults (CTYA) aged <18 years in Great Britain. A face-to-face computer-assisted opinion survey was conducted by Ipsos MORI. Participants were a population-based sample of 1000 adults (475 men, 525 women) aged >18 years, with 26% having children aged 6-15 in their households. Questions covered perception about cumulative cancer risk, confidence in recognising signs and symptoms, recognition and perceived urgency of classical signs and symptoms. Only 32% of respondents felt confident in recognising CTYA cancer signs and symptoms. Symptoms deemed to require medical assessment within 48 hours by over 50% of participants included seizures/fits, blood in urine or stool, and persistent vomiting. All symptoms except one were selected for assessment within 3 months. On average, respondents identified 10.6 out of 42 classical signs and symptoms. The most recognised symptoms included lump, swelling in pelvis, testicle or breast (46%), blood in urine or stool (44%), changes to moles (43%), lump/swelling in the chest wall or armpits (41%) and weight loss (40%). The least recognised symptoms were early/late puberty (10%), developmental delay in children aged <2 years (11%) and slow growth (13%), with 8%, 2% and 6%, respectively, perceiving no need to discuss them with a doctor. Public awareness of childhood cancer risks and symptoms is substantially lower compared with adult cancer awareness in Great Britain. These findings indicate knowledge and awareness gaps among the general public, highlighting the need for a child cancer awareness campaign.


Electromagnetic Duality Anomaly in Curved Spacetimes.
The source-free Maxwell action is invariant under electric-magnetic duality rotations in arbitrary spacetimes. This leads to a conserved classical Noether charge. We show that this conservation law is broken at the quantum level in the presence of a background classical gravitational field with a nontrivial Chern-Pontryagin invariant, in parallel with the chiral anomaly for massless Dirac fermions. Among the physical consequences, the net polarization of the quantum electromagnetic field is not conserved.


Performance characteristics of the PTSD Checklist in retired firefighters exposed to the World Trade Center disaster.
Since the World Trade Center (WTC) attacks on September 11, 2001, the Fire Department, City of New York Monitoring Program has provided physical and mental health screening services to rescue/recovery workers. This study evaluated performance of the self-report PTSD Checklist (PCL) as a screening tool for risk of posttraumatic stress disorder (PTSD) in firefighters who worked at Ground Zero, compared with the interviewer-administered Diagnostic Interview Schedule (DIS). From December 2005 to July 2007, all retired firefighter enrollees completed the PCL and DIS on the same day. Sensitivity, specificity, receiver operating characteristic (ROC) curves, and Youden index (J) were used to assess properties of the PCL and to identify an optimum cutoff score. Six percent of 1,915 retired male firefighters were diagnosed with PTSD using the DIS to assess DSM-IV criteria. Depending on the PCL cutoff, the prevalence of elevated risk relative to DSM-IV criteria varied from 16% to 22%. Youden index identified an optimal cutoff score of 39, in contrast with the frequently recommended cutoff of 44. At 39, PCL sensitivity was 0.85, specificity was 0.82, and the area under the ROC curve was 0.91 relative to DIS PTSD diagnosis. This is the first study to validate the PCL in retired firefighters and determine the optimal cutoff score to maximize opportunities for PTSD diagnosis and treatment.


Overexpression of corticotropin releasing factor in the central nucleus of the amygdala advances puberty and disrupts reproductive cycles in female rats.
Prolonged exposure to environmental stress activates the hypothalamic-pituitary-adrenal (HPA) axis and generally disrupts the hypothalamic-pituitary-gonadal axis. Because CRF expression in the central nucleus of the amygdala (CeA) is a key modulator in adaptation to chronic stress, and central administration of CRF inhibits the hypothalamic GnRH pulse generator, we tested the hypothesis that overexpression of CRF in the CeA of female rats alters anxiety behavior, dysregulates the HPA axis response to stress, changes pubertal timing, and disrupts reproduction. We used a lentiviral vector to increase CRF expression site specifically in the CeA of preweaning (postnatal day 12) female rats. Overexpression of CRF in the CeA increased anxiety-like behavior in peripubertal rats shown by a reduction in time spent in the open arms of the elevated plus maze and a decrease in social interaction. Paradoxically, puberty onset was advanced but followed by irregular estrous cyclicity and an absence of spontaneous preovulatory LH surges associated with proestrous vaginal cytology in rats overexpressing CRF. Despite the absence of change in basal corticosterone secretion or induced by stress (lipopolysaccharide or restraint), overexpression of CRF in the CeA significantly decreased lipopolysaccharide, but not restraint, stress-induced suppression of pulsatile LH secretion in postpubertal ovariectomized rats, indicating a differential stress responsivity of the GnRH pulse generator to immunological stress and a potential adaptation of the HPA axis to chronic activation of amygdaloid CRF. These data suggest that the expression profile of this key limbic brain CRF system might contribute to the complex neural mechanisms underlying the increasing incidence of early onset of puberty on the one hand and infertility on the other attributed to chronic stress in modern human society.


Chemical profiles of cannabis sativa medicinal oil using different extraction and concentration methods.
The present study shows the variability in chemical profiles of three different varieties of Cannabis sativa extracts used in medicinal cannabis oil when using two different extraction and evaporation methods. Procedures were compared by analyzing rate of total terpenoids to the principal cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD), using gas chromatography coupled to mass spectrometry (GC-MS). The extraction of inflorescences using soxhlet method showed the highest mass of final extract. Also, the use of heating and the presence of oxygen when evaporating the solvents, greatly modified the final profiles due to evaporation or chemical reactions. These variations in chemical profiles must be carefully taken into account and standardized in the elaboration of medicinal oils.


Catfish hepcidin gene is expressed in a wide range of tissues and exhibits tissue-specific upregulation after bacterial infection.
Antimicrobial peptides (AMPs) are important components of the host innate immune response against microbial invasion. The cysteine-rich AMPs such as defensin and hepcidin have been extensively studied from various organisms, but their role in disease defense in catfish is unknown. As a first step, we sequenced a hepcidin cDNA from both channel catfish and blue catfish, and characterized the channel catfish hepcidin gene. The channel catfish hepcidin gene consists of two introns and three exons that encode a peptide of 96 amino acids. The amino acid sequences and gene organization were conserved between catfish and other organisms. In contrast to its almost exclusive expression in the liver in humans, the channel catfish hepcidin gene was expressed in a wide range of tissues except brain. Its expression was detected early during embryonic and larval development, and induced after bacterial infection with Edwardsiella ictaluri, the causative agent of enteric septicemia of catfish (ESC) in a tissue-specific manner. The upregulation was observed in the spleen and head kidney, but not in the liver. The expression of hepcidin was upregulated 1--3 days after challenge, but returned to normal levels at 7 days after challenge. The expression profile of the catfish hepcidin gene during the course of bacterial infection mirrors those of inflammatory proteins such as chemokines, suggesting an important role for hepcidin during inflammatory responses.


Evaluation of the modifying effect of inhalation of mainstream cigarette smoke on mouse bladder carcinogenesis.
Cigarette smoking is one of the major risk factors of bladder cancer in humans. To date, however, there is no experimental evidence for the effects of inhalation exposure to mainstream cigarette smoke on bladder carcinogenesis. The purpose of the present study was to evaluate the effect of inhalation of mainstream cigarette smoke on mouse bladder carcinogenesis using a cigarette smoke inhalation exposure system. Six-week-old male C57BL mice were administered 0.025% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water for 8 weeks and then divided into 2 groups and exposed to 0 or 300 mg/m(3) wet total particulate matter mainstream cigarette smoke for 2 h per day, five times per week, for 22 weeks. The incidences of bladder tumors (papilloma and urothelial carcinoma) tended to increase in the cigarette smoke-exposed group (25.0%) compared with the controls (15.8%), albeit without a statistically significant difference. We also evaluated mRNA expression levels of cytochrome P450 (cyp) enzymes and proliferating cell nuclear antigen (PCNA) in the bladder epithelium. Expression of cyp1a1 was significantly increased in the cigarette smoke-exposed group. Cigarette smoke exposure did not have a significant effect on the expression of cyp1a2, cyp 1b1, cyp 2a4, cyp 2b10, cyp 2e1, or PCNA. In conclusion, limited exposure to mainstream cigarette smoke for 22 weeks, caused a significant increase in cyp1a1 expression. This increase coupled with the nonsignificant increase in bladder tumors suggests that a longer period of exposure is required to clarify the effects of cigarette smoke on bladder carcinogenesis.


Man2C1, an alpha-mannosidase, is involved in the trimming of free oligosaccharides in the cytosol.
The endoplasmic-reticulum-associated degradation of misfolded (glyco)proteins ensures that only functional, correctly folded proteins exit from the endoplasmic reticulum and that misfolded ones are degraded by the ubiquitin-proteasome system. During the degradation of misfolded glycoproteins, they are deglycosylated by the PNGase (peptide:N-glycanase). The free oligosaccharides released by PNGase are known to be further catabolized by a cytosolic alpha-mannosidase, although the gene encoding this enzyme has not been identified unequivocally. The findings in the present study demonstrate that an alpha-mannosidase, Man2C1, is involved in the processing of free oligosaccharides that are formed in the cytosol. When the human Man2C1 orthologue was expressed in HEK-293 cells, most of the enzyme was localized in the cytosol. Its activity was enhanced by Co2+, typical of other known cytosolic alpha-mannosidases so far characterized from animal cells. The down-regulation of Man2C1 activity by a small interfering RNA drastically changed the amount and structure of oligosaccharides accumulating in the cytosol, demonstrating that Man2C1 indeed is involved in free oligosaccharide processing in the cytosol. The oligosaccharide processing in the cytosol by PNGase, endo-beta-N-acetylglucosaminidase and alpha-mannosidase may represent the common 'non-lysosomal' catabolic pathway for N-glycans in animal cells, although the molecular mechanism as well as the functional importance of such processes remains to be determined.


Preventative therapeutic approaches for hypertrophic cardiomyopathy.
Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Current drug therapeutics for HCM patients are effective in relieving symptoms, but do not prevent or reverse disease progression. Moreover, due to heterogeneity in the clinical manifestations of the disease, patients experience variable outcomes in response to therapeutics. Mechanistically, alterations in calcium handling, sarcomeric disorganization, energy metabolism and contractility participate in HCM disease progression. While some similarities exist, each mutation appears to lead to mutation-specific pathophysiology. Furthermore, these alterations may precede or proceed development of the pathology. This review assesses the efficacy of HCM therapeutics from studies performed in animal models of HCM and human clinical trials. Evidence suggests that a preventative rather than corrective therapeutic approach may be more efficacious in the treatment of HCM. In addition, a clear understanding of mutation-specific mechanisms may assist in informing the most effective therapeutic mode of action.


MotorSkins-a bio-inspired design approach towards an interactive soft-robotic exosuit.
The work presents a bio-inspired design approach to a soft-robotic solution for assisting the knee-bending in users with reduced mobility in lower limbs. Exosuits and fluid-driven actuators are fabric-based devices that are gaining increasing relevance as alternatives assistive technologies that can provide simpler, more flexible solutions in comparison with the rigid exoskeletons. These devices, however, commonly require an external energy supply or a pressurized-fluid reservoir, which considerably constrain the autonomy of such solutions. In this work, we introduce an event-based energy cycle (EBEC) design concept, that can harvest, store, and release the required energy for assisting the knee-bending, in a synchronised interaction with the user and the environment, thus eliminating any need for external energy or control input. Ice-plant hydro-actuation system served as the source of inspiration to address the specific requirements of such interactive exosuit through a fluid-driven material system. Based on the EBEC design concepts and the abstracted bio-inspired principles, a series of (material and process driven) design experimentations helped to address the challenges of realising various functionalities of the harvest, storage, actuation and control instances within a closed hydraulic circuit. Sealing and defining various areas of water-tight seam made out of thermoplastic elastomers provided the base material system to program various chambers, channels, flow-check valves etc of such EBEC system. The resulting fluid-driven EBEC-skin served as a proof of concept for such active exosuit, that brings these functionalities into an integrated 'sense-acting' material system, realising an auto-synchronised energy and information cycles. The proposed design concept can serve as a model for development of similar fluid-driven EBEC soft-machines for further applications. On the more general scheme, the work presents an interdisciplinary design-science approach to bio-inspiration and showcases how biological material solutions can be looked at from a design/designer perspective to bridge the bottom-up and top-down approach to bio-inspiration.


Rapid reconstitution of antibody responses following transplantation of purified allogeneic hematopoietic stem cells.
Allogeneic hematopoietic cell transplantation has broad clinical applications extending from the treatment of malignancies to induction of immunologic tolerance. However, adaptive cellular and humoral immunity frequently remain impaired posttransplantation. Here, recovery of T-dependent and T-independent Ab responses was evaluated in mice transplanted with purified hematopoietic stem cells (HSCs) devoid of the mature immune cells believed to hasten immune recovery. Mixed and full donor chimeras were created by conditioning recipients with sublethal or lethal irradiation, respectively, across different donor/host genetic disparities. By 6 wk posttransplantation, all animals demonstrated robust T-independent Ab responses, and all mixed chimeras and recipients of MHC-matched or haploidentical HSCs with a shared MHC haplotype had T-dependent Ab responses equivalent to those of untransplanted controls. Full chimeras that received fully MHC-disparate HSCs showed delayed T-dependent Ab responses that recovered by 12 wk. This delay occurred despite early reconstitution and proper migration to germinal centers of donor-derived T(follicular helper) (T(FH)) cells. Congenic transplants into T(FH)-deficient CD4(-/-) mice revealed restoration of T-dependent Ab responses by 6 wk, leading us to conclude that MHC disparity caused delay in humoral recovery. These findings, together with our previous studies, show that, contrary to the view that depletion of graft lymphocytes results in poor posttransplant immunity, elimination of immune-suppressing graft-versus-host reactions permits superior immune reconstitution. This study also provides insight into the regeneration of T(FH) cells and humoral immunity after allogeneic HSC transplantation.


Ecological aspects of the Jos Plateau, Nigeria.
The Jos Plateau has an area of about 6 700 km(2), lies at 1 280 m above sea level, and contains approximately 1 million inhabitants. Annual rainfall averaged 137 cm in the period 1965-68; in 1969 rainfall totalled 170 cm and lasted for a month longer than usual.The rural population is engaged in agriculture, tin mining, and cattle grazing. Animal life consists chiefly of domestic species; there are few large wild animals. Wild primates are apparently rare, although baboons and red patas monkeys are sometimes seen. Tree cover is restricted to small patches along streams and some hillsides; there are euphorbia hedges and scattered trees in rural communities and along roadsides.


Suicides by mentally ill people.
In 1992, following consultations with the Royal College of Psychiatrists, the confidential inquiry into homicides and suicides by mentally ill people was set up by the United Kingdom Department of Health. The inquiry collects detailed information on contact with secondary mental health services by means of a questionnaire from clinical audit or information departments from these organisations. In Leeds, however, a wider range of available records including Coroner Reports, police, social, educational, and all health records were consulted. This resulted in a series of health/life event histories of suicide cases that had been in contact with psychiatric services. This paper presents an exploratory analysis of these data. The Leeds suicide cases formed less than one-third of all suicide cases in Leeds; the remainder had not come into contact with psychiatric services. This proportion is consistent with the U.K. national figures. Records show that 46% of the sample"s first contact with the psychiatric services was through a first failed attempted suicide. Other results include the role of prescribed drugs in repeat suicide attempts, education levels, and employment stability. It is concluded that the link between mental illness and suicide is questionable. Life event history type data on all suicide cases is desperately required to study suicide as a social process.


Losartan, an angiotensin II type 1 receptor antagonist, lowers hematocrit in posttransplant erythrocytosis.
The mechanism by which angiotensin-converting enzyme inhibitors reduce red cell mass in renal transplant recipients with erythrocytosis is unclear. To examine the role of angiotensin II in this disorder, losartan (a competitive antagonist of the angiotensin II type 1 [AT1] receptor) was administered to 23 patients with erythrocytosis. Fourteen patients took 25 mg/d for 8 wk; nine others were treated with 50 mg/d for 8 wk. Hematocrit decreased from 0.527 +/- 0.027 to 0.487 +/- 0.045 after 8 wk (P < 0.01)--by at least 0.04 in 19 patients. Decrement in hematocrit in the initial 8 wk of therapy was significantly greater in patients administered 50 mg/d than in patients on 25 mg/d. Twelve of 14 patients initially treated with 25 mg/d showed a small change in hematocrit; the dose was increased to 50 mg/d for 8 more wk. Hematocrit decreased from 0.528 +/- 0.030 before losartan treatment to 0.483 +/- 0.055 after 16 wk (P < 0.01). After therapy, serum erythropoietin significantly decreased in eight patients with elevated baseline levels, but not in 15 patients with normal baseline levels; however, hematocrit significantly decreased in both groups. Losartan was withdrawn in 16 patients; hematocrit increased from 0.440 +/- 0.057 to 0.495 +/- 0.049 after 8.9 +/- 7.5 wk (P < 0.001), without change in serum erythropoietin. Thus, specific blockade of AT1 receptors inhibited erythropoiesis, suggesting a pathogenic role for angiotensin II in posttransplant erythrocytosis.


Designing a Pediatric Study for an Antimalarial Drug by Using Information from Adults.
The objectives of this study were to design a pharmacokinetic (PK) study by using information about adults and evaluate the robustness of the recommended design through a case study of mefloquine. PK data about adults and children were available from two different randomized studies of the treatment of malaria with the same artesunate-mefloquine combination regimen. A recommended design for pediatric studies of mefloquine was optimized on the basis of an extrapolated model built from adult data through the following approach. (i) An adult PK model was built, and parameters were estimated by using the stochastic approximation expectation-maximization algorithm. (ii) Pediatric PK parameters were then obtained by adding allometry and maturation to the adult model. (iii) A D-optimal design for children was obtained with PFIM by assuming the extrapolated design. Finally, the robustness of the recommended design was evaluated in terms of the relative bias and relative standard errors (RSE) of the parameters in a simulation study with four different models and was compared to the empirical design used for the pediatric study. Combining PK modeling, extrapolation, and design optimization led to a design for children with five sampling times. PK parameters were well estimated by this design with few RSE. Although the extrapolated model did not predict the observed mefloquine concentrations in children very accurately, it allowed precise and unbiased estimates across various model assumptions, contrary to the empirical design. Using information from adult studies combined with allometry and maturation can help provide robust designs for pediatric studies.


Rapid identification and typing of listeria species by matrix-assisted laser desorption ionization-time of flight mass spectrometry.
Listeria monocytogenes is a food-borne pathogen that is the causative agent of human listeriosis, an opportunistic infection that primarily infects pregnant women and immunologically compromised individuals. Rapid, accurate discrimination between Listeria strains is essential for appropriate therapeutic management and timely intervention for infection control. A rapid method involving matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) that shows promise for identification of Listeria species and typing and even allows for differentiation at the level of clonal lineages among pathogenic strains of L. monocytogenes is presented. A total of 146 strains of different Listeria species and serotypes as well as clinical isolates were analyzed. The method was compared with the pulsed-field gel electrophoresis analysis of 48 Listeria strains comprising L. monocytogenes strains isolated from food-borne epidemics and sporadic cases, isolates representing different serotypes, and a number of Listeria strains whose genomes have been completely sequenced. Following a short inactivation/extraction procedure, cell material from a bacterial colony was deposited on a sample target, dried, overlaid with a matrix necessary for the MALDI process, and analyzed by MALDI-TOF MS. This technique examines the chemistry of major proteins, yielding profile spectra consisting of a series of peaks, a characteristic "fingerprint" mainly derived from ribosomal proteins. Specimens can be prepared in a few minutes from plate or liquid cultures, and a spectrum can be obtained within 1 minute. Mass spectra derived from Listeria isolates showed characteristic peaks, conserved at both the species and lineage levels. MALDI-TOF MS fingerprinting may have potential for Listeria identification and subtyping and may improve infection control measures.


Vascular Dynamics and Peripheral Oxygen Uptake in Obese Individuals during Progressive Physical Exercise.
Obese men show higher O2 consumption than lean men during physical exercise, with a trend toward higher peripheral O2 extraction; this is probably due to their larger muscle mass. The aim of this study was to examine this phenomenon by measuring 2 vasoactive substances, endothelin-1 (ET-1) and nitric oxide (NO), during a progressive submaximal exercise. Seventeen obese (body mass index [BMI] 38.6) and 15 lean (BMI 22.5) men performed a maximal progressive cycle ergometer exercise to determine peak power output (PPO) and peak O2 consumption (V∙O2peak); thereafter, they performed a submaximal cycle ergometer incremental test (every 6 min) at the same percentage of V∙O2peak until they reached 57.5% PPO. Blood samples were collected at rest and at the end of every step to measure ET-1 and NO concentrations. At rest, the ET-1 and NO concentrations in obese men and lean controls were the same. However, during exercise, the ET-1 concentration at each step was significantly lower (p < 0.05) in the obese group. There was no significant difference in NO concentration between the 2 groups, although the increase at the beginning of the exercise session was faster in obese individuals. During submaximal exercise, end-tidal O2 pressure (PETO2) was lower in the obese group, with a significant difference in the PETO2/fat-free mass ratio at each step. ET-1 and NO levels during physical exercise are different in obese versus lean men. This may support the notion that increased O2 consumption in obesity is due to different behaviors of the cardiorespiratory and circulatory systems.


Modeling compound-target interaction network of traditional Chinese medicines for type II diabetes mellitus: insight for polypharmacology and drug design.
In this study, in order to elucidate the action mechanism of traditional Chinese medicines (TCMs) that exhibit clinical efficacy for type II diabetes mellitus (T2DM), an integrated protocol that combines molecular docking and pharmacophore mapping was employed to find the potential inhibitors from TCM for the T2DM-related targets and establish the compound-target interaction network. First, the prediction capabilities of molecular docking and pharmacophore mapping to distinguish inhibitors from noninhibitors for the selected T2DM-related targets were evaluated. The results show that molecular docking or pharmacophore mapping can give satisfactory predictions for most targets but the validations are still quite necessary because the prediction accuracies of these two methods are variable across different targets. Then, the Bayesian classifiers by integrating the predictions from molecular docking and pharmacophore mapping were developed, and the well-validated Bayesian classifiers for 15 targets were utilized to find the potential inhibitors from TCM and establish the compound-target interaction network. The analysis of the compound-target network demonstrates that a small portion (18.6%) of the predicted inhibitors can interact with multitargets. The pharmacological activities for some potential inhibitors have been experimentally confirmed, highlighting the reliability of the Bayesian classifiers. Besides, it is interesting to find that a considerable number of the predicted multitarget inhibitors have free radical scavenging/antioxidant activities, which are closely related to T2DM. It appears that the pharmacological effect of the TCM formulas is determined not only by the compounds that interact directly with one or more T2DM-related targets, but also by the compounds with other supplementary bioactivities important for relieving T2DM, such as free radical scavenging/antioxidant effects. The mechanism uncovered by this study may offer a deep insight for understanding the theory of the classical TCM formulas for combating T2DM. Moreover, the predicted inhibitors for the T2DM-related targets may provide a good source to find new lead compounds against T2DM.


A Diverse Array of Fluvial Depositional Systems in Arabia Terra: Evidence for mid-Noachian to Early Hesperian Rivers on Mars.
Branching to sinuous ridges systems, hundreds of kilometers in length and comprising layered strata, are present across much of Arabia Terra, Mars. These ridges are interpreted as depositional fluvial channels, now preserved as inverted topography. Here we use high-resolution image and topographic data sets to investigate the morphology of these depositional systems and show key examples of their relationships to associated fluvial landforms. The inverted channel systems likely comprise indurated conglomerate, sandstone, and mudstone bodies, which form a multistory channel stratigraphy. The channel systems intersect local basins and indurated sedimentary mounds, which we interpret as paleolake deposits. Some inverted channels are located within erosional valley networks, which have regional and local catchments. Inverted channels are typically found in downslope sections of valley networks, sometimes at the margins of basins, and numerous different transition morphologies are observed. These relationships indicate a complex history of erosion and deposition, possibly controlled by changes in water or sediment flux, or base-level variation. Other inverted channel systems have no clear preserved catchment, likely lost due to regional resurfacing of upland areas. Sediment may have been transported through Arabia Terra toward the dichotomy and stored in local and regional-scale basins. Regional stratigraphic relations suggest these systems were active between the mid-Noachian and early Hesperian. The morphology of these systems is supportive of an early Mars climate, which was characterized by prolonged precipitation and runoff.


The hemodynamic effects of warm versus room-temperature crystalloid fluid bolus therapy in post-cardiac surgery patients.
The contribution of fluid temperature to the effect of crystalloid fluid bolus therapy (FBT) in post-cardiac surgery patients is unknown. We evaluated the hemodynamic effects of FBT with fluid warmed to 40°C (warm FBT) versus room-temperature fluid. In this single centre prospective before-and-after study, we evaluated the effects of 500 ml of warm versus room-temperature compound sodium lactate administered over <30 minutes, in 50 cardiac surgery patients admitted to ICU. We recorded hemodynamics continuous before and for 30 minutes after the first FBT. We defined CI responsiveness (CI-R) as an CI increase >15% of baseline immediately after FBT and effect dissipation if the CI returned to <5% of baseline and MAP responsiveness as >10% increase and dissipation as return to <3 mmHg of baseline. Hypotension (56%) and low CI (40%) typically triggered FBT. Temperature decreased >0.3°C in 13 (52%) patients after room-temperature FBT versus 0 (0%) after warm FBT (p < 0.01). CI and MAP responsiveness was similar (16 [64%] versus 11 [44%], p = 0.15 and 15 [60%] versus 17 [68%], p = 0.77, respectively). Among CI responders, CI increased more with room-temperature FBT (+0.6 [IQR, 0.5-1.1] versus +0.5 [IQR, 0.4-0.6] L/min/m2, p = 0.01). However, dissipation was more common after room-temperature versus warm FBT (9/16 [56%] versus 1/11 [9%], p = 0.02). In postoperative cardiac surgery patients, warm FBT preserved core temperature and induced smaller but more sustained CI increases among responders. Fluid temperature appears to impact both core temperature and the duration of CI response.


Instruments for the assessment of patient adherence to oral anticoagulation with warfarin protocol for a systematic review.
Non-adherence can be highlighted as one of the main contributors to the occurrence of adverse events in patients treated with warfarin. The usefulness of self-reporting measures of drug adherence could be improved by following psychometric properties in the development of the measurement scales. Thus, we aimed to describe the protocol of a systematic literature review designed to investigate and describe validated instruments used to assess adherence to warfarin therapy. We will perform a systematic review will include observational and experimental studies involving the use of validated instruments to assess adherence to warfarin therapy. Dimensions of adherence raised by the selected studies will be extracted to be compared. We will systematically search electronic databases including MEDLINE, LILACS, EMBASE, and Cochrane Library using a comprehensive strategy from inception to June 31, 2019. Two reviewers will revise the literature independently using a standardized form and assess the potential bias. After the comparison of results, discrepancies will be solved after the analysis of a third reviewer. The development of the present systematic will help to summarize and evaluate the validated instruments that have been previously published to assess adherence to warfarin therapy. This review will substantiate the discussion of relevant topics that should be assessed while providing care to patients taking warfarin. This knowledge will enable a comprehensive approach for healthcare professionals to improve treatment outcomes and the design of future investigations. The systematic review is registered in the PROSPERO international prospective register of systematic review (PROSPERO# CRD42019128324).


Light-evoked responses of the retinal pigment epithelium: changes accompanying photoreceptor loss in the mouse.
Mutations in genes expressed in the retinal pigment epithelium (RPE) underlie a number of human inherited retinal disorders that manifest with photoreceptor degeneration. Because light-evoked responses of the RPE are generated secondary to rod photoreceptor activity, RPE response reductions observed in human patients or animal models may simply reflect decreased photoreceptor input. The purpose of this study was to define how the electrophysiological characteristics of the RPE change when the complement of rod photoreceptors is decreased. To measure RPE function, we used an electroretinogram (dc-ERG)-based technique. We studied a slowly progressive mouse model of photoreceptor degeneration (Prph(Rd2/+)), which was crossed onto a Nyx(nob) background to eliminate the b-wave and most other postreceptoral ERG components. On this background, Prph(Rd2/+) mice display characteristic reductions in a-wave amplitude, which parallel those in slow PIII amplitude and the loss of rod photoreceptors. At 2 and 4 mo of age, the amplitude of each dc-ERG component (c-wave, fast oscillation, light peak, and off response) was larger in Prph(Rd2/+) mice than predicted by rod photoreceptor activity (Rm(P3)) or anatomical analysis. At 4 mo of age, the RPE in Prph(Rd2/+) mice showed several structural abnormalities including vacuoles and swollen, hypertrophic cells. These data demonstrate that insights into RPE function can be gained despite a loss of photoreceptors and structural changes in RPE cells and, moreover, that RPE function can be evaluated in a broader range of mouse models of human retinal disease.


[Occurrence and distribution of drug resistant enterobacteria in extra enteral habitats (author's transl)].
In the period 1971-73 various extra enteral habitats have been examined for the occurrence of resistant E. coli. Of 172 isolates of E. coli from retail butcher's meat products 9.9% were resistant and 3.5% R+ E. coli. Of 203 isolates of E. coli from bakery products 7.9% were resistant and 3.5% R+ E. coli. Of 52 isolates of E. coli from freshly killed carcases of chickens 40.4% contained weak non-transferable monoresistance against sulphonamides (Table I). Of 92 isolates of E. coli from seawater receiving human sewage 15.2% were resistant and 4.4% R+ E. coli (Table III). All but one samples of sewage and crude sludge contained resistant E. coli of which 11% harboured R factors (Table II). Of 117 Salmonella isolates from human sewage 11.1% were resistant and in 4.2% resistance were transferable (Table VI). Quantitative examinations of untreated and treated sewage did not indicate any selective reduction of resistant E. coli compared to sensitive (Table IV). However, more di- and multiresistant E. coli were found in sewage than in seawater (Fig. 1). The food hygienic implications of resistant E. coli are discussed.


Failure of intensive care unit support to influence mortality from pneumococcal bacteremia.
One hundred thirty-four consecutive cases of pneumococcal bacteremia observed during a six-year period were evaluated. One hundred nineteen (89%) were associated with pneumonia. Factors associated with increased mortality were advanced age, a leukocyte count at admission of less than 5,000/cu mm, neoplastic disease, and involvement of two or more pulmonary lobes in patients with pneumonia. Mortality was 30.5% overall, and 76% in patients admitted to the intensive care unit with pneumococcal bacteremia. Pneumococcal infection continues to be an important cause of morbidity and mortality despite modern supportive care and antimicrobial therapy.


Reversible thermosensitive biodegradable polymeric actuators based on confined crystallization.
We discovered a new and unexpected effect of reversible actuation of ultrathin semicrystalline polymer films. The principle was demonstrated on the example of thin polycaprolactone-gelatin bilayer films. These films are unfolded at room temperature, fold at temperature above polycaprolactone melting point, and unfold again at room temperature. The actuation is based on reversible switching of the structure of the hydrophobic polymer (polycaprolactone) upon melting and crystallization. We hypothesize that the origin of this unexpected behavior is the orientation of polycaprolactone chains parallel to the surface of the film, which is retained even after melting and crystallization of the polymer or the "crystallization memory effect". In this way, the crystallization generates a directed force, which causes bending of the film. We used this effect for the design of new generation of fully biodegradable thermoresponsive polymeric actuators, which are highly desirable for bionano-technological applications such as reversible encapsulation of cells and design of swimmers.


Alpha-onocerin: an acetylcholinesterase inhibitor from Lycopodium clavatum.
In order to find new acetylcholinesterase inhibitors from natural sources which have therapeutic potential in the treatment of Alzheimer's disease, the chloroform : methanol (1 : 1) extracts of five Lycopodium species ( L. clavatum L., L. selago L., L. annotinum L., L. alpinum L., and L. complanatum ssp. chamaecyparissus A. (Br.) Döll.), growing in Turkey (Lycopodiaceae), were screened in vitro by the Ellman spectrophotometric method at 1 mg/ml concentration. Among these extracts, only the extract of L. clavatum was found to be active (49.85 %). Bioassay-guided fractionation of the chloroform extract of L. clavatum led to the isolation of alpha-onocerin (IC 50 = 5.2 microM), a well-known triterpenoid, as the responsible compound for the activity.


Sport and Physical Activity Level Impacts Health-Related Quality of Life Among Collegiate Students.
To examine and compare the role of self-assessed sport and physical activity involvement on the health-related quality of life among undergraduate student-athletes and general undergraduate college students. Cross-sectional survey. Data set was examined for differences in physical and mental health by self-assessed sport and physical activity level. Large Midwestern University in the fall of 2016. A combined data set representing undergraduate Division I student athletes (n = 842) and general undergraduate students (n = 1322). Veterans RAND 12 Item Health Survey (VR-12), as measure of health-related quality of life, comprised of physical component score (PCS) and mental component score (MCS). Self-assessed sport and physical activity level categorized as Division I athlete, club athlete, intramural player, student who works out regularly, or student who is physically inactive. Standard univariable statistics described the study population. Two-sample t tests and χ2 tests were conducted, as appropriate, to compare Division I student-athletes to the general undergraduate group. Multivariable linear regression models were then built to assess associations between physical activity level and year in school with VR-12 outcomes, after adjusting for sex. All pairwise interactions were considered for inclusion in the final models. Adjusted least-square means were calculated for all variables in the model; pairwise comparisons were adjusted for multiple comparisons via Tukey-Kramer adjustment criteria. A linear test for trend was also conducted for the association between VR-12 MCS and increasing physical activity. Significant differences in MCS were noted between levels of sport and physical activity; however, such differences were not detected in PCS. After controlling for sex, a positive relationship between increased sport and physical activity level and greater MCS was found. This study represents the first prospective assessment of health-related quality of life among undergraduate athletes and general college students. Higher levels of sport and physical activity were associated with more positive mental health in these populations.


The evolution of the randomized controlled trial and its role in evidence-based decision making.
The randomized controlled trial has been used in medical research for a little over half a century. This manuscript provides an overview of some of the history and evolution of the randomized controlled trial during this period. There exists hierarchies of evidence for therapeutic, diagnostic and prognostic questions, and the randomized controlled trial is at the top of the therapeutic hierarchy. Despite being at the top of the therapeutic hierarchy randomization in itself does not guarantee the trial results approximate the true effect. Issues that result in systematic and nonsystematic deviations from the truth in randomized controlled trials must also be considered. We present a model for evidence-based decision making that includes the following components: the clinical state, patient preferences, research evidence from a range of studies and clinical expertise. We discuss the role of the randomized controlled trial within evidence-based decision making.


Fennel and anise as estrogenic agents.
Fennel, Foeniculum vulgare, and anise, Pimpinella anisum, are plants which have been used as estrogenic agents for millennia. Specifically, they have been reputed to increase milk secretion, promote menstruation, facilitate birth, alleviate the symptoms of the male climacteric, and increase libido. In the 1930s, some interest was shown in these plants in the development of synthetic estrogens. The main constituent of the essential oils of fennel and anise, anethole, has been considered to be the active estrogenic agent. However, further research suggests that the actual pharmacologically active agents are polymers of anethole, such as dianethole and photoanethole.


Collection and visualization of dietary behavior and reasons for eating using Twitter.
Increasing an individual's awareness and understanding of their dietary habits and reasons for eating may help facilitate positive dietary changes. Mobile technologies allow individuals to record diet-related behavior in real time from any location; however, the most popular software applications lack empirical evidence supporting their efficacy as health promotion tools. The purpose of this study was to test the feasibility and acceptability of a popular social media software application (Twitter) to capture young adults' dietary behavior and reasons for eating. A secondary aim was to visualize data from Twitter using a novel analytic tool designed to help identify relationships among dietary behaviors, reasons for eating, and contextual factors. Participants were trained to record all food and beverages consumed over 3 consecutive days (2 weekdays and 1 weekend day) using their mobile device's native Twitter application. A list of 24 hashtags (#) representing food groups and reasons for eating were provided to participants to guide reporting (eg, #protein, #mood). Participants were encouraged to annotate hashtags with contextual information using photos, text, and links. User experience was assessed through a combination of email reports of technical challenges and a 9-item exit survey. Participant data were captured from the public Twitter stream, and frequency of hashtag occurrence and co-occurrence were determined. Contextual data were further parsed and qualitatively analyzed. A frequency matrix was constructed to identify food and behavior hashtags that co-occurred. These relationships were visualized using GMap algorithmic mapping software. A total of 50 adults completed the study. In all, 773 tweets including 2862 hashtags (1756 foods and 1106 reasons for eating) were reported. Frequently reported food groups were #grains (n=365 tweets), #dairy (n=221), and #protein (n=307). The most frequently cited reasons for eating were #social (activity) (n=122), #taste (n=146), and #convenience (n=173). Participants used a combination of study-provided hash tags and their own hash tags to describe behavior. Most rated Twitter as easy to use for the purpose of reporting diet-related behavior. "Maps" of hash tag occurrences and co-occurrences were developed that suggested time-varying diet and behavior patterns. Twitter combined with an analytical software tool provides a method for capturing real-time food consumption and diet-related behavior. Data visualization may provide a method to identify relationships between dietary and behavioral factors. These findings will inform the design of a study exploring the use of social media and data visualization to identify relationships between food consumption, reasons for engaging in specific food-related behaviors, relevant contextual factors, and weight and health statuses in diverse populations.


Hypophysectomy for a dog with coexisting Cushing's disease and diabetes mellitus.
An 11-year-old male mixed breed dog diagnosed with Cushing's disease and diabetes mellitus was treated by hypophysectomy. After surgery, the hypercortisolemia disappeared and the diabetes status improved. The insulin requirement to control hyperglycemia gradually decreased. At 12 weeks after surgery, there was no requirement for insulin and we suspected the diabetes was completely resolved. In the present case, diabetes mellitus seems to be secondary to Cushing's disease. In conclusion, this mixed breed dog with coexisting Cushing's disease and diabetes mellitus is the first case showing the effectiveness of hypophysectomy to treat diabetes mellitus secondary to Cushing's disease in dogs.


Utility-free heuristic models of two-option choice can mimic predictions of utility-stage models under many conditions.
Economists often model choices as if decision-makers assign each option a scalar value variable, known as utility, and then select the option with the highest utility. It remains unclear whether as-if utility models describe real mental and neural steps in choice. Although choices alone cannot prove the existence of a utility stage, utility transformations are often taken to provide the most parsimonious or psychologically plausible explanation for choice data. Here, we show that it is possible to mathematically transform a large set of common utility-stage two-option choice models (specifically ones in which dimensions are can be decomposed into additive functions) into a heuristic model (specifically, a dimensional prioritization heuristic) that has no utility computation stage. We then show that under a range of plausible assumptions, both classes of model predict similar neural responses. These results highlight the difficulties in using neuroeconomic data to infer the existence of a value stage in choice.


Oncogenic ALK F1174L drives tumorigenesis in cutaneous squamous cell carcinoma.
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer characterized by increased mortality. Here, we show for the first time that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase of the insulin receptor superfamily, plays a pivotal role in the pathogenesis of cSCC. Our data demonstrate that the overexpression of the constitutively active, mutated ALK, ALK F1174L , is sufficient to initiate the development of cSCC and is 100% penetrant. Moreover, we show that cSCC development upon ALK F1174L overexpression is independent of the cell-of-origin. Molecularly, our data demonstrate that ALK F1174L cooperates with oncogenic Kras G12D and loss of p53, well-established events in the biology of cSCC. This cooperation results in a more aggressive cSCC type associated with a higher grade histological morphology. Finally, we demonstrate that Stat3 is a key downstream effector of ALK F1174L and likely plays a role in ALK F1174L -driven cSCC tumorigenesis. In sum, these findings reveal that ALK can exert its tumorigenic potential via cooperation with multiple pathways crucial in the pathogenesis of cSCC. Finally, we show that human cSCCs contain mutations in the ALK gene. Taken together, our data identify ALK as a new key player in the pathogenesis of cSCC, and this knowledge suggests that oncogenic ALK signaling can be a target for future clinical trials.


An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity.
Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. We have developed a family of compounds that modulate sirtuin 2, an NAD+-dependent deacylase, and now report the properties of a member of that family, FLS-359. Biochemical and x-ray structural studies show that the drug binds to sirtuin 2 and allosterically inhibits its deacetylase activity. FLS-359 inhibits the growth of RNA and DNA viruses, including members of the coronavirus, orthomyxovirus, flavivirus, hepadnavirus, and herpesvirus families. FLS-359 acts at multiple levels to antagonize cytomegalovirus replication in fibroblasts, causing modest reductions in viral RNAs and DNA, together with a much greater reduction in infectious progeny, and it exhibits antiviral activity in humanized mouse models of infection. Our results highlight the potential of sirtuin 2 inhibitors as broad-spectrum antivirals and set the stage for further understanding of how host epigenetic mechanisms impact the growth and spread of viral pathogens.


Progesterone and mental imagery interactively predict emotional memories.
Different lines of research suggest that the consolidation of emotional memories is influenced by (a) endogenous levels of sex hormones, and (b) individual differences in the capacity to use vivid mental imagery. No studies to date have investigated how these factors may interact to influence declarative emotional memories. This study examined the interacting influence of progesterone and mental imagery strength on emotional memory consolidation. Twenty-four men, 20 women from the low progesterone (follicular) menstrual phase, and 20 women from the high progesterone (mid-luteal) phase of the cycle were assessed using an objective performance-based measure of mental imagery strength, and then shown a series of aversive and neutral images. Half of the images were accompanied by instructions to process sensory features, and the remaining half to process the conceptual characteristics of the images. Two days later, all participants returned for a surprise free recall memory test. The interaction of progesterone and mental imagery strength significantly predicted recall of visually processed, but not verbally processed, negative images. These data suggest that mental imagery strength may be one mechanism underlying the documented association between endogenous progesterone and enhanced emotional memory performance in the literature.


Vaccination before or after SARS-CoV-2 infection leads to robust humoral response and antibodies that effectively neutralize variants.
Current coronavirus disease 2019 (COVID-19) vaccines effectively reduce overall morbidity and mortality and are vitally important to controlling the pandemic. Individuals who previously recovered from COVID-19 have enhanced immune responses after vaccination (hybrid immunity) compared with their naïve-vaccinated peers; however, the effects of post-vaccination breakthrough infections on humoral immune response remain to be determined. Here, we measure neutralizing antibody responses from 104 vaccinated individuals, including those with breakthrough infections, hybrid immunity, and no infection history. We find that human immune sera after breakthrough infection and vaccination after natural infection broadly neutralize SARS-CoV-2 (severe acute respiratory coronavirus 2) variants to a similar degree. Although age negatively correlates with antibody response after vaccination alone, no correlation with age was found in breakthrough or hybrid immune groups. Together, our data suggest that the additional antigen exposure from natural infection substantially boosts the quantity, quality, and breadth of humoral immune response regardless of whether it occurs before or after vaccination.


Constraining Aging Processes of Black Carbon in the Community Atmosphere Model Using Environmental Chamber Measurements.
The direct radiative forcing of black carbon aerosol (BC) on the Earth system remains unsettled, largely due to the uncertainty with physical properties of BC throughout their lifecycle. Here we show that ambient chamber measurements of BC properties provide a novel constraint on the crude BC aging representation in climate models. Observational evidence for significant absorption enhancement of BC can be reproduced when the aging processes in the four-mode version of the Modal Aerosol Module (MAM4) aerosol scheme in the Community Atmosphere Model version 5 are calibrated by the recent in situ chamber measurements. An observation-based scaling method is developed in the aging timescale calculation to alleviate the influence of biases in the simulated model chemical composition. Model sensitivity simulations suggest that the different monolayer settings in the BC aging parameterization of MAM4 can cause as large as 26% and 24% differences in BC burden and radiative forcing, respectively. We also find that an increase in coating materials (e.g., sulfate and secondary organic aerosols) reduces BC lifetime by increasing the hygroscopicity of the mixture but enhances its absorption, resulting in a net increase in BC direct radiative forcing. Our results suggest that accurate simulations of BC aging processes as well as other aerosol species are equally important in reducing the uncertainty of BC forcing estimation.


Enkephalin and capsaicin-resistant substance P-like immunoreactivities in intra-ocular grafts of different fetal spinal cord areas.
Fetal spinal cord tissue was grafted to the anterior chamber of the eye of adult rats in order to evaluate survival and distribution of substance P- and enkephalin-immunoreactive neurons. Capsaicin treatment was used to evaluate any possible contribution of host iris-derived substance P fibres to the innervation of the grafts and to check for capsaicin sensitivity of graft substance P-positive systems. Substance P- and enkephalin-immunoreactive nerve fibres were present in grafts of half-transverse segments of the spinal cord and were clearly co-distributed throughout the grafts. Areas with a high density of substance P- and enkephalin-positive fibres resembling substantia gelatinosa were seen. Grafts of the dorsal horn alone had a moderate to high density of substance P- and enkephalin-positive fibres, while ventral horn grafts contained a low amount of such fibres. Capsaicin eliminated the substance P innervation of the host iris and the dorsal root ganglion-derived substance P innervation of the host spinal cord, while sparing the intrinsic substance P innervation of both host spinal cord and spinal cord grafts. These experiments show that intra-ocular grafts of defined spinal cord areas express relatively organotypic amounts of substance P- and enkephalin-positive nerve fibres, and thus emphasize the importance of intrinsic genetic determinants for spinal cord development.