Inflammasome activity in leucocytes decreases with abdominal aortic aneurysm progression.
Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammatory cell infiltration. The present extended immunohistochemistry study aimed to characterize inflammation in AAA and aortic control samples. In specific, the composition of the infiltrating immune cells and the expression of five inflammasome components in these immune cells were evaluated, in order to characterize their role in AAA development. A total of 104 biopsies from 48 AAA patients and 40 healthy specimens from organ donors were evaluated for their grade of inflammation. Infiltrating leukocytes were characterized by specific markers (CD3, CD20 and CD68), intramural localization and inflammasome protein expression [NLR family pyrin domain containing 3 (NLRP3), absent in melanoma 2 (AIM2), apoptosis‑associated speck‑like protein containing a caspase recruitment domain (ASC), Caspase‑1 and Caspase‑5]. Macrophages, B and T lymphocytes were detected to a similar extent in grade 1, 2 and 3 AAA specimens, whereas in control samples, B and T lymphocytes were rarely observed in grade 1 lesions. Expression frequencies of NLRP3, AIM2 and Caspase‑5 were significantly higher in grade 1 lesions of AAA samples compared with grade 1 lesions in control samples. Finally, AIM2, ASC, and Caspase‑5 displayed significantly lower expression frequencies in grade 3 compared with grade 2 AAA specimens, and all inflammasome components were less frequently detected in grade 3 than in grade 1 lesions of AAA. This indicates that inflammasome activities decrease with AAA progression in infiltrating leukocytes. No statistically significant association was found for grade 2 and grade 3 lesions and total leukocyte count, C‑reactive protein levels, maximal aortic diameter, plasma cholesterol level or biomechanical parameters (derived from finite element analysis) of the respective patients. Overall, the aortic wall of AAA contained lymphocytes and macrophages with different states of activity. The present data suggested that therapeutic inhibition of specific inflammasome components might counteract AAA development and progression.


Action of antitumoral platinum complexes on in vitro platelet functions.
This report presents a comparison of the effects of cis- and trans-diamminedichloroplatinum complexes on in vitro platelet functions. Pretreatment of platelets with cis-platinum (cisplatin) induced a slow, dose-dependent (0.1-0.45 mM), increase in the cytosolic Ca2+ concentration, pleckstrin (47 kDa) phosphorylation and serotonin secretion, as well as a slight shape modification with emission of a few pseudopodia. All these effects were remarkably increased in platelets exposed to trans-platinum (transplatin). The rise in cytosolic Ca2+ concentration and serotonin secretion evoked by stimulation of platelets with thrombin were not significantly influenced by cellular exposure to cis-platinum, whereas they were enhanced and inhibited, respectively, by exposure to trans-platinum. Trans-platinum also inhibited thrombin-promoted platelet aggregation to a greater extent than the cis-isomer. While the viscosity of platelet rich-plasma tended to decrease in the presence of cis-platinum, it tended to increase in the presence of trans-platinum. Taken together, these results indicate that the effects on platelet functions of the efficacious antitumor complex cis-platinum is rather different from that of the inactive complex trans-platinum. Therefore, the in vitro tests of platelet functions employed in this study might provide an index of antitumor drug toxicity and serve as a preliminary indicator of therapeutic efficacy.


Psychosocial treatments for bipolar disorder: cost-effectiveness, mediating mechanisms, and future directions.
Randomized trials of adjunctive psychotherapy for bipolar disorder are reviewed, in tandem with discussion of cost-effectiveness, mediating mechanisms, and moderators of effects. Systematic searches of the MEDLINE and PSYCHLIT databases yielded 19 randomized controlled trials of individual family and group therapies. Outcome variables included time to recovery, relapse or recurrence, symptom severity, medication adherence, and psychosocial functioning. Meta-analyses consistently show that disorder-specific psychotherapies [cognitive-behavioral therapy (CBT), interpersonal, family, and group] augment mood stabilizers in reducing rates of relapse (OR = 0.57; 95% CI: 0.39-0.82) over 1-2 years. Specific mediating mechanisms include, but are not limited to, increasing medication adherence, teaching self-monitoring and early intervention with emergent episodes, and enhancing interpersonal functioning and family communication. All therapies have strengths and weaknesses. One group psychoeducation trial, demonstrated effect sizes for recurrence that are at least equivalent to individual therapies, but findings await replication. Family interventions have been successfully administered in both single and multi-family formats, but no studies report the comparative cost-effectiveness of these formats. The best-studied psychotherapy modality, CBT, can have beneficial effects on depression, but findings are inconsistent across studies and vary with sample characteristics and comparison treatments. Adjunctive psychotherapies can be cost-effective when weighed against observed reductions in recurrence, hospitalization and functional impairments. Future trials need to (i) clarify which populations are most likely to benefit from which strategies; (ii) identify putative mechanisms of action; (iii) systematically evaluate costs, benefits, and generalizability; and (iv) record adverse effects. The application of psychosocial interventions to young-onset populations deserves further study.


Predictors of Ischemic and Hemorrhagic Strokes Among People Living With HIV: The D:A:D International Prospective Multicohort Study.
Hypertension is a stronger predictor of hemorrhagic than ischemic strokes in the general population. We aimed to identify whether hypertension or other risk factors, including HIV-related factors, differ in their associations with stroke subtypes in people living with HIV (PLWHIV). HIV-1-positive individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed from the time of first blood pressure (BP) measurement after 1/1/1999 or study entry until the first of a validated stroke, 6 months after last follow-up or 1/2/2014. Stroke events were centrally validated using standardized criteria. Hypertension was defined as one systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg. Poisson and Cox proportional hazards regression models determined associations of established cerebro/cardiovascular disease and HIV-related risk factors with stroke and tested whether these differed by stroke subtype. 590 strokes (83 hemorrhagic, 296 ischemic, 211 unknown) occurred over 339,979 person-years (PYRS) (incidence rate/1000 PYRS 1.74 [95% confidence interval (CI) 1.60-1.88]). Common predictors of both hemorrhagic and ischemic strokes were hypertension (relative hazard 3.55 [95% CI 2.29-5.50] and 2.24 [1.77-2.84] respectively) and older age (1.28 [1.17-1.39] and 1.19 [1.12-1.25]). Male gender (1.62 [1.14-2.31] and 0.60 [0.35-0.91]), previous cardiovascular events (4.03 [2.91-5.57] and 1.44 [0.66-3.16]) and smoking (1.90 [1.41-2.56] and 1.08 [0.68-1.71]) were stronger predictors of ischemic then hemorrhagic strokes, whereas hypertension, hepatitis C (1.32 [0.72-2.40] and 0.46 [0.30-0.70]) and estimated glomerular filtration rate < 60 mL/min/1.72 m3 (4.80 [2.47-9.36] and 1.04 [0.67-1.60]) were stronger predictors of hemorrhagic than ischemic strokes. A CD4 count < 200 cells/μL was associated with an increased risk of hemorrhagic stroke only. Risk factors for stroke may differ by subtype in PLWHIV, emphasizing the importance of further research to increase the precision of stroke risk estimation.


Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal.
RUNX1/CBFβ (core binding factor [CBF]) is a heterodimeric transcription factor complex that is frequently involved in chromosomal translocations, point mutations, or deletions in acute leukemia. The mixed lineage leukemia (MLL) gene is also frequently involved in chromosomal translocations or partial tandem duplication in acute leukemia. The MLL protein interacts with RUNX1 and prevents RUNX1 from ubiquitin-mediated degradation. RUNX1/CBFβ recruits MLL to regulate downstream target genes. However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We confirmed this finding in Mll-Af9 knock-in mice and human M4/M5 acute myeloid leukemia (AML) cell lines, with or without MLL translocations, showing that MLL translocations cause a hypomorph phenotype of RUNX1/CBFβ. Overexpression of RUNX1 inhibits the development of AML in Mll-Af9 knock-in mice; conversely, further reducing Runx1/Cbfβ levels accelerates MLL-AF9-mediated AML in bone marrow transplantation assays. These data reveal a newly defined negative regulation of RUNX1/CBFβ by MLL fusion proteins and suggest that targeting RUNX1/CBFβ levels may be a potential therapy for MLLs.


The interpretation of time-varying data with DIAMON-1.
Applying the methods of Artificial Intelligence to clinical monitoring requires some kind of signal-to-symbol conversion as a prior step. Subsequent processing of the derived symbolic information must also be sensitive to history and development, as the failure to address temporal relationships between findings invariably leads to inferior results. DIAMON-1, a framework for the design of diagnostic monitors, provides two methods for the interpretation of time-varying data: one for the detection of trends based on classes of courses, and one for the tracking of disease histories modelled through deterministic automata. Both methods make use of fuzzy set theory taking account of the elasticity of medical categories and allowing discrete disease models to mirror the patient's continuous progression through the stages of illness.


Layer-specific fMRI reflects different neuronal computations at different depths in human V1.
Recent work has established that cerebral blood flow is regulated at a spatial scale that can be resolved by high field fMRI to show cortical columns in humans. While cortical columns represent a cluster of neurons with similar response properties (spanning from the pial surface to the white matter), important information regarding neuronal interactions and computational processes is also contained within a single column, distributed across the six cortical lamina. A basic understanding of underlying neuronal circuitry or computations may be revealed through investigations of the distribution of neural responses at different cortical depths. In this study, we used T(2)-weighted imaging with 0.7 mm (isotropic) resolution to measure fMRI responses at different depths in the gray matter while human subjects observed images with either recognizable or scrambled (physically impossible) objects. Intact and scrambled images were partially occluded, resulting in clusters of activity distributed across primary visual cortex. A subset of the identified clusters of voxels showed a preference for scrambled objects over intact; in these clusters, the fMRI response in middle layers was stronger during the presentation of scrambled objects than during the presentation of intact objects. A second experiment, using stimuli targeted at either the magnocellular or the parvocellular visual pathway, shows that laminar profiles in response to parvocellular-targeted stimuli peak in more superficial layers. These findings provide new evidence for the differential sensitivity of high-field fMRI to modulations of the neural responses at different cortical depths.


Antibody screening identifies 78 putative host proteins involved in Cyprinid herpesvirus 3 infection or propagation in common carp, Cyprinus carpio L.
Cyprinid herpesvirus 3 (CyHV-3) is the aetiological agent of a serious and notifiable disease afflicting common and koi carp, Cyprinus carpio L., termed koi herpesvirus disease (KHVD). Significant progress has been achieved in the last 15 years, since the initial reports surfaced from Germany, USA and Israel of the CyHV-3 virus, in terms of pathology and detection. However, relatively few studies have been carried out in understanding viral replication and propagation. Antibody-based affinity has been used for detection of CyHV-3 in enzyme-linked immunosorbent assay and PCR-based techniques, and immunohistological assays have been used to describe a CyHV-3 membrane protein, termed ORF81. In this study, monoclonal antibodies linked to N-hydroxysuccinimide (NHS)-activated spin columns were used to purify CyHV-3 and host proteins from tissue samples originating in either CyHV-3 symptomatic or asymptomatic fish. The samples were next analysed either by polyacrylamide gel electrophoresis (PAGE) and subsequently by electrospray ionization coupled to mass spectrometry (ESI-MS) or by ESI-MS analysis directly after purification. A total of 78 host proteins and five CyHV-3 proteins were identified in the two analyses. These data can be used to develop novel control methods for CyHV-3, based on pathways or proteins identified in this study.


The immunotoxicity mechanism of hemocytes in Chlamys farreri incubated with noradrenaline and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide alone or in combination.
Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) is the active intermediate metabolite of benzo[a]pyrene (B[a]P) and is considered the ultimate immunotoxicant. The neuroendocrine immunoregulatory network of bivalves is affected under pollutant stress. Besides, bivalves are frequently affected by pollutants in marine environments, yet the combined effects of neuroendocrine factors and detoxification metabolites on bivalves under pollutant stress and the signal pathways that mediate this immunoregulation are not well understood. Therefore, we incubated the hemocytes of Chlamys farreri with the neuroendocrine factor noradrenaline (NA) and the B[a]P detoxification metabolite BPDE, alone or in combination, to examine the immunotoxic effects of NA and BPDE on the hemocytes in C. farreri. Furthermore, the effects of NA and BPDE on the hemocyte signal transduction pathway were investigated by assessing potential downstream targets. The results revealed that NA and BPDE, alone or in combination, resulted in a significant decrease in phagocytic activity, bacteriolytic activity and the total hemocyte count. In addition, the immunotoxicity induced by BPDE was further exacerbated by co-treatment with NA, and the two showed synergistic effects. Analysis of signaling pathway factors showed that NA activated G proteins by binding to α-AR, which transmitted information to the Ca2+-NF-κB signaling pathway to regulate the expression of phagocytosis-associated proteins and regulated cytokinesis through the cAMP signaling pathway. BPDE could activate PTK and affect phagocytosis and cytotoxicity proteins through Ca2+-NF-κB signal pathway, also affect the regulation of phagocytosis and cytotoxicity by inhibiting the AC-cAMP-PKA pathway to down-regulate the expression of NF-κB and CREB. In addition, BPDE and NA may affect the immunity of hemocytes by down-regulating phagocytosis-related proteins through inhibition of the lectin pathway, while regulating the expression of cytotoxicity-related proteins through the C-type lectin. In summary, immune parameters were suppressed through Ca2+ and cAMP dependent pathways exposed to BPDE and the immunosuppressive effects were enhanced by the neuroendocrine factor NA.


Protection against Schistosoma mansoni infection with a recombinant baculovirus-expressed subunit of calpain.
Infections by human schistosomes, in particular Schistosoma mansoni, account for significant morbidity and mortality every year in tropical and sub-tropical areas. The eggs of the parasite induce pathological changes in the infected host; in chronic and heavy infections, these changes may lead to death. A well-designed anti-schistosomal vaccine, alone or in concert with existing control measures such as chemotherapy, may prove to be a safe, inexpensive, and effective means of reducing the occurrence of severe disease and death in S. mansoni infection. Previous studies have demonstrated the importance of the syncytial layer containing the apical plasma membrane (APM) of S. mansoni in both the survival of the parasite in the mammalian host and as a potential source of immunogens which may be utilized as vaccine candidates. In this paper, we present evidence for the protective capacity of several schistosomal antigen preparations, including a calcium binding protein of the APM, S. mansoni calpain (GenBank accession no. M74233). We have constructed and characterized expression of a recombinant baculovirus expressing the large subunit of S. mansoni calpain, Sm-p80. This recombinant Sm-p80 is recognized by IgA, IgM, IgG1, and IgG3 isotype antibodies found in S. mansoni-infected human sera and partially-purified recombinant Sm-p80 provided a 29-39% reduction in worm burden in immunized mice challenged with S. mansoni. Our data indicate that Sm-p80 may be a useful vaccine antigen for the reduction of the morbidity associated with S. mansoni infections of mammalian hosts.


Measuring engagement in HIV care: Measurement invariance in three racial/ethnic patient groups.
Objective: The objective of the study was to evaluate a novel measure of HIV care engagement in a large sample of non-Latino White, Latino, and African American patients. The Index of Engagement in HIV care (the Index) measures the degree to which a patient feels engaged/disengaged from HIV care. However, its measurement invariance, or the degree to which observed scores can be meaningfully compared across racial/ethnic groups, has not been established. Methods: The 10-item Index is a self-report measure initially validated in the Center for AIDS Research Network of Integrated Systems cohort study. Using Center for AIDS Research Network of Integrated Systems survey data, Index scores were linked to patients' electronic medical records, which included viral load (VL) and appointment attendance data. We conducted measurement invariance analyses to test the Index's performance in the 3 racial/ethnic groups and its cross-sectional association with VL and retention in HIV care (2 primary outcomes). Results: A total of 3,127 patients completed the Index, which showed good reliability across the 3 groups (alphas >.84). Confirmatory factor analysis model fit statistics showed that the Index demonstrated configural, metric, and scalar invariance, supporting the conclusion that the Index is a single factor construct. Lastly, lower Index scores associated with a concurrent detectable VL and poor retention in HIV care for all 3 groups. Conclusion: Having demonstrated invariance, the Index scores can be used to compare engagement levels across non-Latino Whites, Latinos, and African Americans in HIV care settings. Improving HIV care retention requires tools that can accurately identify people struggling to stay engaged in HIV care, especially racial/ethnic minorities. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Subgenual anterior cingulate cortex activity covariation with cardiac vagal control is altered in depression.
We tested the hypothesis that subgenual anterior cingulate cortex (sgACC) participates in concurrently regulating shifts in both affective state and cardiac vagal control. Eleven healthy adults and 8 depressed subjects performed the Emotional Counting Stroop task in alternating 15-second blocks of emotion words and neutral words while undergoing functional magnetic resonance imaging (fMRI) and electrocardiography (ECG). We measured the absolute value of change between adjacent 15-second blocks in both cardiac vagal control and the BOLD signal in specific regions of interest. Strong positive correlations were observed in healthy control participants between changes in cardiac vagal control and changes in BOLD signal intensity in sgACC (BA25) (right: r=.67, p<.02; left r=.69, p<.02), as well as other key structures in the medial visceromotor network. Depressed subjects showed no significant correlations between cardiac vagal control and BOLD signal intensity within BA25 or any other brain region examined. During the transition from depression-specific emotion blocks to neutral blocks, the correlation between BOLD signal change in BA25 and cardiac vagal control change was significantly greater in controls than in depressed subjects (p<.04). Findings in healthy volunteers suggest that sgACC participates in affective state shifting. The latter function appears to be altered in depressed individuals, and may have implications for the unvarying mood and vagal dysfunction associated with depression. Limitations include a small sample size, an inability to disentangle afferent versus efferent contributions to the results, and the lack of a whole-brain analysis.


COP 27 insights to increase food-systems climate adaptation and resilience.
The limited resilience of agricultural and food systems has become an agenda in the time of more extreme natural hazards. The impact of such events is extensive, and the level of damage and recovery strongly depends on ecosystem services, including their own resilience capacity. Most of the time, ecosystems themselves can offer mitigation measures based on the benefits people get from nature, including cultivated and wild biomass for nutrition, materials, or energy; pest and disease control; and regulation of baseline flows, among others. The 27th Conference of the Parties to the United Nations Framework Convention on Climate Change, held in Sharm el-Sheikh, Egypt, addressed issues related to crop production, food security, and nutrition. The information garnered from this conference provided impetus for actions that we believe can ensure a future with the resources needed for sustainable development and that support the health and nutrition for all the inhabitants on Earth.


Vitamin D Attenuates Oxidative Damage and Inflammation in Retinal Pigment Epithelial Cells.
Age-related macular degeneration (AMD), the most common visual disorder in elderly people, is characterized by the formation of deposits beneath the retinal pigment epithelium (RPE) and by dysfunction of RPE and photoreceptor cells. The biologically active form of vitamin D, 1,25-(OH)2D3 (VITD), is categorized as a multifunctional steroid hormone that modulates many transcriptional processes of different genes and is involved in a broad range of cellular functions. Epidemiological and genetic association studies demonstrate that VITD may have a protective role in AMD, while single nucleotide polymorphisms in the vitamin D metabolism gene (CYP24A1) increase the risk of AMD. However, the functional mechanisms of VITD in AMD are not fully understood. In the current study, we investigated the impact of VITD on H2O2-induced oxidative stress and inflammation in human RPE cells. We demonstrate that exposure to H2O2 caused significantly reduced cell viability, increased production of reactive oxygen species (ROS), lowered expression of antioxidant enzymes and enhanced inflammation. VITD exposure notably counteracted the above H2O2-induced effects. Our data suggest that VITD protects the RPE from oxidative damage and elucidate molecular mechanisms of VITD deficiency in the development of AMD.


Intranasal administration of sertraline ensures sustained brain delivery and antidepressant effect in a mouse model of depression.
The pursuit of more potent and efficacious antidepressant therapies is of utmost significance. Herein, intranasal (IN) route was investigated for sertraline brain delivery, encompassing a comparative pharmacokinetic study after a single-dose administration to mice by IN, intravenous (IV) (4.87 mg/kg) and oral (10 mg/kg) routes, and an efficacy/toxicity study to explore the therapeutic effect in mice subjected to the unpredictable chronic mild stress (UCMS) protocol. Neurotransmitters and melatonin were quantified in prefrontal cortex and plasma, respectively. A different drug biodistribution behavior was unveiled for a CNS-acting drug administered by means of the IN route. For the first time, IN administration of sertraline exhibited heightened systemic exposure (bioavailability = 166 %), and a sustained drug release into the brain, in opposition to IV and oral routes, avoiding drug fluctuation. The lower lung exposition (given by normalized area under the curve) observed after IN instillation envisions the reduction of sertraline pulmonary side effects and similarly other peripheral side effects. IN sertraline treatment displayed significant efficacy in ameliorating anhedonia after one week of administration while the 14-day IN treatment regimen translated to decreased immobility time and increased swimming time in the forced swimming test, suggesting an improvement of the depressive-like behavior displayed by animal depressive-model. Remarkably, these effects were absent with oral sertraline, despite the higher dose used. Noteworthy neurotransmitter alterations were observed, with IN sertraline markedly reducing adrenaline in the prefrontal cortex, while serotonin and melatonin increased following both administration routes. With its sustained brain delivery and serotonin- and melatonin-enhancing potential, the innovative strategy of IN sertraline holds the potential not only to effectively address depressive symptoms but also to mitigate challenges inherent to classic treatments.


Imaging in multiple myeloma: How? When?
Bone disease is the most frequent feature of multiple myeloma (MM) and represents a marker of end-organ damage; it is used to establish the diagnosis and to dictate the immediate need for therapy. For this reason, imaging plays a significant role in the management of MM patients. Although conventional radiography has traditionally been the standard imaging modality, its low sensitivity in detecting osteolytic lesions and inability to evaluate response to therapy has called for the use of more sophisticated techniques, such as whole-body low-dose computed tomography (WBLDCT), whole-body magnetic resonance imaging, and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT). In this review, the advantages, indications of use, and applications of the 3 techniques in the management of patients with MM in different settings will be discussed. The European Myeloma Network and the European Society for Medical Oncology guidelines have recommended WBLDCT as the imaging modality of choice for the initial assessment of MM-related lytic bone lesions. Magnetic resonance imaging is the gold-standard imaging modality for detection of bone marrow involvement, whereas PET/CT provides valuable prognostic data and is the preferred technique for assessment of response to therapy. Standardization of most of the techniques is ongoing.


A review of 21 curricula for abstinence-only-until-marriage programs.
The authors reviewed the content, methods, and overall quality of 21 curricula used in abstinence-only-until-marriage programs. Only materials designed for use in middle school grades (fifth to eighth) or with middle school-aged audiences (9-13 years of age), which presented the abstinence message in at least 40% of their content, were included. A rating instrument adapted from 2 sets of education guidelines structured the assessment of each curriculum. Four experienced teachers rated each curriculum. Curricula exhibited considerable variability in overall quality ratings. While on average, materials scored a 3.33 on a 1-to-5 scale (1 = Unacceptable; 5 = Excellent), 12 curricula received summative scores above the average, with 4 scoring 4.0 or higher. Eight curricula, however, received a below-average rating. While abstinence materials vary considerably in terms of overall quality, the values and world views underlying this sample of curricula were clear and consistent: those who develop abstinence education curricula value nonsexual antecedents of sexual behavior such as skills (goal setting, decision making, and assertiveness), ideals (fidelity, friendships), and psychological factors such as self-esteem.


Park availability and major depression in individuals with chronic conditions: Is there an association in urban India?
Green space exposure has been positively correlated with better mental-health indicators in several high income countries, but has not been examined in low- and middle-income countries undergoing rapid urbanization. Building on a study of mental health in adults with a pre-existing chronic condition, we examined the association between park availability and major depression among 1208 adults surveyed in Delhi, India. Major depression was measured using the Mini International Neuropsychiatric Interview. The ArcGIS platform was used to quantify park availability indexed as (i) park distance from households, (ii) area of the nearest park; and within one km buffer area around households - the (iii) number and (iv) total area of all parks. Mixed-effects logistic regression models adjusted for socio-demographic characteristics indicated that relative to residents exposed to the largest nearest park areas (tertile 3), the odds [95% confidence interval] of major depression was 3.1 [1.4-7.0] times higher among residents exposed to the smallest nearest park areas (tertile 1) and 2.1 [0.9-4.8] times higher in residents with mid-level exposure (tertile 2). There was no statistically significant association between other park variables tested and major depression. We hypothesized that physical activity in the form of walking, perceived stress levels and satisfaction with the neighborhood environment may have mediating effects on the association between nearest park area and major depression. We found no significant mediation effects for any of our hypothesized variables. In conclusion, our results provide preliminary and novel evidence from India that availability of large parks in the immediate neighborhood positively impacts mental well-being of individuals with pre-existing chronic conditions, at the opportune time when India is embarking on the development of sustainable cities that aim to promote health through smart urban design - one of the key elements of which is the inclusion of urban green spaces.


Synthesis of Phenol-derivatives and Biological Screening for Anticancer Activity.
Phenolic compounds are known for their cytotoxic properties against cancer cells despite their still unclear general mechanism of action. Herein is reported the evaluation of the cytotoxic effects of on human osteosarcoma cells of nine phenol derivatives against osteosarcoma cells, and some insights on their mechanism. The cytotoxicity was characterized by cell viability, scratch assay, cellular DNA content measurement, Annexin V apoptosis, mitochondrial calcium and caspase 3/7 assays. The study shows that out of the nine compounds used in this study, a tetrahydroquinoline derivative, 2-((1,2,3,4-tetrahydroquinolin-1-yl)(4- methoxyphenyl)methyl) phenol, was found to exhibit strong inhibitory response with IC50 of 50.5 ± 3.8 µM, and therefore can be a potential chemotherapeutic agent. Further experiments revealed that this compound induces cell death by apoptosis and also act as a migration inhibitor. Analysis of the mitochondrial calcium following treatment with the compound on U2OS cells showed a significant reduction in the level of mitochondrial calcium concentration suggesting a mitochondrial calcium-independent mechanism in triggering apoptosis. Treatment of HEK293 cells with the compound confirmed the cytotoxic effects of the compound, however, an increase in the level of mitochondrial calcium was observed. Moreover, the caspase 3/7 mediated cell death was also observed in both cell types. Overall, the study suggests that the derivatives of this compound can be used for development of new therapeutics for osteosarcoma and other cancers.


Peers and parents: a comparison between neural activation when winning for friends and mothers in adolescence.
Rewards reliably elicit ventral striatum activity. More recently studies have shown that vicarious rewards elicit similar activation. Ventral striatum responses to rewards for self peak during adolescence. However, it is currently not well understood how ventral striatum responses to vicarious rewards develop. In this study, we test this question using behavioral and fMRI data. A total of 233 participants aged 9-26 years old played a gambling game in the scanner in which they could win or lose money for themselves, their best friend and mother. Participants rated how close they felt to their friend and mother and how much they liked winning for them. These ratings were positively correlated. On the neural level males showed higher responses to winning for a friend, but there were no age differences. In contrast, there was a quadratic effect of age when winning for mother, showing heightened ventral striatum activity in mid-adolescence. Furthermore, there was an interaction between age and sex; for females responses to winning for friends become stronger with age relative to winning for mothers. In conclusion, this study provided evidence for elevated ventral striatum responses for mothers in mid-adolescence, and a shift in ventral striatum responses towards peers in girls.


Embolization of Vascular Malformations via In Situ Photocrosslinking of Mechanically Reinforced Alginate Microfibers using an Optical-Fiber-Integrated Microfluidic Device.
Embolization, which is a minimally invasive endovascular treatment, is a safe and effective procedure for treating vascular malformations (e.g., aneurysms). Hydrogel microfibers obtained via spatiotemporally controllable in situ photocrosslinking exhibit great potential for embolizing aneurysms. However, this process is challenging because of the absence of biocompatible and morphologically stable hydrogels and the difficulty in continuously spinning the microfibers via in situ photocrosslinking in extreme endovascular environments such as those involving a tortuous geometry and high absorbance. A double-crosslinked alginate-based hydrogel with tantalum nanopowder (DAT) that exploits the synergistic effect of covalent crosslinking by visible-light irradiation and ionic crosslinking using Ca2+ , which is present in the blood, is developed in this study. Furthermore, an effective strategy to design and produce an optical-fiber-integrated microfluidic device (OFI-MD) that can continuously spin hydrogel microfibers via in situ photocrosslinking in extreme endovascular environments is proposed. As an embolic material, DAT exhibits promising characteristics such as radiopacity, nondissociation, nonswelling, and constant mechanical strength in blood, in addition to excellent cyto- and hemo-compatibilities. Using OFI-MD to spin DAT microfibers continuously can help fill aneurysms safely, uniformly, and completely within the endovascular simulator without generating microscopic fragments, which demonstrates its potential as an effective embolization strategy.


Molecular recognition and molecular sensors.
Enzyme-substrate recognition provides a convenient and powerful basis on which to construct molecular sensors. In direct enzyme electrodes the rate of the enzyme reaction is transduced into a current using an electrode made of a conducting organic salt. In vivo microelectrodes designed to measure glucose have been constructed and used in the brain of the freely moving rat. Another strategy is to use enzymes that operate with NADH; the NADH can readily be oxidized on conducting organic salt electrodes. Results for the measurement of micellar equilibria involving bile acids are presented. The packed-bed wall-jet electrode provides a device of greater sensitivity; results for the measurement of femtomoles of acetylcholine obtained by microdialysis from cerebral fluid demonstrate the power of this method. The wall-jet ring-disc electrode can be used in an electrochemical immunoassay again at the femtomole level. Finally, enzyme inhibition can be used to make a sensor for toxic substances such as H2S at the p.p.m. level.


Involution of changes in lesser circulation after closure of prolonged aortopulmonary anastomosis.
Possibilities of involution of changes in lesser circulation after closure of experimental aortopulmonary anastomosis were studied. 37 observations at various intervals after closure of anastomosis (several minutes to 13.5 months) in 25 dogs were analyzed. Before closure the anastomosis had functioned for 1-7 months. The results of histological examinations of lungs, pressure measurements in lesser circulation, heart weight, electrocardiographic and spirographic examinations were analyzed. It was found that complete involution of changes in lesser circulation was possible only in first month of existence of anastomosis, in this case with changes of both "early" and "late" types. "Late"-type changes after four months function of anastomosis had both reversible and irreversible character, whereas "early"-type changes became irreversible already after three-month duration of anastomosis. With the "late"-type changes, the operation itself (closure of anastomosis) was accompanied by symptoms of pulmonary vasomotor paresis and heart failure, whereas in the presence of "early"-type changes the operation elicited no morphological or functional changes.


Recurrent expressive aphasia as a presentation of cat-scratch encephalopathy.
Cat-scratch disease is a common disease, occurring in an estimated 24,000 patients annually in the United States, and is one of the most common causes of chronic lymphadenitis in children. A wide array of neurologic complications occurs as a result of cat-scratch disease. However, there have been no reports of acute-onset, self-resolving, recurrent, expressive aphasia, as we report here in an adolescent boy. In our case, establishing the diagnosis of cat-scratch encephalopathy saved time and resources and afforded the family a benign diagnosis. Cat-scratch encephalopathy must be considered in the differential diagnoses when pediatric patients present with unusual neurologic symptoms.


Addressing the standardisation of internal standards and preservative used in human bio fluids for NMR analysis: a method optimization.
A database comprising multivariate data in developing a model from nuclear magnetic resonance (NMR) analysis using human bio fluids are necessary to have reproducibility and reliability of the data. To achieve reproducibility of the data, standardised experiments, including internal standard and preservative used should be attained, especially for samples such as human bio fluids to hinder the variation among samples. The aim of the study was to optimise in commonly used human bio fluids (serum and urine) for a suitable internal standard and preservative used in extended storage samples for NMR analysis. Serum and urine samples were collected from healthy human subjects. The experiment was divided into two parts, part one to evaluate 2,2,2,2-tetradeutero-4,4-dimethyl-4-silapentanoic acid (TSP) and 4,4-dimethyl-4-silapentane-1-ammonium trifluoroacetate (DSA) as the optimal internal standard for the serum and urine samples. The second part investigated the effects of preservatives in the serum and urine samples on extended storage. Overall, TSP and DSA are suitable to be used as an internal standard in human urine samples. However, DSA is a superior internal standard in serum samples for NMR analysis. For the effect of preservative, the results indicated that human serum and urine samples could be stored without addition of preservative in -80 °C, as no changes in NMR fingerprinting have been observed during storage in the absence or presence of the preservative. The findings suggest the use of DSA and TSP as an internal standard in serum and urine samples, respectively. Storage of serum and urine samples without any addition of preservative for an extended period has no effect on the metabolites changes. By having a standardised method, it will offer a considerable saving in both operator and spectrometer time and most importantly produce reproducible and reliable data.


Crypt cells are involved in kin recognition in larval zebrafish.
Zebrafish larvae imprint on visual and olfactory kin cues at day 5 and 6 postfertilization, respectively, resulting in kin recognition later in life. Exposure to non-kin cues prevents imprinting and kin recognition. Imprinting depends on MHC class II related signals and only larvae sharing MHC class II alleles can imprint on each other. Here, we analyzed which type of olfactory sensory neuron (OSN) detects kin odor. The single teleost olfactory epithelium harbors ciliated OSNs carrying OR and TAAR gene family receptors (mammals: main olfactory epithelium) and microvillous OSNs with V1R and V2R gene family receptors (mammals: vomeronasal organ). Additionally, teleosts exhibit crypt cells which possess microvilli and cilia. We used the activity marker pERK (phosphorylated extracellular signal regulated kinase) after stimulating 9 day old zebrafish larvae with either non-kin conspecific or food odor. While food odor activated both ciliated and microvillous OSNs, only the latter were activated by conspecific odor, crypt cells showed no activation to both stimuli. Then, we tested imprinted and non-imprinted larvae (full siblings) for kin odor detection. We provide the first direct evidence that crypt cells, and likely a subpopulation of microvillous OSNs, but not ciliated OSNs, play a role in detecting a kin odor related signal.


[Evaluation of an experimental model of necrotizing enterocolitis in rats].
To evaluate an experimental model of necrotizing enterocolitis in rats proposed by OKUR e col. in 1995. On their first day of life, 28 EPM-Wistar rats weighing between 4 and 6 grams were submitted to hypoxia (H) by placing them in a CO2 gas chamber for rodents' sacrifice, where they received a 100% CO2 air flow for 5 minutes. After the hypoxia the animals were reanimated (R) with a 100% O2 air flow, also for 5 minutes. The animals were allocated in two groups: G1: control (n=12): rats not submitted to H-R; G2: (n=16): rats submitted to H-R. Segments of the small intestine and colon were prepared for histological analysis. The remaining intestine was used to measure tissular malondialdehyde. Mean malondialdehyde dosages were 1.05 (0.44-2.03) and 2.60 (0.59- 6.4) nmol MDA/mg protein for G1 and G2, respectively. G2's mean value was significantly higher than in the control group (p<0.002). Significant statistical difference between the studied groups was found in relation the level of injury, with G1 presenting significantly lower levels than G2. The model showed that neonatal hypoxia may cause intestinal wall injury in rats. Despite the discreet histological injuries found, the method is suitable for evaluation of tissular free radicals.


Developmental Exposure to PCB153 (2,2',4,4',5,5'-Hexachlorobiphenyl) Alters Circadian Rhythms and the Expression of Clock and Metabolic Genes.
Polychlorinated biphenyls (PCBs) are highly persistent and ubiquitously distributed environmental pollutants. Based on their chemical structure, PCBs are classified into non-ortho-substituted and ortho-substituted congeners. Non-ortho-substituted PCBs are structurally similar to dioxin and their toxic effects and mode of action are well-established. In contrast, very little is known about the effects of ortho-substituted PCBs, particularly, during early development. The objective of this study is to investigate the effects of exposure to an environmentally prominent ortho-substituted PCB (2,2',4,4',5,5'-hexachlorobiphenyl; PCB153) on zebrafish embryos. We exposed zebrafish embryos to 3 different concentrations of PCB153 starting from 4 to 120 hours post-fertilization (hpf). We quantified gross morphological changes, behavioral phenotypes, gene expression changes, and circadian behavior in the larvae. There were no developmental defects during the exposure period, but starting at 7 dpf, we observed spinal deformity in the 10 μM PCB153 treated group. A total of 633, 2227, and 3378 differentially expressed genes were observed in 0.1 μM (0.036 μg/ml), 1 μM (0.36 μg/ml), and 10 μM (3.6 μg/ml) PCB153-treated embryos, respectively. Of these, 301 genes were common to all treatment groups. KEGG pathway analysis revealed enrichment of genes related to circadian rhythm, FoxO signaling, and insulin resistance pathways. Behavioral analysis revealed that PCB153 exposure significantly alters circadian behavior. Disruption of circadian rhythms has been associated with the development of metabolic and neurological diseases. Thus, understanding the mechanisms of action of environmental chemicals in disrupting metabolism and other physiological processes is essential.


Evaluation of the relation between cardiac biomarkers and thorax computed tomography findings in COVID-19 patients.
Background: Troponin levels may be elevated in COVID-19 infection. The aim of this study was to the explore relation between troponin levels and COVID-19 severity. Materials, methods & Results: One hundred and forty consecutive patients with COVID-19 pneumonia were included. Diagnosis of COVID-19 pneumonia was based on positive chest computed tomography (CT) findings. Quantitative PCR test was performed in all patients. Only 74 patients were quantitative PCR-positive. Twenty four patients had severe CT findings and 27 patients had progressive disease. These patients had significantly lower albumin and higher ferritin, D-dimer, lactate dehydrogenase, C-reactive protein, and high-sensitivity cardiac troponin I (hs-cTnI). Conclusion: COVID-19 patients with severe CT findings and progressive disease had higher hs-cTnI levels suggesting the use of hs-cTnI in risk stratification.


Hand therapist use of patient report outcome (PRO) in practice: a survey study.
The purpose of this survey was to gain greater insight into hand therapists' use of Patient Report Outcome (PRO) measures. An 11-question survey that evaluated therapists' perceptions, preferences, and patterns of use of patient report outcome measures was sent to members of ASHT. A total of 633 ASHT members participated in the survey study. A large majority of participants (92%) responded affirmatively to using a PRO measure in practice. The DASH was reported as the most frequently used measure (90%). The majority of therapists (84%) discuss the results of the outcome measurement score with their patients. Of the participants who use more than one outcome measure, 44% report that this allows them to better establish their patient's functional and physical limitations. The findings in this study suggest that a large percentage of hand therapists are currently including a PRO measure in their hand therapy practice.


A dynamic analysis of the LO noise transfer mechanism in a Rb-cell frequency standard.
Frequency noise of the local oscillator at even harmonics of the modulation frequency is known to contribute to the short-term instability of passive frequency standards. The mechanism by which this noise transfer takes place in Rb-cell standards is described here in a comprehensive approach that includes both signal theory methods and a time-dependent quantum mechanical analysis. The resulting calculated transfer coefficients for the various even harmonics are discussed in relationship with measured coefficients in an actual experiment.


Effect of liposomalization on the antitumor activity, side-effects and tissue distribution of CPT-11.
We have examined the efficacy of liposomalization and polyethyleneglycol (PEG) modification of liposomes on the antitumor activity, side-effects and tissue distribution of irinotecan hydrochloride (CPT-11). PEG-liposome was confirmed to elevate the plasma circulation of CPT-11 and SN-38 (active metabolite) concentrations. The tumor accumulation of CPT-11 and SN-38 was increased by the PEG-modified liposomes. The antitumor activity of CPT-11 increased due to the elevated tumor distribution of CPT-11 and SN-38 levels by the PEG-modified liposomes. In the tumor, CPT-11 was converted to SN-38. Thus, it is considered that passive targeting to the tumor by liposomalization elevated the SN-38 level in the tumor especially and increased the antitumor activity of CPT-11. Furthermore, intestinal disorder, a side toxicity of CPT-11, decreased dependent on the CPT-11 and SN-38 concentrations in the bile by liposomalization. Although the liposomes induce improved tissue distribution of the prodrug, the tissue distribution of active metabolites does not always improve. However, CPT-11-entrapped liposome was useful, as CPT-11 is converted to SN-38 in the tumor. These results suggested that the usefulness of CPT-11 could be extended.


[Changes in the stages of nocturnal sleep in man with a lesion of the hypothalamus-brain stem structures].
Polygraphic study of nocturnal sleep in 18 patients with affection of the hypothalamo-mesencephalic structures showed a reduction of the duration of the II stage and a prolongation of the III and IV stages of slow sleep in comparison with the corresponding indices in the patients with involvement of the ponto-bulbar structures (9) and in healthy persons (8) of control group. Analysis of the qualitative indices of the EEG of slow sleep (a relative amount of the sleep spindles per 1 min of the II stage, delta-index and the delta-wave amplitude at the II and the IV stages) demonstrated a tendency to their increase in the patients with affection of the hypothalamo-mesencephalic structures. Patients of this group showed a decreased frequency of spontaneous changes of sleep from deeper to more superficial stages.


Viscoelastic characteristics of the canine cranial cruciate ligament complex at slow strain rates.
Ligaments including the cruciate ligaments support and transfer loads between bones applied to the knee joint organ. The functions of these ligaments can get compromised due to changes to their viscoelastic material properties. Currently there are discrepancies in the literature on the viscoelastic characteristics of knee ligaments which are thought to be due to tissue variability and different testing protocols. The aim of this study was to characterise the viscoelastic properties of healthy cranial cruciate ligaments (CCLs), from the canine knee (stifle) joint, with a focus on the toe region of the stress-strain properties where any alterations in the extracellular matrix which would affect viscoelastic properties would be seen. Six paired CCLs, from skeletally mature and disease-free Staffordshire bull terrier stifle joints were retrieved as a femur-CCL-tibia complex and mechanically tested under uniaxial cyclic loading up to 10 N at three strain rates, namely 0.1%, 1% and 10%/min, to assess the viscoelastic property of strain rate dependency. The effect of strain history was also investigated by subjecting contralateral CCLs to an ascending (0.1%, 1% and 10%/min) or descending (10%, 1% and 0.1%/min) strain rate protocol. The differences between strain rates were not statistically significant. However, hysteresis and recovery of ligament lengths showed some dependency on strain rate. Only hysteresis was affected by the test protocol and lower strain rates resulted in higher hysteresis and lower recovery. These findings could be explained by the slow process of uncrimping of collagen fibres and the contribution of proteoglycans in the ligament extracellular matrix to intra-fibrillar gliding, which results in more tissue elongations and higher energy dissipation. This study further expands our understanding of canine CCL behaviour, providing data for material models of femur-CCL-tibia complexes, and demonstrating the challenges for engineering complex biomaterials such as knee joint ligaments.


[Age-related changes in splenic lymphocyte migration in mice].
Age changes of distribution of the labelled mouse lymphocytes in the organs of syngeneic recipients were followed. The changes were shown to concern both the circulating lymphocytes and their environment, the latter having suffered greater changes. On the contrary, changes in the lymphocytes played the leading role in this process in the autoimmune mice NZB. The disturbances described resulted in the decrease of tropism of the migrating lymphocytes to the lymphoid organs (homing) what might be one of the causes of decrease of immunological reactivity upon senescence.


Effects of nanosilver on Mytilus galloprovincialis hemocytes and early embryo development.
Silver nanoparticles (AgNP), one of the main nanomaterials for production and use, are expected to reach the aquatic environment, representing a potential threat to aquatic organisms. In this study, the effects of bare AgNPs (47 nm) on the marine mussel Mytilus galloprovincialis were evaluated at the cellular and whole organism level utilizing both immune cells (hemocytes) and developing embryos. The effects were compared with those of ionic Ag+(AgNO3). In vitro short-term exposure (30 min) of hemocytes to AgNPs induced small lysosomal membrane destabilization (LMS EC50 = 273.1 μg/mL) and did not affect other immune parameters (phagocytosis and ROS production). Responses were little affected by hemolymph serum (HS) as exposure medium in comparison to ASW. However, AgNPs significantly affected mitochondrial membrane potential and actin cytoskeleton at lower concentrations. AgNO3 showed much higher toxicity, with an EC50 = 1.23 μg/mL for LMS, decreased phagocytosis and induced mitochondrial and cytoskeletal damage at similar concentrations. Both AgNPs and AgNO3 significantly affected Mytilus embryo development, with EC50 = 23.7 and 1 μg/L, respectively. AgNPs caused malformations and developmental delay, but no mortality, whereas AgNO3 mainly induced shell malformations followed by developmental arrest or death. Overall, the results indicate little toxicity of AgNPs compared with AgNO3; moreover, the mechanisms of action of AgNP appeared to be distinct from those of Ag+. The results indicate little contribution of released Ag+ in our experimental conditions. These data provide a further insight into potential impact of AgNPs in marine invertebrates.


A Comparison of Black-blood T2 Mapping Sequences for Carotid Vessel Wall Imaging at 3T: An Assessment of Accuracy and Repeatability.
This study is to compare the accuracy of four different black-blood T2 mapping sequences in carotid vessel wall. Four different black-blood T2 mapping sequences were developed and tested through phantom experiments and 17 healthy volunteers. The four sequences were: 1) double inversion-recovery (DIR) prepared 2D multi-echo spin-echo (MESE); 2) DIR-prepared 2D multi-echo fast spin-echo (MEFSE); 3) improved motion-sensitized driven-equilibrium (iMSDE) prepared 3D FSE and 4) iMSDE prepared 3D fast spoiled gradient echo (FSPGR). The concordance correlation coefficient and Bland-Altman statistics were used to compare the sequences with a gold-standard 2D MESE, without blood suppression in phantom studies. The volunteers were scanned twice to test the repeatability. Mean and standard deviation of vessel wall T2, signal-to-noise (SNR), the coefficient of variance and interclass coefficient (ICC) of the two scans were compared. The phantom study demonstrated that T2 measurements had high concordance with respect to the gold-standard (all r values >0.9). In the volunteer study, the DIR 2D MEFSE had significantly higher T2 values than the other three sequences (P < 0.01). There was no difference in T2 measurements obtained using the other three sequences (P > 0.05). iMSDE 3D FSE had the highest SNR (P < 0.05) compared with the other three sequences. The 2D DIR MESE has the highest repeatability (ICC: 0.96, [95% CI: 0.88-0.99]). Although accurate T2 measurements can be achieved in phantom by the four sequences, in vivo vessel wall T2 quantification shows significant differences. The in vivo images can be influenced by multiple factors including black-blood preparation and acquisition method. Therefore, a careful choice of acquisition methods and analysis of the confounding factors are required for accurate in vivo carotid vessel wall T2 measurements. From the settings in this study, the iMSDE prepared 3D FSE is preferred for the future volunteer/patient scans.


The impact of dog walking on leisure-time physical activity: results from a population-based survey of Michigan adults.
The extent to which dog walking promotes leisure-time physical activity (LTPA) remains unresolved. We describe the characteristics of people who walk their dog, and assess the impact on LTPA. Information on dog ownership, dog walking patterns, total walking activity and LTPA were assessed in the 2005 Michigan Behavioral Risk Factor Survey. Multiple logistic regression was used to generate adjusted odds ratios (AOR) for the effect of dog walking on total walking and LTPA. Of 5902 respondents 41% owned a dog, and of these, 61% walked their dog for at least 10 minutes at a time. However, only 27% walked their dog at least 150 minutes per week. Dog walking was associated with a significant increase in walking activity and LTPA. Compared with non-dog owners, the odds of obtaining at least 150 minutes per week of total walking were 34% higher for dog walkers (AOR = 1.34, 95% CI = 1.13 to 1.59), and the odds of doing any LTPA were 69% higher (AOR = 1.69, 95% CI = 1.33 to 2.15). Dog walking was associated with more walking and LTPA, however a substantial proportion of dog owners do not walk their dog. The promotion of dog walking could help increase LTPA.


Interrogating RNA and protein spatial subcellular distribution in smFISH data with DypFISH.
Advances in single-cell RNA sequencing have allowed for the identification of cellular subtypes on the basis of quantification of the number of transcripts in each cell. However, cells might also differ in the spatial distribution of molecules, including RNAs. Here, we present DypFISH, an approach to quantitatively investigate the subcellular localization of RNA and protein. We introduce a range of analytical techniques to interrogate single-molecule RNA fluorescence in situ hybridization (smFISH) data in combination with protein immunolabeling. DypFISH is suited to study patterns of clustering of molecules, the association of mRNA-protein subcellular localization with microtubule organizing center orientation, and interdependence of mRNA-protein spatial distributions. We showcase how our analytical tools can achieve biological insights by utilizing cell micropatterning to constrain cellular architecture, which leads to reduction in subcellular mRNA distribution variation, allowing for the characterization of their localization patterns. Furthermore, we show that our method can be applied to physiological systems such as skeletal muscle fibers.


[Electrophysiological comparison between patients with Binswanger's encephalopathy and Alzheimer's disease].
Short-latency somatosensory (SSEPs), brainstem auditory evoked potentials (BAEPs) and event-related potentials (ERPs) were studied in 7 patients with Binswanger's encephalopathy, 12 patients with Alzheimer's disease and 17 normal subjects. Patients with Binswanger's encephalopathy showed significantly prolonged central conduction time (CCT) and P300 latency, and prolonged tendency of I-V IPL compared to those of normal subjects. In particular, CCT showed significant prolongation compared to that of patients with Alzheimer's disease. In patients with Alzheimer's disease, I-V IPL and P300 latency were significantly prolonged compared to those of normals although there was no significant difference in CCT between Alzheimer's disease and normal subjects. These results indicate some difference between Binswanger's encephalopathy and Alzheimer's disease from the electrophysiological aspects although both of these entities are characterized by progressive mental deterioration.


Evaluation of fever in the returned traveler.
The differential diagnosis of a febrile illness in the returned traveler is extensive. The most commonly encountered tropical infections are malaria, dysentery, hepatitis, and dengue fever; a substantial number of febrile illnesses are never diagnosed. Malaria is by far the most important infection to consider in the returned traveler who presents with fever. As international travel continues to increase in popularity, the ongoing need for clinicians to broaden their knowledge of travel-related diseases is evident. The ability to recognize and manage tropical diseases in travelers is essential because the morbidity and mortality of these infections are often preventable with prompt therapy. When expertise in this area is lacking, febrile returned travelers should be referred to a tropical disease unit or an infectious disease consultant for urgent assessment.


Evaluation of different signal processing options in unilateral and bilateral cochlear freedom implant recipients using R-Space background noise.
Difficulty understanding in background noise is a common complaint of cochlear implant (CI) recipients. Programming options are available to improve speech recognition in noise for CI users including automatic dynamic range optimization (ADRO), autosensitivity control (ASC), and a two-stage adaptive beamforming algorithm (BEAM). However, the processing option that results in the best speech recognition in noise is unknown. In addition, laboratory measures of these processing options often show greater degrees of improvement than reported by participants in everyday listening situations. To address this issue, Compton-Conley and colleagues developed a test system to replicate a restaurant environment. The R-SPACE™ consists of eight loudspeakers positioned in a 360 degree arc and utilizes a recording made at a restaurant of background noise. The present study measured speech recognition in the R-SPACE with four processing options: standard dual-port directional (STD), ADRO, ASC, and BEAM. A repeated-measures, within-subject design was used to evaluate the four different processing options at two noise levels. Twenty-seven unilateral and three bilateral adult Nucleus Freedom CI recipients. The participants' everyday program (with no additional processing) was used as the STD program. ADRO, ASC, and BEAM were added individually to the STD program to create a total of four programs. Participants repeated Hearing in Noise Test sentences presented at 0 degrees azimuth with R-SPACE restaurant noise at two noise levels, 60 and 70 dB SPL. The reception threshold for sentences (RTS) was obtained for each processing condition and noise level. In 60 dB SPL noise, BEAM processing resulted in the best RTS, with a significant improvement over STD and ADRO processing. In 70 dB SPL noise, ASC and BEAM processing had significantly better mean RTSs compared to STD and ADRO processing. Comparison of noise levels showed that STD and BEAM processing resulted in significantly poorer RTSs in 70 dB SPL noise compared to the performance with these processing conditions in 60 dB SPL noise. Bilateral participants demonstrated a bilateral improvement compared to the better monaural condition for both noise levels and all processing conditions, except ASC in 60 dB SPL noise. The results of this study suggest that the use of processing options that utilize noise reduction, like those available in ASC and BEAM, improve a CI recipient's ability to understand speech in noise in listening situations similar to those experienced in the real world. The choice of the best processing option is dependent on the noise level, with BEAM best at moderate noise levels and ASC best at loud noise levels for unilateral CI recipients. Therefore, multiple noise programs or a combination of processing options may be necessary to provide CI users with the best performance in a variety of listening situations.


Debris ingestion by juvenile marine turtles: an underestimated problem.
Marine turtles are an iconic group of endangered animals threatened by debris ingestion. However, key aspects related to debris ingestion are still poorly known, including its effects on mortality and the original use of the ingested debris. Therefore, we analysed the impact of debris ingestion in 265 green turtles (Chelonia mydas) over a large geographical area and different habitats along the Brazilian coast. We determined the death rate due to debris ingestion and quantified the amount of debris that is sufficient to cause the death of juvenile green turtles. Additionally, we investigated the original use of the ingested debris. We found that a surprisingly small amount of debris was sufficient to block the digestive tract and cause death. We suggested that debris ingestion has a high death potential that may be masked by other causes of death. An expressive part of the ingested debris come from disposable and short-lived products.


A descriptive analysis of EUS-FNA for mediastinal lymphadenopathy: an emphasis on clinical impact and false negative results.
Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been shown to accurately diagnose mediastinal lymph node pathology. We investigated the clinical impact of EUS-FNA in the management of patients with mediastinal lymphadenopathy, and determined the nature and clinical consequences of false negative results. We analyzed a cohort of patients who were found to have mediastinal lymph nodes by EUS and underwent FNA. The diagnostic standard included FNA cytology, histopathology, and clinical follow-up. Sixty EUS-FNAs of mediastinal lymph nodes were performed on 59 patients (mean age 61 years old, 74.5% men) over a 24-month period. Prior to EUS, 20 (34%) patients had known malignancy. The most frequent indication for EUS was failed diagnosis by bronchoscopy (54%). EUS-FNA of lymph nodes showed malignant cells in 38%. The diagnostic accuracy of EUS-FNA was 84%. Among the 47 patients who were available for follow-up, EUS-FNA provided new information by changing the clinical diagnosis, and subsequently changed the management in 18 (38%) patients. The false negative rate was 20% (95% exact CI, 8.4-31.6%). Two of the 7 false negative cases received empiric chemoradiation without tissue diagnosis, and 4 received palliative treatment for advanced malignancy. The most common indication for EUS-FNA of the mediastinum in our institution is nondiagnostic transbronchial FNA. EUS-FNA is a valuable diagnostic method for sampling mediastinal lymph nodes and affecting management. False negative results do not appear to delay appropriate treatment or adversely affect clinical outcome.


Differential recognition of a BCR/ABL peptide by lymphocytes from normal donors and chronic myeloid leukemia patients.
The BCR/ABL oncogenic fusion protein transforms normal bone marrow stem cells into neoplastic cells. It has been shown that peptides derived from the junctional region of this oncogenic fusion protein can be recognized by human T-lymphocytes obtained from normal donors. In this study, we investigated the immunogenicity in patients with chronic myeloid leukemia (CML) of a 17 mer b3/a2 Bcr/abl peptide (B/A1), which was shown to induce proliferative responses in lymphocytes from normal donors. A total of 56 CML patients in chronic phase were studied. Twenty-two patients were studied at diagnosis without any treatment (group I). Fourteen patients were receiving IFN (group II), 14 patients were being treated with hydroxyurea (group III), and 6 patients were on different regimens (group IV). Patients were initially assessed for general immunological competence using both in vivo and in vitro assays. Patients were also selected for the expression of HLA-DR0401, the HLA specificity known to present peptide B/A1 to CD4 lymphocytes. With the exception of the six patients in group IV, the results of all these assays (in vitro phytohemagglutinin/tetanus toxoid responses, in vivo skin reaction to ubiquitous antigens) in CML patients did not significantly differ from those obtained in normal donors, thus excluding the presence of generalized immunosuppression. Eight patients with HLA-DR0401 and a b3/a2 type of fusion were identified and further studied. In these eight patients dendritic cells were obtained from adherent peripheral blood mononuclear cells and used to stimulate CD4 lymphocytes. No patient developed a specific response to the bcr/abl peptide, although patients' lymphocytes proliferated in response to a promiscuous tetanus toxoid peptide in all but one case. In contrast, response to the bcr/abl peptide was observed in seven of eight HLA-DR0401 healthy donors tested. These data suggest that immunocompetent, HLA-DR0401+ CML patients are unable to respond to peptide B/A1, at difference from healthy donors. The implication of these results for the immunotherapy of CML is discussed.


Liver function tests in the critically ill patient.
The liver has a wide range of functions that may be disturbed in different ways by the many diseases which affect it and, in consequence, there are a large number of tests which look at different aspects of its function. Specific diagnoses are made using a range of clinical, biochemical, histological and radiological methods. Measurement of the plasma concentration of alanine aminotransferase (ALT, SGPT), gamma-glutamyl transpeptidase (gammaGT) and albumin are particularly valuable as these substances are specifically affected by liver disease. Their elevation can reveal increases in the membrane permeability of hepatocytes (ALT), cholestasis and toxic damage (gammaGT), or an impairment of liver protein synthesis and secretion (albumin), respectively. If their activities remain within the normal range the likelihood of significant liver disease is less than 2%. A series of quantitative liver function tests are described which each examine one aspect of hepatic function. Table 1 lists several situations where the assessment of hepatic function is necessary. Liver function tests are classified in Table 2.


Secretome Analysis of the Pine Wood Nematode Bursaphelenchus xylophilus Reveals the Tangled Roots of Parasitism and Its Potential for Molecular Mimicry.
Since it was first introduced into Asia from North America in the early 20(th) century, the pine wood nematode Bursaphelenchus xylophilus has caused the devastating forest disease called pine wilt. The emerging pathogen spread to parts of Europe and has since been found as the causal agent of pine wilt disease in Portugal and Spain. In 2011, the entire genome sequence of B. xylophilus was determined, and it allowed us to perform a more detailed analysis of B. xylophilus parasitism. Here, we identified 1,515 proteins secreted by B. xylophilus using a highly sensitive proteomics method combined with the available genomic sequence. The catalogue of secreted proteins contained proteins involved in nutrient uptake, migration, and evasion from host defenses. A comparative functional analysis of the secretome profiles among parasitic nematodes revealed a marked expansion of secreted peptidases and peptidase inhibitors in B. xylophilus via gene duplication and horizontal gene transfer from fungi and bacteria. Furthermore, we showed that B. xylophilus secreted the potential host mimicry proteins that closely resemble the host pine's proteins. These proteins could have been acquired by host-parasite co-evolution and might mimic the host defense systems in susceptible pine trees during infection. This study contributes to an understanding of their unique parasitism and its tangled roots, and provides new perspectives on the evolution of plant parasitism among nematodes.


Blood group-related antigens in human germ cell tumors.
With the use of immunohistochemical techniques, seven mouse monoclonal antibodies and the lectin from Ulex europaeus, detecting blood group antigens of the ABH and Lewis systems, have been used to define the distribution of these antigenic structures in germ cell tumors. The reagents used recognize the following blood group antigens: A, B, H, Lewisa, Lewisb, X (Lewisx), Y (Lewisy), and type I precursor antigen. Tumors from 29 patients were studied. Tumors studied consisted of pure embryonal carcinoma for eight patients, pure yolk sac tumor for two patients, embryonal carcinoma plus yolk sac tumor in one patient, and yolk sac tumor plus seminoma in one patient. Also studied were nine classic seminomas and a group of six patients with tumors classified as seminomas that exhibited atypical histological features. One patient had an anaplastic carcinoma arising from the mediastinum which could not be conclusively identified as a germ cell tumor morphologically and was analyzed separately. All embryonal carcinomas and yolk sac tumors exhibited strong positivity for type I precursor structure as detected by the K-21 monoclonal antibody. In marked contrast, there was non staining in classic seminomas but heterogeneous staining in five of six atypical seminomas. The majority of embryonal carcinomas and all yolk sac tumors studied demonstrated strong positivity for blood group antigen H. For seminoma, however, only one of the atypical cases and two of the classic cases (occasional cells) stained for H. Focal expression of the Y antigen was identified in 5 of 17 seminomas and in the majority of embryonal carcinomas and yolk sac tumors. Two yolk sac tumors and two classic seminomas expressed blood group X. The remaining blood group antigens were not expressed by seminomas while they were variably expressed by embryonal carcinoma and yolk sac tumors. These data suggest that K-21 and blood group antigen H may be distinguishing markers of nonseminomatous germ cell tumor versus seminoma. If so, it is possible that the heterogeneous expression of blood group substances in seminomas with atypical histologies is an indication of differentiation towards nonseminomatous germ cell tumor.


Primary meniscal-bearing knee replacements: 8- to 15-year followup.
This study presents the survivorship data of a consecutive series of primary meniscal-bearing total knee replacements at one institution at 8 to 15 years followup. We reviewed 125 meniscal-bearing knee replacements in 93 patients at a minimum followup of 96 months (mean, 130 months; range, 96-191 months). The tibial and femoral components were cemented in 71 knees; uncemented femurs and tibias were used in 48 knees; and cemented tibias and uncemented femurs were used in six knees. One patient was lost to followup. Seventeen knees failed, three as a result of infection. Five knees were revised for loose tibial components and one for a loose femoral component. A second femoral component was identified as radiographically loose. All the loose components were uncemented. Five knees had reoperation for fractured bearings and one for a dislocated bearing. This knee was later rerevised for a loose uncemented tibia. One knee was revised for instability and a second knee was identified as grossly unstable but not revised. Kaplan-Meier survival analysis showed survivorship of approximately 90% at 9 years, which decreased to 71% at 15 years. Uncemented components had an increased aseptic loosening rate compared with cemented components. Meniscal-bearing replacements with cement fixation appeared successful, although bearing fracture seems to be a predominant failure mode at long-term followup.


Breast tomosynthesis: Accuracy of tumor measurement compared with digital mammography and ultrasonography.
Mammographic tumor size measurement can be difficult because breast structures are superimposed onto a two-dimensional (2D) plane, potentially obscuring the tumor outline. Breast tomosynthesis (BT) is a 3D X-ray imaging technique in which low-dose images are acquired over a limited angular range at a total dose comparable to digital mammography (DM). These low-dose images are used to mathematically reconstruct a 3D image volume of the breast, thus reducing the problem of superimposed tissue. To investigate whether breast cancer size can be more accurately assessed with breast tomosynthesis than with digital mammography and ultrasonography (US), by reducing the disturbance effect of the projected anatomy. A prototype BT system was used. The main inclusion criterion for BT examination was subtle but suspicious findings of breast cancer on 2D mammography. Sixty-two women with 73 breast cancers were included. BT, DM, and US sizes were measured independently by experienced radiologists without knowledge of the pathology results, which were used as reference. The tumor outline could be determined in significantly more cases with BT (63) and US (60) than DM (49). BT and US size correlated well with pathology (R=0.86 and R=0.85, respectively), and significantly better than DM size (R=0.71). Accordingly, staging was significantly more accurate with BT than with DM. The study indicates that BT is superior to DM in the assessment of breast tumor size and stage.


Reactivity of digermylenes toward potassium graphite: synthesis and characterization of germylidenide anions.
The synthesis and characterization of the digermylenes [LGe-GeL] [L = L(1) (3A), L(2) (3B)] supported by the 2,6-diiminophenyl (L(1)) and 2-imino-5,6-methylenedioxylphenyl (L(2)) ligands are described. Their reactivities toward potassium graphite are also reported. The reaction of [LGeCl] [L = L(1) (2A), L(2) (2B)] with KC(8) in tetrahydrofuran (THF) at room temperature afforded the digermylenes [LGe-GeL] [L = L(1) (3A), L(2) (3B)], which are the first examples of diaryldigermylenes stabilized by o-imino donor(s). The treatment of 3A with 2 equiv of KC(8) in Et(2)O, followed by the addition of excess tetramethylethylenediamine (TMEDA), results in cleavage of the Ge(I)-Ge(I) bond to afford the germylidenide anion [L(1)GeK·TMEDA] (4A). Similarly, the reaction of 3B with excess KC(8) in THF afforded the germylidenide anion [L(2)GeK] (4B). The molecular structures of compounds 4A and 4B as determined by single-crystal X-ray diffraction analysis show that the K atoms are η(1)-coordinated with the low-valent Ge atoms. Moreover, the negative charges at the Ge atoms in compounds 4A and 4B are stabilized by electron delocalization in the germanium heterocycles.


Facilitating job retention for chronically ill employees: perspectives of line managers and human resource managers.
Chronic diseases are a leading contributor to work disability and job loss in Europe. Recent EU policies aim to improve job retention among chronically ill employees. Disability and occupational health researchers argue that this requires a coordinated and pro-active approach at the workplace by occupational health professionals, line managers (LMs) and human resource managers (HRM). Little is known about the perspectives of LMs an HRM on what is needed to facilitate job retention among chronically ill employees. The aim of this qualitative study was to explore and compare the perspectives of Dutch LMs and HRM on this issue. Concept mapping methodology was used to elicit and map statements (ideas) from 10 LMs and 17 HRM about what is needed to ensure continued employment for chronically ill employees. Study participants were recruited through a higher education and an occupational health services organization. Participants generated 35 statements. Each group (LMs and HRM) sorted these statements into six thematic clusters. LMs and HRM identified four similar clusters: LMs and HRM must be knowledgeable about the impact of chronic disease on the employee; employees must accept responsibility for work retention; work adaptations must be implemented; and clear company policy. Thematic clusters identified only by LMs were: good manager/employee cooperation and knowledge transfer within the company. Unique clusters identified by HRM were: company culture and organizational support. There were both similarities and differences between the views of LMs and HRM on what may facilitate job retention for chronically ill employees. LMs perceived manager/employee cooperation as the most important mechanism for enabling continued employment for these employees. HRM perceived organizational policy and culture as the most important mechanism. The findings provide information about topics that occupational health researchers and planners should address in developing job retention programs for chronically ill workers.


PARK2/Parkin-mediated mitochondrial clearance contributes to proteasome activation during slow-twitch muscle atrophy via NFE2L1 nuclear translocation.
Skeletal muscle atrophy is thought to result from hyperactivation of intracellular protein degradation pathways, including autophagy and the ubiquitin-proteasome system. However, the precise contributions of these pathways to muscle atrophy are unclear. Here, we show that an autophagy deficiency in denervated slow-twitch soleus muscles delayed skeletal muscle atrophy, reduced mitochondrial activity, and induced oxidative stress and accumulation of PARK2/Parkin, which participates in mitochondrial quality control (PARK2-mediated mitophagy), in mitochondria. Soleus muscles from denervated Park2 knockout mice also showed resistance to denervation, reduced mitochondrial activities, and increased oxidative stress. In both autophagy-deficient and Park2-deficient soleus muscles, denervation caused the accumulation of polyubiquitinated proteins. Denervation induced proteasomal activation via NFE2L1 nuclear translocation in control mice, whereas it had little effect in autophagy-deficient and Park2-deficient mice. These results suggest that PARK2-mediated mitophagy plays an essential role in the activation of proteasomes during denervation atrophy in slow-twitch muscles.


A physiologically-based model to predict individual pharmacokinetics and pharmacodynamics of remifentanil.
Remifentanil based anesthesia is nowadays spread worldwide. This drug is characterized by a rapid onset of the analgesic effects, but also by a rapid onset of the side effects. For this reason, the knowledge of the remifentanil concentration in the human body is a key topic in anesthesiology. The aims of this work are to propose and validate a physiologically based pharmacokinetic model capable to predict both the pharmacokinetics and pharmacodynamics of remifentanil, and to take into account the inter-individual differences among the patients (such as height and body mass). The blood concentration of remifentanil has been successfully simulated and compared with experimental literature data. The pharmacodynamics, in terms of effect of remifentanil on minute ventilation and electroencephalogram, has been implemented in this model. Moreover, the remifentanil concentration in various organs and tissues is predicted, which is a significant improvement with respect to the traditional compartmental models. The availability of the model makes possible the prediction of the effects of remifentanil administration, also accounting for individual parameters.


Physiologically active chloroplasts contain pools of unassembled extrinsic proteins of the photosynthetic oxygen-evolving enzyme complex in the thylakoid lumen.
The oxygen-evolving complex (OEC) of photosystem II (PS II) consists of at least three extrinsic membrane-associated protein subunits, OE33, OE23, and OE17, with associated Mn2+, Ca2+, and Cl- ions. These subunits are bound to the lumen side of PS II core proteins embedded in the thylakoid membrane. Our experiments reveal that a significant fraction of each subunit is normally present in unassembled pools within the thylakoid lumen. This conclusion was supported by immunological detection of free subunits after freshly isolated pea thylakoids were fractionated with low levels of Triton X-100. Plastocyanin, a soluble lumen protein, was completely released from the lumen by 0.04% Triton X-100. This gentle detergent treatment also caused the release from the thylakoids of between 10 and 20%, 40 and 60%, and 15 and 50% of OE33, OE23, and OE17, respectively. Measurements of the rates of oxygen evolution from Triton-treated thylakoids, both in the presence and absence of Ca2+, and before and after incubation with hydroquinone, demonstrated that the OEC was not dissociated by the detergent treatment. Thylakoids isolated from spinach released similar amounts of extrinsic proteins after Triton treatment. These data demonstrate that physiologically active chloroplasts contain significant pools of unassembled extrinsic OEC polypeptide subunits free in the lumen of the thylakoids.


Parental attitudes about sexually transmitted infection vaccination for their adolescent children.
To evaluate parental attitudes about adolescent vaccination as a function of vaccine characteristics, including whether the vaccine prevented a sexually transmitted infection (STI), and to explore possible sociodemographic predictors of acceptability of STI vaccines. Participants were 278 parents who accompanied their children (69.1% female, aged 12-17 years) to appointments at medical clinics. By using computer-based questionnaires, parents rated 9 hypothetical vaccine scenarios, each of which was defined along 4 dimensions: mode of transmission (STI or non-STI), severity of infection (curable, chronic, or fatal), vaccine efficacy (50%, 70%, or 90%), and availability of behavioral methods for prevention (available or not available). Willingness by parents to vaccinate their adolescents under each vaccine scenario was assessed on a scale that ranged from 0 to 100. Conjoint analysis was used to determine the relative contribution of each dimension to the ratings. The mean vaccine scenario rating was 81.3. Sexually transmitted infection vaccines (mean, 81.3) were not rated differently than non-STI vaccines (mean, 80.0). Conjoint analysis indicated that severity of infection and vaccine efficacy had the strongest influence on ratings, followed by availability of behavioral prevention. Mode of transmission had a negligible effect on ratings. Child age (P = .08) and sex (P = .77), parent age (P = .32) and education (P = .34), insurance status (P = .08), and data collection site (P = .48) were not significantly associated with STI vaccine acceptability. Parents were accepting of the idea of vaccinating their adolescent children against STIs. The most salient issues were severity of infection and vaccine efficacy, not sexual transmissibility. Parents also favored vaccines for infections that had no method of behavioral prevention available.


Adverse reaction to intravenous fluorescein: evidence for sex difference.
Males react adversely more frequently than females to intravenous fluorescein angiography, as shown in a study of 547 patients. Approximately 10% of all cases reacted: 12.8% of the male patients and 7.3% of the female patients had adverse responses. Nausea was most common; vomiting was infrequent, and urticaria rare (1.1%). Ten males as opposed to one female reacted markedly. More serious reactions did not occur during the 7 year testing period. No apparent cause for the increased frequency in the male cases was found.


Lateral-flow assay for rapid quantitative detection of clorprenaline residue in swine urine.
Clorprenaline (CLP), a β2-adrenergic agonist, was first found in veterinary drugs for cold treatment in China in 2013. It is a potential new lean meat-boosting feed additive because it can promote animal muscular mass growth and decrease fat accumulation. A competitive colloidal gold-based lateral flow immunoassay system with a portable strip reader was successfully developed for rapid quantitative detection of CLP residue in swine urine. The detection system was optimized so that the detection can be completed within 9 min with a limit of detection of 0.15 μg · liter(-1). The assay exhibited good linear range from 3.0 to 20.0 μg · liter(-1), with reliable correlation of 0.9970 and with no obvious cross-reaction with five other β2-agonist compounds. Twenty spiked swine urine samples were tested by lateral flow immunoassay and liquid chromatography-tandem mass spectrometry to confirm the accuracy of the system. Results show good correlation between the two methods. This method is rapid, sensitive, specific, and convenient. It can be applied in the field for on-site detection of CLP in urine samples.


Antibacterial and Anti-Inflammatory Activity of an Antimicrobial Peptide Synthesized with D Amino Acids.
The peptide SET-M33 is a molecule synthesized in tetra-branched form which is being developed as a new antibiotic against Gram-negative bacteria. Its isomeric form with D amino acids instead of the L version (SET-M33D) is also able to kill Gram-positive bacteria because of its higher resistance to bacterial proteases (Falciani et al., PLoS ONE, 2012, 7, e46259). Here we report the strong in vitro activity of SET-M33D (MIC range 0.7-6.0 µM) against multiresistant pathogens of clinical interest, including Gram-positives Staphylococcus aureus, Staphylococcus saprophyticus, and Enterococcus faecalis, and various Gram-negative enterobacteriaceae. SET-M33D antibacterial activity is also confirmed in vivo against a MRSA strain of S. aureus with doses perfectly compatible with clinical use (5 and 2.5 mg/Kg). Moreover, SET-M33D strongly neutralized lipopolysaccharide (LPS) and lipoteichoic acid (LTA), thus exerting a strong anti-inflammatory effect, reducing expression of cytokines, enzymes, and transcription factors (TNF-α, IL6, COX-2, KC, MIP-1, IP10, iNOS, NF-κB) involved in the onset and evolution of the inflammatory process. These results, along with in vitro and in vivo toxicity data and the low frequency of resistance selection reported here, make SET-M33D a strong candidate for the development of a new broad spectrum antibiotic.


Quantifying the nutritional and income loss caused by crop raiding in a rural African subsistence farming community in South Africa.
Globally, crop damage by wildlife contributes to food insecurity through the direct loss of food and income. We investigated the calories lost and the potential economic impact of crop raiding at subsistence homesteads abutting the Hluhluwe Game Reserve, and assessed mitigation measures to combat crop raiding. We quantified the seasonal loss of calories (kJ/g) of four common crops, namely, beetroot, common bean, maize, and spinach, and determined the seasonal potential income loss. We used a stratified sampling approach to sample the homesteads. We found that season, crop type and the interaction between season and crop type predicted relative calorie loss and potential income loss, with the highest income loss recorded for spinach in the dry season. Significant differences were found for the potential income loss for all crop types in the wet season, and for the interaction between the crop types (maize, spinach) and the wet season. Farm slope was also a significant predictor of the relative calorie loss. Crop raiding animals, crops raided and distance of farms from the reserve all had a significant effect on the choice of mitigation measures of farmers. The highest relative calorie loss was for maize during the dry season, which could affect the subsistence farmers by reducing their daily calorie intake. This has an impact on their food security, especially during the dry season. Moreover, the most preferred mitigation measure used by farmers can have opportunity costs. These results have important implications for food security policies and practices.


Reactive oxygen species in cancer: a dance with the devil.
Reactive oxygen species (ROS) can initiate cancer, but oxidant generation in tumors leaves them vulnerable to further stresses. In this issue of Cancer Cell, Harris and colleagues show that augmenting oxidant stress in normal cells limits tumor initiation and progression. Hence, strategic targeting of antioxidant systems may undermine survival of new tumor cells.


Relation of depression with health behaviors and social conditions of dependent community-dwelling older persons in the Republic of Chile.
Depressive symptoms are a leading cause of disability and emotional suffering, particularly in old age. However, evidence on depression and old age in developing countries remains largely ignored. The aim of this study was to examine the relation between health behavior and social conditions with depression among dependent community-dwelling older persons in the Republic of Chile. This is a cross-sectional and inferential study, using nationally representative secondary data. Two models used logistic regression on 640 dependent community-dwelling older persons from all over Chile, who personally answered a depression assessment, excluding those taking antidepressants. The geriatric depression scale (GDS-15) was used as outcome. The first model aims at any kind of depression (GDS 5>). The second aims at severe depression (GDS 10>). As exposure, we used the health behavior and social conditions of the older persons. Socio-demographic and physical conditions were used as adjustment. 44.5% of the older persons presented depressive symptoms. Among them, 11% had severe depression. Logistic regression showed that significant detrimental factors for being depressed in both models were visiting the doctor five times or over because of acute diseases, feeling uncomfortable with their living arrangement, and feeling discriminated. On the other hand, every additional day of physical exercise and living alone had a beneficial and detrimental effect only in model one. Analyses on ways to support older persons living alone and the promotion of physical exercise to avoid depression are needed, along with a deeper understanding of the comfort with their living arrangement. Finally, ways to address the discrimination among older persons should be further explored.


Inside Front Cover: Polarized-Light-Emitting Quantum-Rod Diodes (Adv. Mater. 11/2005).
Polarized-light-emitting quantum-rod diodes have been successfully produced using thin layers of quantum rods oriented by a rubbing technique, as shown on the inside cover. Hikmet and co-workers report on p. 1436 that diode emission at 620 nm with a luminance efficiency of 0.65 cd A-1 and an external quantum efficiency of 0.49 % is obtained. Light emitted polarized parallel to the long axis of the rods is 1.5 times more intense than that polarized perpendicular to the rods.


Maternal PPAR gamma protects nursing neonates by suppressing the production of inflammatory milk.
Lactation is a highly demanding lipid synthesis and transport process that is crucial for the development of newborn mammals. While PPAR gamma is known to promote adipogenesis and lipogenesis in adipose tissue, its role in the lactating mammary gland is unexplored. Here, we report that a targeted deletion of PPAR gamma in mice results in the production of "toxic milk" containing elevated levels of inflammatory lipids. Surprisingly, ingestion of this "toxic milk" causes inflammation, alopecia, and growth retardation in the nursing neonates. Genomic profiling reveals that PPAR gamma deficiency leads to increased expression of lipid oxidation enzymes in the lactating mammary gland. Consistently, metabolomic profiling detects increased levels of oxidized free fatty acids in the pups nursed by PPAR gamma-deficient mothers. Therefore, maternal PPAR gamma is pivotal for maintaining the quality of milk and protecting the nursing newborns by suppressing the production of inflammatory lipids in the lactating mammary gland.


Addressing Bias in Small RNA Library Preparation for Sequencing: A New Protocol Recovers MicroRNAs that Evade Capture by Current Methods.
Recent advances in sequencing technology have helped unveil the unexpected complexity and diversity of small RNAs. A critical step in small RNA library preparation for sequencing is the ligation of adapter sequences to both the 5' and 3' ends of small RNAs. Studies have shown that adapter ligation introduces a significant but widely unappreciated bias in the results of high-throughput small RNA sequencing. We show that due to this bias the two widely used Illumina library preparation protocols produce strikingly different microRNA (miRNA) expression profiles in the same batch of cells. There are 102 highly expressed miRNAs that are >5-fold differentially detected and some miRNAs, such as miR-24-3p, are over 30-fold differentially detected. While some level of bias in library preparation is not surprising, the apparent massive differential bias between these two widely used adapter sets is not well appreciated. In an attempt to mitigate this bias, the new Bioo Scientific NEXTflex V2 protocol utilizes a pool of adapters with random nucleotides at the ligation boundary. We show that this protocol is able to detect robustly several miRNAs that evade capture by the Illumina-based methods. While these analyses do not indicate a definitive gold standard for small RNA library preparation, the results of the NEXTflex protocol do correlate best with RT-qPCR. As increasingly more laboratories seek to study small RNAs, researchers should be aware of the extent to which the results may differ with different protocols, and should make an informed decision about the protocol that best fits their study.


Isoforms of JSAP1 scaffold protein generated through alternative splicing.
We have identified four isoforms of c-Jun NH(2)-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1), a scaffold protein that participates in JNK mitogen-activated protein kinase cascades, termed JSAP1a, JSAP1b, JSAP1c, and JSAP1d. The previously identified JSAP1 was renamed JSAP1a to avoid confusion. Analyses of the exon-intron structure of the jsap1 gene indicated that the isoforms are generated through alternative splicing involving exons 5 and 6. The mRNA expression levels of the JSAP1 isoforms differed among the mouse tissues examined. We also investigated the region of JSAP1 responsible for its interaction with JNK, and found that the JNK-binding domain is located between aa residues 201 and 217 in JSAP1a, which is encoded by part of exon 6. As all the JSAP1 isoforms contain this binding domain, we examined the binding affinity of the JSAP1 isoforms for JNK1, JNK2, and JNK3. JSAP1c and JSAP1d, which contain a 31-aa sequence not present in JSAP1a or JSAP1b, had a lower binding affinity for the JNKs, especially JNK3. These results suggest that JSAP1c and JSAP1d may attenuate the scaffolding activity of JSAP1a and/or JSAP1b in JNK cascades, especially the JNK3 cascades.