How does stigma affect work in people with serious mental illnesses?
How does stigma influence whether people with serious mental illness work? We examine the relationship of public stigma (the effects that occur when people with mental illness endorse the common prejudice of mental illness) and self-stigma (the results of people with psychiatric disorders internalizing prejudice) on current and lifetime histories of work. Eighty-five persons with serious mental illness reported current work history (i.e., in the past 3 months and in the past year) and lifetime work history (i.e., "have you ever worked?"). They also completed measures of self- and public stigma, focusing on the stereotypes of responsibility and dangerousness. Endorsement of public stigma was shown to be significantly associated with lifetime history of work and self-stigma with current history. The dangerousness cluster of public stigma was specifically associated with lifetime work. We also tested a hierarchical model of self-stigma: that people need to first be aware of the prejudice, then agree to it, next apply it to themselves, and finally experience some harm to self-esteem. Only the latter stages of self-stigma-apply and harm-were correlated with current work. Implications of these findings for meaningfully impacting stigma change are considered. In particular, we discuss ways to change public and self-stigma in order to enhance work.


Hydration: Tactical and Practical Strategies.
Full-spectrum Human Performance Optimization (HPO) is essential for Special Operations Forces (SOF). Adequate hydration is essential to all aspects of performance (physical and cognitive) and recovery. Water losses occur as a result of physical activity and can increase further depending on clothing and environmental conditions. Without intentional and appropriate strategic hydration planning, Operators are at increased risk for degradation in performance and exertional heat illness. The purpose of this article is to highlight current best practices for maintaining hydration before, during, and after activity, while considering various environmental conditions. Effective leadership and planning are necessary for preparing Operators for successful military operations.


Failure to show decrease in small pulmonary blood vessels in rats with experimental pulmonary hypertension.
We induced chronic pulmonary hypertension in one group of rats by exposing them to chronic hypobaric hypoxia (380 mm Hg for three weeks) and in another group by administering a single subcutaneous dose of monocrotaline (60 mg/kg body weight). Both groups of rats showed increase of the right ventricular mean systolic blood pressure and right ventricular hypertrophy. We measured the surface area of histological sections of the left or right lungs and counted all small blood vessels with an external diameter of less than 50 microns and with a definite elastic coat lying distal to respiratory bronchioles. In the 10 rats with chronic hypoxic pulmonary hypertension the mean total number of small pulmonary blood vessels was 428.8 +/- 96.9 (SD) compared with 337.8 +/- 91.9 in 10 untreated control rats. The number of small pulmonary blood vessels per mm2 of lung tissue was 4.0 +/- 1.3 in the chronically hypoxic rats compared with 3.8 +/- 1.2 in the controls. The mean total number of small pulmonary blood vessels in nine rats with monocrotaline-induced pulmonary hypertension was 396.8 +/- 61.7 compared with 384 +/- 55.4 in three control rats. The number of small pulmonary blood vessels per mm2 lung tissue was 3.3 +/- 0.6 in the rats treated with monocrotaline compared with 3.6 +/- 0.6 in the control group. We conclude that the number of small pulmonary blood vessels is not reduced in rats with pulmonary hypertension induced by chronic hypoxia or monocrotaline.


PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance.
Androgen receptor (AR) transcriptional activity contributes to prostate cancer development and castration resistance. The growth and survival pathways driven by AR remain incompletely defined. Here, we found PDCD4 to be a new target of AR signaling and a potent regulator of prostate cancer cell growth, survival, and castration resistance. The 3' untranslated region of PDCD4 is directly targeted by the androgen-induced miRNA, miR-21. Androgen treatment suppressed PDCD4 expression in a dose responsive and miR-21-dependent manner. Correspondingly, AR inhibition dose-responsively induced PDCD4 expression. Using data from prostate cancer tissue samples in The Cancer Genome Atlas (TCGA), we found a significant and inverse correlation between miR-21 and PDCD4 mRNA and protein levels. Higher Gleason grade tumors exhibited significantly higher levels of miR-21 and significantly lower levels of PDCD4 mRNA and protein. PDCD4 knockdown enhanced androgen-dependent cell proliferation and cell-cycle progression, inhibited apoptosis, and was sufficient to drive androgen-independent growth. On the other hand, PDCD4 overexpression inhibited miR-21-mediated growth and androgen independence. The stable knockdown of PDCD4 in androgen-dependent prostate cancer cells enhanced subcutaneous tumor take rate in vivo, accelerated tumor growth, and was sufficient for castration-resistant tumor growth. IMPLICATIONS: This study provides the first evidence that PDCD4 is an androgen-suppressed protein capable of regulating prostate cancer cell proliferation, apoptosis, and castration resistance. These results uncover miR-21 and PDCD4-regulated pathways as potential new targets for castration-resistant prostate cancer.


The role of in vitro-induced lymphocyte apoptosis in feline immunodeficiency virus infection: correlation with different markers of disease progression.
Human immunodeficiency virus infection is characterized by a progressive decline in the number of peripheral blood CD4(+) T lymphocytes, which finally leads to AIDS. This T-cell decline correlates with the degree of in vitro-induced lymphocyte apoptosis. However, such a correlation has not yet been described in feline AIDS, caused by feline immunodeficiency virus (FIV) infection. We therefore investigated the intensity of in vitro-induced apoptosis in peripheral blood lymphocytes from cats experimentally infected with a Swiss isolate of FIV for 1 year and for 6 years and from a number of long-term FIV-infected cats which were coinfected with feline leukemia virus. Purified peripheral blood lymphocytes were either cultured overnight under nonstimulating conditions or stimulated with phytohemagglutinin and interleukin-2 for 60 h. Under stimulating conditions, the isolates from the infected cats showed significantly higher relative counts of apoptotic cells than did those from noninfected controls (1-year-infected cats, P = 0.01; 6-year-infected cats, P = 0.006). The frequency of in vitro-induced apoptosis was inversely correlated with the CD4(+) cell count (P = 0. 002), bright CD8(+) cell count (P = 0.009), and CD4/CD8 ratio (P = 0. 01) and directly correlated with the percentage of bright major histocompatibility complex class II-positive peripheral blood lymphocytes (P = 0.004). However, we found no correlation between in vitro-induced apoptosis and the viral load in serum samples. Coinfection with feline leukemia virus enhanced the degree of in vitro-induced apoptosis compared with that in FIV monoinfected cats. We concluded that the degree of in vitro-induced apoptosis was closely related to FIV-mediated T-cell depletion and lymphocyte activation and could be used as an additional marker for disease progression in FIV infection.


European Society of Cardiology (ESC) Congress Report from Munich 2012.
The Annual Congress of the European Society of Cardiology (ESC) was held in Munich from the 26(th) to 29(th) of August 2012. The daily attendance ranged from 26,600 to 27,407 up to the 28(th) and several important issues were presented and discussed, including antiplatelet therapy for acute coronary syndrome (TRILOGY ACS), transcatheter aortic valve implantation, renal denervation, novel oral anticoagulants for atrial fibrillation (AFib), AFib ablation, the impact of the Great East Japan Earthquake on cardiovascular disease, management of vasospastic angina, plaque rupture and erosion (ESC-JCS [Japanese Circulation Society] joint session), heart failure, and FFR-guided percutaneous coronary intervention outcome. Three ESC "GOLD MEDALS" were awarded, including one to Professor Ryozo Nagai, the first Asian to receive this award. The ESC meeting has become one of the most important for updating not only general cardiologists' education but also specialists' expertise. Japan topped the number of abstracts submitted to ESC 2012 (>1,200 abstracts), while the ESC would like to establish a strong collaboration with the Japanese Cardiology Society. Relations between ESC and JCS will become closer and more favorable year by year.


Reduction of the correlation sensitivity to the changes of the input illumination by a post processing based on the correlation statistics.
Linear-correlation amplitude changes when the intensity level of the input image is modified. As recognition is often based on the correlation-peak level, a change of the input illumination may result in a false recognition. We propose an illumination-change compensation by a post processing of the correlation distribution that is based on statistical measures of the correlation histograms. The theoretical background and simulation results are provided in the frame of an actual application in biology.


Relationship between vitreous levels of matrix metalloproteinases and vascular endothelial growth factor in proliferative diabetic retinopathy.
To investigate which matrix metalloproteinases (MMPs) are more likely to be involved in the angiogenic process in proliferative diabetic retinopathy (PDR), we measured the levels of MMPs in the vitreous fluid from patients with PDR and controls and correlated these levels with the levels of vascular endothelial growth factor (VEGF). Vitreous samples from 32 PDR and 24 nondiabetic patients were studied by mosaic multiplex MMPs enzyme-linked immunosorbent assay (ELISA), single ELISA, Western blot and zymography analysis. Epiretinal membranes from 11 patients with PDR were studied by immunohistochemistry. MMP-8 and MMP-13 were not detected. ELISA, Western blot and gelatin ymography assays revealed significant increases in the expression levels of MMP-1, MMP-7, MMP-9 and VEGF in vitreous samples from PDR patients compared to nondiabetic controls, whereas MMP-2 and MMP-3 were not upregulated in vitreous samples from PDR patients. Significant correlations existed between ELISA and zymography assays for the quantitation of MMP-2 (r=0.407; p=0.039) and MMP-9 (r=0.711; p<0.001). Significant correlations were observed between levels of VEGF and levels of MMP-1 (r=0.845; P<0.001) and MMP-9 (r=0.775; p<0.001), and between levels of MMP-1 and MMP-9 (r=0.857; p<0.001). In epiretinal membranes, cytoplasmic immunoreactivity for MMP-9 was present in vascular endothelial cells and stromal monocytes/macrophages and neutrophils. Our findings suggest that among the MMPs measured, MMP-1 and MMP-9 may contribute to the angiogenic switch in PDR.


Dietary exposure and risk assessment of mercury from the Korean total diet study.
As a national project, obtaining information on the amount of heavy metal exposure of individuals through food intake is an important basic parameter for risk assessment. This study was conducted to evaluate dietary exposure levels and various risks from mercury (Hg) in Korean foods. In total, 342 samples comprising 114 food items were collected and then cooked prior to analysis. As found by Hg analysis, the mean content of metal in the fish and shellfish group was highest among the 15 Korean food groups. The total daily amount of Hg intake from typical Korean foods was 2.40 microg/person/d. The daily amount (microg/person/d) of Hg intake from each food group was 0.155 in grains and cereals, 0.008 potatoes and starch, 0.005 sugars and sweets, 0.0093 pulses, 0.0018 nuts and seeds, 0.203 vegetables, 0.027 fruits, 0.021 meats and poultry, 0.004 eggs, 1.826 fish and shellfish, 0.022 seaweed, 0.043 milk and dairy products, 0.008 oils and fats, 0.042 beverages, and 0.023 seasonings. The fish and shellfish group contributed most to total dietary intake at 76%. For risk assessment, probable daily intake (PDI) was calculated and compared with provisional tolerable weekly intake (PTWI) of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). The level of Hg intake through fish and shellfish of 0.001 mg/kg body weight bw/wk corresponded to 4.54% of the PTWI value of 0.005 mg/kg bw/wk, the safety standard for JECFA. The level of Hg intake through selected foods from the Food list for Koreans was 0.001 mg/kg bw/wk, corresponding to 5.95% of PTWI value. Therefore, overall intake was at levels below the recommended JECFA levels. The relative gender Hg hazard from Korean foods was 6.26% and 5.5% for males and females, respectively. The relative age Hg hazard from Korean foods was, 8.9% in those 3-6 yr old, 6.7% in those 7-12 yr old, 5.2% in those 13-19 yr old, 5.9% in those 20-29 yr old, 6.3% in those 30-49 yr old, 5.6% in those ages 50-64 yr, and 3.7% in the group of those over 65 yr of age. Relative regional Hg hazard from Korean foods was 6.3% in urban versus 5.5% in rural areas. Thus, the amount of Hg intake through consumption of Korean foods was found to be at a relatively safe level. These data may be thus used to establish safety standards for fish and shellfish consumption.


The Evolutionary Tale and Future Directions of Aromatase Inhibitors in Breast Carcinoma.
Aromatase inhibitors have often been likened to that of 'medical scalpels' for the treatment of breast carcinoma. By inhibiting the singular step of aromatisation, they have proven to be extremely effective allies in the treatment of breast cancer among postmenopausal women. However, their relevance soon may not be limited to the post-menopausal age group alone. Recent studies have hinted at their utility amongst the premenopausal women; combined with ovarian ablation techniques, aromatase inhibitors may prove to be equally effective and more, as compared to tamoxifen in this age-group. Additionally, explorations aimed at ascertaining their potential utility as an effective preventive strategy against breast carcinoma have yielded encouraging results. However, for aromatase inhibitors to be able to attain their full potential, further strategic fine-tuning aimed at maximising their efficacy and minimising their potentially far-reaching adverse effects, is the need of the hour. Despite the recent diversification, the issue of resistance to aromatase inhibitors in breast cancer threatens to derail the advances so gained till date. Fortunately, a few novel ploys have come to the fore, for instance combining aromatase inhibitors with HER-2 antibodies that could potentially help circumvent the menace of resistance in the near future. Till date, the utility of aromatase inhibitors can at best be described as onedimensional. However, with the unearthing of potential new avenues for its application, this assortment of molecules today stands on the precipice of ushering in a new revolution in the treatment of breast carcinoma.


Unusual complication of fulminant congenital cytomegalovirus infection.
Persistent pulmonary hypertension of newborn (PPHN) is a very rare manifestation of congenital cytomegalovirus (CMV) infection. PPHN associated with CMV can be severe but is usually transient and responds well to antiviral therapy. We report a rare case of PPHN that occurred in the setting of fulminant congenital CMV infection and successful treatment with antiviral therapy along with review of the very few cases reported in literature. A male appropriate for gestational Age (AGA) newborn developed rapidly progressive respiratory distress starting at 11 hours of life requiring ventilatory support and 100% oxygen. He developed hypotension and wide difference between pre and postductal saturations. Echocardiography revealed findings consistent with severe PPHN. Examination also revealed multiple purpuric skin lesions and soft hepatosplenomegaly. MRI Brain showed intraventricular hemorrhage, bilateral periventricular calcification, bilateral cerebral and cerebellar intraparenchymal hemorrhage. Complete Cell Count (CBC) revealed severe thrombocytopenia and blood serum showed positive Immunoglobulin M (IgM) for CMV and Urinary CMV was positive by nucleic acid test. He was treated with ganciclovir, inhaled nitric oxide and inotropes. He recovered and was discharged on day 24 of life. Severe PPHN is a rare manifestation of congenital CMV infection and carries a high risk of morbidity and mortality. Congenital CMV should be considered in neonates with PPHN of unknown etiology. Early institution of antiviral therapy in these babies is associated with favorable outcome.


Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress.
Age-dependent elevation in mitochondrial oxidative stress is widely posited to be a major factor underlying the loss of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's disease (PD). However, mechanistic links between aging and oxidative stress are not well understood. Sirtuin-3 (Sirt3) is a mitochondrial deacetylase that could mediate this connection. Indeed, genetic deletion of Sirt3 increased oxidative stress and decreased the membrane potential of mitochondria in SNc dopaminergic neurons. This change was attributable to increased acetylation and decreased activity of manganese superoxide dismutase (MnSOD). Site directed mutagenesis of lysine 68 to glutamine (K68Q), mimicking acetylation, decreased MnSOD activity in SNc dopaminergic neurons, whereas mutagenesis of lysine 68 to arginine (K68R), mimicking deacetylation, increased activity. Introduction of K68R MnSOD rescued mitochondrial redox status and membrane potential of SNc dopaminergic neurons from Sirt3 knockouts. Moreover, deletion of DJ-1, which helps orchestrate nuclear oxidant defenses and Sirt3 in mice led to a clear age-related loss of SNc dopaminergic neurons. Lastly, K68 acetylation of MnSOD was significantly increased in the SNc of PD patients. Taken together, our studies suggest that an age-related decline in Sirt3 protective function is a major factor underlying increasing mitochondrial oxidative stress and loss of SNc dopaminergic neurons in PD.


Occupational asbestos exposure and lung cancer--a systematic review of the literature.
The objective of this study was to evaluate the scientific literature concerning asbestos and lung cancer, emphasizing low-level exposure. A literature search in PubMed and Embase resulted in 5,864 citations. Information from included studies was extracted using SIGN. Twenty-one statements were evidence graded. The results show that histology and location are not helpful in differentiating asbestos-related lung cancer. Pleural plaques, asbestos bodies, or asbestos fibers are useful as markers of asbestos exposure. The interaction between asbestos and smoking regarding lung cancer risk is between additive and multiplicative. The findings indicate that the association between asbestos exposure and lung cancer risk is basically linear, but may level off at very high exposures. The relative risk for lung cancer increases between 1% and 4% per fiber-year (f-y)/mL, corresponding to a doubling of risk at 25-100 f-y/mL. However, one high-quality case-control study showed a doubling at 4 f-y/mL.


A Multilevel Computational Characterization of Endophenotypes in Addiction.
Addiction is characterized by a profound intersubject (phenotypic) variability in the expression of addictive symptomatology and propensity to relapse following treatment. However, laboratory investigations have primarily focused on common neural substrates in addiction and have not yet been able to identify mechanisms that can account for the multifaceted phenotypic behaviors reported in the literature. To fill this knowledge gap theoretically, here we simulated phenotypic variations in addiction symptomology and responses to putative treatments, using both a neural model, based on cortico-striatal circuit dynamics, and an algorithmic model of reinforcement learning (RL). These simulations rely on the widely accepted assumption that both the ventral, model-based, goal-directed system and the dorsal, model-free, habitual system are vulnerable to extra-physiologic dopamine reinforcements triggered by addictive rewards. We found that endophenotypic differences in the balance between the two circuit or control systems resulted in an inverted-U shape in optimal choice behavior. Specifically, greater unbalance led to a higher likelihood of developing addiction and more severe drug-taking behaviors. Furthermore, endophenotypes with opposite asymmetrical biases among cortico-striatal circuits expressed similar addiction behaviors, but responded differently to simulated treatments, suggesting personalized treatment development could rely on endophenotypic rather than phenotypic differentiations. We propose our simulated results, confirmed across neural and algorithmic levels of analysis, inform on a fundamental and, to date, neglected quantitative method to characterize clinical heterogeneity in addiction.


Intestinal alkaline phosphatase isoenzyme in patients with primary liver cancer during treatment with N10-propargyl 5, 8-dideazafolic acid (CB 3717).
Serum aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (gamma GT) activities and the serum ALP isoenzyme pattern have been measured in eleven patients undergoing treatment with CB3717. There were increases in the activity of all three enzymes. The ALP isoenzyme pattern showed an increased contribution of the intestinal isoenzyme to the serum ALP activity. This may be due to increased intestinal mucosal leakage or impaired uptake and breakdown of the intestinal isoenzyme by the liver.


Mycelial Mattress from a Sporangia Formation-Delayed Mutant of Rhizopus stolonifer as Wound Healing-Enhancing Biomaterial.
A mycelial mattress of Rhizopus stolonifer obtained from a liquid static culture was utilized for wound dressing and biomedical use. Following screening of mutants induced by UV radiation, F6, exhibiting delayed sporangium formation was selected because its sporangium maturation exhibited a 5-day delay without significant loss of mycelial weight compared to the wild type. The sporangium-free mycelial mattress from the sporangiospore culture of F6 was treated with 1N sodium hydroxide NaOH at 85°C for 2 h to produce a sponge-like membrane named Rhizochitin. The trifluoroacetic acid hydrolysate of Rhizochitin contained 36% N-acetylglucosamine and 53% hexose respectively detected by the Elson-Morgen and phenol-sulfuric acid methods. Results indicated the wound area in rats covered with Rhizochitin was 40% less than that of the uncovered group. Rhizochitin decreased the expression of PDGF in the proliferation stage, increased the expression of TGF-β in the inflammation and proliferation stages, and increased the expression of VEGF in the inflammation and proliferation stages. Rhizochitin inhibited secretion of matrix metalloproteinase-9 on days 1, 7, 9, and 12 and matrix metalloproteinase-2 on days 3, 7, 9, and 12. It was concluded that Rhizochitin has beneficial properties of biocompatible, biodegradable, and wound healing.


Physical activity patterns and preferences among Latinos in different types of public parks.
Centers for Disease Control (CDC) data suggest that Latinos are less likely to be physically active and more likely to be overweight and suffer from resulting complications than are Whites and that within the Latino population, Latina women are especially at risk. Therefore, promoting physical activity among Latinos, and understanding gender participation patterns within that population, is particularly important. One strategy for encouraging physical activity is to promote active uses of public parks. A national, multiyear, multisite study funded by the USDA Forest Service sought to understand use of public parks by Latinos and Latinas in Los Angeles, Minneapolis, and Chicago. More than 50% of our sample visited parks to engage in physical activity, and in part, activity choice was related to gender. Furthermore, nearly half of all respondents walked to city park sites, whereas few or none walked to state or regional park sites. Our data suggest that Latinos are using some parks repeatedly and, in the case of city parks, are using them for physical as well as social activity. Therefore, we suggest specific ways that parks could be managed to encourage more physical activity while taking into account gender variations.


Broadband electromagnetic cloaking with smart metamaterials.
The ability to render objects invisible with a cloak that fits all objects and sizes is a long-standing goal for optical devices. Invisibility devices demonstrated so far typically comprise a rigid structure wrapped around an object to which it is fitted. Here we demonstrate smart metamaterial cloaking, wherein the metamaterial device not only transforms electromagnetic fields to make an object invisible, but also acquires its properties automatically from its own elastic deformation. The demonstrated device is a ground-plane microwave cloak composed of an elastic metamaterial with a broad operational band (10-12 GHz) and nearly lossless electromagnetic properties. The metamaterial is uniform, or perfectly periodic, in its undeformed state and acquires the necessary gradient-index profile, mimicking a quasi-conformal transformation, naturally from a boundary load. This easy-to-fabricate hybrid elasto-electromagnetic metamaterial opens the door to implementations of a variety of transformation optics devices based on quasi-conformal maps.


Hormone effects on fMRI and cognitive measures of encoding: importance of hormone preparation.
We compared fMRI and cognitive data from nine hormone therapy (HT)-naive women with data from women exposed to either opposed conjugated equine estrogens (CEE) (n = 10) or opposed estradiol (n = 4). Exposure to either form of HT was associated with healthier fMRI response; however, CEE-exposed women exhibited poorer memory performance than either HT-naive or estradiol-exposed subjects. These preliminary findings emphasize the need to characterize differential neural effects of various HTs.


Antibody response in white-footed mice (Peromyscus leucopus) experimentally infected with the Lyme disease spirochete (Borrelia burgdorferi).
White-footed mice (Peromyscus leucopus), the primary reservoir for Borrelia burgdorferi in the northern midwest and northeastern United States, were experimentally inoculated with an infectious strain or a noninfectious strain of the Lyme disease spirochete and examined for their specific antibody response with the enzyme-linked immunosorbent assay and Western blot (immunoblot) analysis. Immunoglobulin M (IgM) anti-B. burgdorferi antibodies were detected in mice 1 to 2 days after inoculation with either the infectious or noninfectious strain of spirochetes and peaked on days 4 and 5. Mice inoculated with the infectious strain of spirochete had a secondary increase in IgM 21 days after inoculation. Mice also produced both IgG1 and IgG2 antibodies beginning 5 to 7 days after inoculation and they increased in titer until 84 days after inoculation when the experiment was terminated. Western blot analysis of sequential plasma samples from mice inoculated with the infectious strain of spirochete demonstrated the development of IgM, IgG1, and IgG2 antibodies to numerous spirochetal antigens, whereas mice inoculated with the noninfectious strain had reduced blot patterns with antibodies reactive primarily to the 31,000-kilodalton outer surface protein A. Persistent spirochetal infection in some mice, in spite of a strong and diverse antibody response, deserves further investigation.


Application of Zataria multiflora Boiss. and Cinnamon zeylanicum essential oils as two natural preservatives in cake.
Oxidation of oils has an important effect on nutritional and organoleptic properties of foodstuffs. Nowadays, new tendency has created a necessity to use natural compounds such as essential oils for producing functional foods. In this study, antioxidant, antifungal, and organoleptic properties of Zataria multiflora Boiss. (ZMEO) and Cinnamon zeylanicum essential oils (CZEO) have been checked as two natural preservatives in the cakes. The antioxidant activity of essential oils were determined by measuring thiobarbituric, peroxide, and free fatty acid values of prepared cakes during 60 days storage at 25 ˚C. Antifungal properties of essential oils were determined and given as the ratio of colony number in samples containing ZMEO and CZEO to the control. Different concentrations of essential oils prevented oxidation rate and reducd preliminary and secondary oxidation products compared with butylate hydroxyanisole (BHA (100 and 200 ppm)) and control cakes. Moreover, ZMEO and CZEO at three concentrations (500, 1000, and 1500 ppm) reduced the fungal growth more than samples containing BHA (100 and 200 ppm) and the control. Our results showed that optimum concenteration of ZMEO and CZEO for using in the cakes was 500 ppm therefore it can be replaced instead of synthetic preservatives in foodstuffs.


Upregulation of cognitive control networks in older adults' speech comprehension.
Speech comprehension abilities decline with age and with age-related hearing loss, but it is unclear how this decline expresses in terms of central neural mechanisms. The current study examined neural speech processing in a group of older adults (aged 56-77, n = 16, with varying degrees of sensorineural hearing loss), and compared them to a cohort of young adults (aged 22-31, n = 30, self-reported normal hearing). In a functional MRI experiment, listeners heard and repeated back degraded sentences (4-band vocoded, where the temporal envelope of the acoustic signal is preserved, while the spectral information is substantially degraded). Behaviorally, older adults adapted to degraded speech at the same rate as young listeners, although their overall comprehension of degraded speech was lower. Neurally, both older and young adults relied on the left anterior insula for degraded more than clear speech perception. However, anterior insula engagement in older adults was dependent on hearing acuity. Young adults additionally employed the anterior cingulate cortex (ACC). Interestingly, this age group × degradation interaction was driven by a reduced dynamic range in older adults who displayed elevated levels of ACC activity for both degraded and clear speech, consistent with a persistent upregulation in cognitive control irrespective of task difficulty. For correct speech comprehension, older adults relied on the middle frontal gyrus in addition to a core speech comprehension network recruited by younger adults suggestive of a compensatory mechanism. Taken together, the results indicate that older adults increasingly recruit cognitive control networks, even under optimal listening conditions, at the expense of these systems' dynamic range.


Epigenetics in rheumatoid arthritis.
To give an overview of recently published articles addressing the role of epigenetic modifications in rheumatoid arthritis (RA). Here we focused on DNA methylation and posttranslational histone modifications. Recent studies attempted to link epigenetic modifications with genetic or environmental risk factors for RA. There is evidence that histone deacetylases confer effects of environmental triggers such as smoking, diet or therapy on expression levels of target genes. Additionally, disturbed methylation patterns and cell-type specific histone methylation marks were identified as potential mediators of genetic risk in RA. Altered methylome signatures were found in several cell types in RA, first of all RA synovial fibroblasts, and contribute to the intrinsic fibroblast activation. The reversal of DNA hypomethylation by inhibiting the polyamine recycling pathway was suggested as new epigenetic therapy in RA. Moreover, targeting epigenetic reader proteins, such as bromodomain proteins, emerged as a new field in drug development and the first studies underscored the potential of these drugs not only in malignant and inflammatory conditions but also in autoimmune diseases. Epigenetic factors represent a promising area to link genetics, regulation of gene expression and environmental risk factors.


HIV-1 T cell epitopes targeted to Rhesus macaque CD40 and DCIR: A comparative study of prototype dendritic cell targeting therapeutic vaccine candidates.
HIV-1 infection can be controlled by anti-retroviral drug therapy, but this is a lifetime treatment and the virus remains latent and rapidly rebounds if therapy is stopped. HIV-1-infected individuals under this drug regimen have increased rates of cancers, cardiovascular diseases, and autoimmunity due to compromised immunity. A therapeutic vaccine boosting cellular immunity against HIV-1 is therefore desirable and, possibly combined with other immune modulating agents, could obviate the need for long-term drug therapies. An approach to elicit strong T cell-based immunity is to direct virus protein antigens specifically to dendritic cells (DCs), which are the key cell type for controlling immune responses. For eliciting therapeutic cellular immunity in HIV-1-infected individuals, we developed vaccines comprised of five T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol (HIV5pep) fused to monoclonal antibodies that bind either, the antigen presenting cell activating receptor CD40, or the endocytic dendritic cell immunoreceptor DCIR. The study aimed to demonstrate vaccine safety, establish efficacy for broad T cell responses in both primed and naïve settings, and identify one candidate vaccine for human therapeutic development. The vaccines were administered to Rhesus macaques by intradermal injection with poly-ICLC adjuvant. The animals were either i) naïve or, ii) previously primed with modified vaccinia Ankara vector (MVA) encoding HIV-1 Gag, Pol, and Nef (MVA GagPolNef). In the MVA-primed groups, both DC-targeting vaccinations boosted HIV5pep-specific blood CD4+ T cells producing multiple cytokines, but did not affect the MVA-elicited CD8+ T cell responses. In the naive groups, both DC-targeting vaccines elicited antigen-specific polyfunctional CD4+ and CD8+ T cell responses to multiple epitopes and these responses were unchanged by a subsequent MVA GagPolNef boost. In both settings, the T cell responses elicited via the CD40-targeting vaccine were more robust and were detectable in all the animals, favoring further development of the CD40-targeting vaccine for therapeutic vaccination of HIV-1-infected individuals.


Reactivity of uranium(iii) with H2E (E = S, Se, Te): synthesis of a series of mononuclear and dinuclear uranium(iv) hydrochalcogenido complexes.
We report the syntheses, electronic properties, and molecular structures of a series of mono- and dinuclear uranium(iv) hydrochalcogenido complexes supported by the sterically demanding but very flexible, single N-anchored tris(aryloxide) ligand (AdArO)3N)3-. The mononuclear complexes [((AdArO)3N)U(DME)(EH)] (E = S, Se, Te) can be obtained from the reaction of the uranium(iii) starting material [((AdArO)3N)UIII(DME)] in DME via reduction of H2E and the elimination of 0.5 equivalents of H2. The dinuclear complexes [{((AdArO)3N)U}2(μ-EH)2] can be obtained by dissolving their mononuclear counterparts in non-coordinating solvents such as benzene. In order to facilitate the work with the highly toxic gases, we created concentrated THF solutions that can be handled using simple glovebox techniques and can be stored at -35 °C for several weeks.


Mode-hop-free electro-optically tuned external-cavity diode laser using volume Bragg grating and PLZT ceramic.
We present a novel electro-optically tuned external-cavity diode laser (ECDL) that utilizes a volume Bragg grating (VBG) as the frequency selective feedback element and a piece of high electro-optic coefficient Lead Lanthanum Zirconate Titanate (PLZT) transparent ceramic as the frequency tuning element. By adjusting the voltage applied onto the PLZT, a single-mode frequency tuning range of 2.5GHz without mode hoping is achieved. The laser wavelength is around 810.0nm with the line-width of 19MHz and the side mode suppression ratio (SMSR) of 37dB. The advantages of combining a VBG and PLZT transparent electro-optic ceramic is that the laser frequency can be tuned finely and rapidly in a range of longitudinal mode spacing without mode hoping. Moreover, the wide-range coarse frequency tuning of 32.7 GHz can also be realized by changing the angle of incident light beam.


Bright and two-photon active red fluorescent dyes that selectively move back and forth between the mitochondria and nucleus upon changing the mitochondrial membrane potential.
Since mitochondrial dysfunction was discovered to be the underlying cause of several severe diseases, fluorescent probes with excellent optical properties for visualising and monitoring the mitochondrial membrane potential (MMP) (a parameter of mitochondrial vitality) have been in high demand. Herein, we present novel pyrene-based dyes exhibiting remarkably large two-photon absorption around 900 nm and bright red emission around 620 nm (two-photon brightness (Φσ2) = 425-525 GM), with selective localisation to the mitochondria or nucleus in response to changes in the MMP, providing several advantages over traditional MMP-monitoring probes such as Rhodamine 123 (Φσ2 = 64 GM). The intracellular behavior of the new dyes was investigated in detail. The driving forces for the dyes to dissociate from the mitochondria and migrate toward the nucleus upon decreasing the MMP were two key molecular characteristics: the dyes' permeability to mitochondrial membranes and their affinity to nuclear DNA. The results provide significant insights into improving the molecular design of the dyes.


A comprehensive analysis of patient satisfaction with anesthesia.
Patient satisfaction with anesthesia after surgical treatment is a complex concept that includes not only the level of satisfaction with the anesthesia itself but also the presence of fears, worries, depression, evaluation of the anesthesiologists' work, as well as cognitive dysfunction as a possible negative consequence of anesthesia. Conducting a comprehensive analysis of patients' satisfaction with anesthesia. Questionnaire of patients' satisfaction with anesthesia (Sinbukhova E.V., Lubnin A.Yu.), State-Trait Anxiety Inventory in the adaptation by Y.L. Hanin, Assessment of Depression, The Montreal Cognitive Assessment (MoCA), and Frontal Assessment Battery. Population consisted of 202 patients. Satisfaction with anesthesia: assessment "good and higher" with primary anesthesia - 59.7% of patients with repeated - 70% of patients. The most common factors that reduce the assessment of patients' satisfaction with anesthesia are: strong excitement before surgery about operation and anesthesia, no postoperative visit of the anesthesiologist, no visit of the anesthesiologist before the operation, not enough attention of anesthesiologist in the surgery room before anesthesia, nausea, vomiting, pain, dizziness, general discomfort, and thirst. MoCA cognitive assessment before and after anesthesia: P < 2.2 e-16 (significant decrease). Depression: major depression in 52% of patients, subclinical depression in 22.8%. Regular survey of patients' satisfaction should help to improve the quality of medical care. The strong excitement of the patient about the upcoming anesthesia and surgery, and the presence of a high level of anxiety and depression can be factors of reducing the patients' satisfaction with anesthesia. It requires psychological support of patients at the stage of surgical treatment.


Methylcobalamin: a potential vitamin of pain killer.
Methylcobalamin (MeCbl), the activated form of vitamin B12, has been used to treat some nutritional diseases and other diseases in clinic, such as Alzheimer's disease and rheumatoid arthritis. As an auxiliary agent, it exerts neuronal protection by promoting regeneration of injured nerves and antagonizing glutamate-induced neurotoxicity. Recently several lines of evidence demonstrated that MeCbl may have potential analgesic effects in experimental and clinical studies. For example, MeCbl alleviated pain behaviors in diabetic neuropathy, low back pain and neuralgia. MeCbl improved nerve conduction, promoted the regeneration of injured nerves, and inhibited ectopic spontaneous discharges of injured primary sensory neurons. This review aims to summarize the analgesic effect and mechanisms of MeCbl at the present.


Validity of measures is no simple matter.
This article aims to promote a better understanding of the nature of measurement, the special problems posed by measurement in the social sciences, and the inevitable limitations on inferences in science (so that results are not overinterpreted), by using the measurement of blood pressure as an example. As it is necessary to raise questions about the meaning and extent of the validity of something as common as measured blood pressure, even more serious questions are unavoidable in relation to other commonly used measures in social science. The central issue is the validity of the inferences about the construct rather than the validity of the measure per se. It is important to consider the definition and validity of the construct at issue as well as the adequacy of its representation in the measurement instrument. By considering a particular construct within the context of a conceptual model, researchers and clinicians will improve their understanding of the construct's validity as measured.


Symptomatology attributable to psychological exposure to a chemical incident: a natural experiment.
Exposure to a complex emergency has a substantial psychological component, which is rarely assessed. This study compares the health impact of physically and psychologically mediated exposure to a complex emergency. The Sea Empress oil tanker spill. A cross-sectional analysis of self-report questionnaire responses collected from inhabitants of 6 different coastal towns-4 of them physically exposed to the oil spill, 2 unexposed-was undertaken. The towns were known to be psychologically homogeneous before the incident. Perceived risk was used as a measure of psychological exposure. Anxiety, depression and symptom reporting were used as measures of health impact. 1089 (69%) men and women aged 18-65 years responded. Perceived risk was associated with raised anxiety and non-toxicologically related symptom reporting, whereas physical exposure to oil was only associated with toxicologically related symptom reporting. The impact of raised perceived risk on the population was greater than that of physical oil exposure, involving more persons over a wider area. Psychological exposure was shown to be quantifiable, and to be a substantially more sensitive measure of health impact than physical exposure in relation to psychological outcomes. This type of analysis has important implications for emergency response planning, and for the interpretation of a complex emergency by the general public.


Modular organization of the white spruce (Picea glauca) transcriptome reveals functional organization and evolutionary signatures.
Transcript profiling has shown the molecular bases of several biological processes in plants but few studies have developed an understanding of overall transcriptome variation. We investigated transcriptome structure in white spruce (Picea glauca), aiming to delineate its modular organization and associated functional and evolutionary attributes. Microarray analyses were used to: identify and functionally characterize groups of co-expressed genes; investigate expressional and functional diversity of vascular tissue preferential genes which were conserved among Picea species, and identify expression networks underlying wood formation. We classified 22 857 genes as variable (79%; 22 coexpression groups) or invariant (21%) by profiling across several vegetative tissues. Modular organization and complex transcriptome restructuring among vascular tissue preferential genes was revealed by their assignment to coexpression groups with partially overlapping profiles and partially distinct functions. Integrated analyses of tissue-based and temporally variable profiles identified secondary xylem gene networks, showed their remodelling over a growing season and identified PgNAC-7 (no apical meristerm (NAM), Arabidopsis transcription activation factor (ATAF) and cup-shaped cotyledon (CUC) transcription factor 007 in Picea glauca) as a major hub gene specific to earlywood formation. Reference profiling identified comprehensive, statistically robust coexpressed groups, revealing that modular organization underpins the evolutionary conservation of the transcriptome structure.


Perceptions and attitudes towards Covid-19 vaccines: narratives from members of the UK public.
The aim of the paper is to enhance understanding of how members of the public make sense of the Covid-19 vaccines and to understand the factors influencing their attitudes towards such artefacts of pandemic governance. The paper draws on 23 online in-depth interviews with members of the UK public and builds on relevant literature to examine participants' perceptions of the benefits and risks of Covid-19 vaccines, the sources that have shaped their attitudes, and the level of trust they have towards the government's handling of the pandemic through vaccines. The findings indicate that participants generally felt that the benefits of having the vaccine outweigh the risks and that Covid-19 vaccines are a crucial mechanism for enabling society to return to normal. Vaccine acceptance was, for some, strongly linked to a sense of social responsibility and the duty to protect others. However, some participants expressed concerns with regard to the side-effects of Covid-19 vaccines and their perceived potential impact on fertility and DNA makeup. Participants used various sources of information to learn about Covid-19 vaccines and understand their function, benefits, and risks. The majority of participants criticised the government's response during the early stages of the pandemic yet felt positive about the vaccine rollout. Just as with any other vaccination programme, the success of the Covid-19 immunisation campaigns does not only depend on the efficacy of the vaccines themselves or the ability to secure access to them, but also on a myriad of other factors which include public compliance and trust in governments and health authorities. To support an effective immunisation campaign that is capable of bringing the pandemic to an end, governments need to understand public concerns, garner trust, and devise adequate strategies for engaging the public and building more resilient societies.


Interpretation criteria for standardized Western blots for three European species of Borrelia burgdorferi sensu lato.
Western blots (WBs; immunoblots) are a widely used tool for the serodiagnosis of Lyme borreliosis, but so far, no defined criteria for performance, analysis, and interpretation have been established in Europe. For the current study WBs were produced with strains PKa2 (Borrelia burgdorferi sensu stricto), PKo (Borrelia afzelii), and PBi (Borrelia garinii). To improve resolution we used gels of 17 cm in length. In a first step, 13 immunodominant proteins were identified with monoclonal antibodies. Then, the apparent molecular masses of all visually distinguishable bands were determined densitometrically. Approximately 40 bands of between 14 and 100 kDa were differentiated for each strain. From a study with 330 serum samples (from 189 patients with Lyme borreliosis and 141 controls), all observed bands were documented. To establish criteria for a positive WB result, the discriminating ability of a series of band combinations (interpretation rules) were evaluated separately for each strain (for immunoglobulin G [IgG] WB, > 40 combinations; for IgM WB, > 15 combinations). The following interpretation criteria resulting in specificities of greater than 96% were recommended: for IgG WB, at least one band of p83/100, p58, p56, OspC, p21, and p17a for PKa2; at least two bands of p83/100, p58, p43, p39, p30, OspC, p21, p17, and p14 for PKo; and at least one band of p83/100, p39, OspC, p21, and p17b for PBi; for IgM WB, at least one band of p39, OspC, and p17a or a strong p41 band for PKa2; at least one band of p39, OspC, and p17 or a strong p41 band for PKo; and at least one band of p39 and OspC or a strong p41 band for PBi. The overall sensitivity was the highest for PKo WB, followed by PBi and PKa2 WB, in decreasing order. Standardization of WB assays is necessary for comparison of results from different laboratories.


Long-term trajectories of positive and negative symptoms in first episode psychosis: A 10year follow-up study in the OPUS cohort.
Knowledge about course of illness can help clinicians to develop effective interventions and improve treatment outcomes. The goal of this study was to construct positive and negative symptom trajectories based on structured clinical assessments collected over 10years within a cohort of people with first episode psychosis. A cohort of 496 people with first episode psychosis (ICD-10, F20-28) originally recruited for the OPUS study (1998-2000) and treated in community psychiatric services were rated on clinical symptoms at 5 different occasions across ten years. Psychopathology was assessed using the Scales for Assessment of Positive and Negative Symptoms. Symptom trajectories were constructed using Latent Class Analysis. Five distinct trajectories were identified for positive symptoms (response - 47%, delayed response - 12%, relapse - 15%, non-response - 13% and episodic response - 13%). Four distinct trajectories were identified for negative symptoms (response - 28%, delayed response - 19%, relapse - 26% and non-response - 27%). Multivariable regression analysis of baseline characteristics identified that longer duration of untreated psychosis (OR 1.27-1.47, p<0.05) and substance abuse (OR 3.47-5.90, p<0.01) were associated with poorer positive symptom trajectories (higher levels of psychotic symptoms) while poor social functioning (OR 1.34-5.55, p<0.05), disorganized symptoms (OR 2.01-2.38, p<0.05) and schizophrenia diagnosis (OR 5.70-8.86, p<0.05) were associated with poorer negative symptom trajectories (higher levels of negative symptoms). A proportion of people displayed significant changes in symptoms several years after diagnosis. Trajectories of illness for positive and negative symptoms were heterogeneous among people with first episode psychosis. Positive symptoms showed a general pattern of reduction and stabilization over time while negative symptoms typically showed less variation over the ten years. Results have implications for the focus, timing and length of interventions in first episode psychosis.


The relationship between early post-stroke cognition and longer term activities and participation: A systematic review.
This systematic review examined whether early cognitive impairment after stroke is predictive of outcome within the "activity" and "participation" domains of the International Classification of Functioning, Disability and Health (ICF) at 6-12 months post-injury. Studies were included if cognitive functioning was assessed within 6 weeks of injury and outcome was measured at least 6 months post-injury. PsycINFO, MEDLINE, CINAHL and EMBASE databases were searched and 14 studies were identified. Studies were categorised according to whether "domain-general" or "domain-specific" cognitive assessment was undertaken and whether outcomes measured the ICF activities or participation domains, as determined by three independent raters using previous established linking rules. Quality of studies was assessed using a modified version of Downs and Black's Quality Index. Overall, early cognitive impairment predicted activities and participation 6-12 months post-stroke. This relationship was more consistent when domain-specific cognitive assessment was used. For the domain of activities, visuospatial perception/construction, visual memory, visual neglect, and attention/executive functioning predicted functioning 6-12 months post-stroke. Early domain-specific cognitive assessment may be clinically informative of longer term activities. For the domain of participation, further well-controlled studies are needed to determine the relationship with early post-stroke cognitive impairments.


Outcome of thyrotoxicosis treatment with 3 different modalities.
To assess the efficacy of 3 different treatment modalities for thyrotoxicosis and a comparison of their cost effectiveness. The case records of 100 patients treated for thyrotoxicosis at King Khalid National Guard Hospital in Jeddah were reviewed, during the period January 1992 through to January 2000. Their various treatments and responses were recorded as well as their thyriometabolic status, one year following the last treatment. The treatment consisted of an average of 9 months of antithyroid medication, thyroidectomy or treatment with radioactive iodide. Cure was defined as a patient being euthyroid or hypothyroid for a minimum period of at least one year. Cost-effectiveness was calculated as the total cost of treating the patient in a specific treatment modality, divided by those who were considered to be cured. For the remainder, the cost could not be definitively determined. The mean age was 41+/- 15.7 years, with female to male ratio of 6:1. Grave's disease was the underlying cause in 76% of cases, toxic multinodular goiter in 13% and toxic nodule in 1%. Ninety-one patients, who were treated with anti-thyroid medication for an average of 9 months, had a success rate of 11%. The success rate with surgery was 54.5%, while of 68 patients treated with radioactive iodide 65 (96%) were cured. Radioactive iodide was the most cost effective modality of treatment costing 1700 Saudi Riyals, followed by surgery at 40,000 Saudi Riyals. Medical treatment was the most expensive at 135,000 Saudi Riyals per cure. A treatment of thyrotoxicosis with radioactive iodine is much more efficacious than medical or surgical modalities. Furthermore, it is by far the most cost effective and has no harmful effects.


Associations of PM₂.₅ constituents and sources with hospital admissions: analysis of four counties in Connecticut and Massachusetts (USA) for persons ≥ 65 years of age.
Epidemiological studies have demonstrated associations between short-term exposure to PM2.5 and hospital admissions. The chemical composition of particles varies across locations and time periods. Identifying the most harmful constituents and sources is an important health and regulatory concern. We examined pollutant sources for associations with risk of hospital admissions for cardiovascular and respiratory causes. We obtained PM2.5 filter samples for four counties in Connecticut and Massachusetts and analyzed them for PM2.5 elements. Source apportionment was used to estimate daily PM2.5 contributions from sources (traffic, road dust, oil combustion, and sea salt as well as a regional source representing coal combustion and other sources). Associations between daily PM2.5 constituents and sources and risk of cardiovascular and respiratory hospitalizations for the Medicare population (> 333,000 persons ≥ 65 years of age) were estimated with time-series analyses (August 2000-February 2004). PM2.5 total mass and PM2.5 road dust contribution were associated with cardiovascular hospitalizations, as were the PM2.5 constituents calcium, black carbon, vanadium, and zinc. For respiratory hospitalizations, associations were observed with PM2.5 road dust, and sea salt as well as aluminum, calcium, chlorine, black carbon, nickel, silicon, titanium, and vanadium. Effect estimates were generally robust to adjustment by co-pollutants of other constituents. An interquartile range increase in same-day PM2.5 road dust (1.71 μg/m3) was associated with a 2.11% (95% CI: 1.09, 3.15%) and 3.47% (95% CI: 2.03, 4.94%) increase in cardiovascular and respiratory admissions, respectively. Our results suggest some particle sources and constituents are more harmful than others and that in this Connecticut/Massachusetts region the most harmful particles include black carbon, calcium, and road dust PM2.5.


Discrete models of autocrine cell communication in epithelial layers.
Pattern formation in epithelial layers heavily relies on cell communication by secreted ligands. Whereas the experimentally observed signaling patterns can be visualized at single-cell resolution, a biophysical framework for their interpretation is currently lacking. To this end, we develop a family of discrete models of cell communication in epithelial layers. The models are based on the introduction of cell-to-cell coupling coefficients that characterize the spatial range of intercellular signaling by diffusing ligands. We derive the coupling coefficients as functions of geometric, cellular, and molecular parameters of the ligand transport problem. Using these coupling coefficients, we analyze a nonlinear model of positive feedback between ligand release and binding. In particular, we study criteria of existence of the patterns consisting of clusters of a few signaling cells, as well as the onset of signal propagation. We use our model to interpret recent experimental studies of the EGFR/Rhomboid/Spitz module in Drosophila development.


Studies on anti-metastatic and anti-invasive effects of harmine using highly metastatic murine B16F-10 melanoma cells.
Harmine is a beta-carboline alkaloid from the plant Peganum harmala. We evaluated the anti-metastatic activity of harmine using in vivo mouse lung metastasis and in vitro models. Lung metastasis was induced using B16F-10 melanoma cells in C57BL/6 mice by three different modalities of administration: simultaneous, prophylactic, and after tumor development. Harmine significantly inhibited tumor nodule formation in the lung tissue and decreased various biochemical parameters associated with lung metastasis. Higher expression levels of pro-metastatic genes such as matrix metalloproteinase-9 (MMP-9), extracellular signal[en]regulated kinase (ERK), and vascular endothelial factors (VEGFs), all of which play important roles in cancer cell migration and invasion, were observed in the metastatic group compared with normal, but were all down-regulated by treatment with harmine. Harmine was also able to inhibit tumor cell proliferation, invasion, and migration in vitro. In conclusion, harmine exerts anti-metastatic activity and this effect could be linked to the metastasis-related signaling pathway that includes ERK, VEGF, and MMPs.


The architecture of cognitive control in the human prefrontal cortex.
The prefrontal cortex (PFC) subserves cognitive control: the ability to coordinate thoughts or actions in relation with internal goals. Its functional architecture, however, remains poorly understood. Using brain imaging in humans, we showed that the lateral PFC is organized as a cascade of executive processes from premotor to anterior PFC regions that control behavior according to stimuli, the present perceptual context, and the temporal episode in which stimuli occur, respectively. The results support an unified modular model of cognitive control that describes the overall functional organization of the human lateral PFC and has basic methodological and theoretical implications.


Multi-dimensional analysis identified rheumatoid arthritis-driving pathway in human T cell.
Rheumatoid arthritis (RA) is an autoimmune disease accompanied by lymphocyte infiltration into joint synovium. While T cells are considered to be important for its pathogenesis, the features that are the most relevant to disease and how they change after treatment remain unclear. The aim of this study was to clarify the characteristics of T cells in RA, comprehensively. We enrolled a total of 311 patients with RA and 73 healthy participants, and carefully classified them by disease state, constructed multiple cohorts and analysed clinical samples from them in a stepwise manner. We performed immunophenotyping with multiple evaluation axes, and two independent transcriptome analyses complementary to each other. We identified that 'effector memory-Tfh' subset was specifically expanded in the peripheral blood (PB) of patients with RA in correlation with disease activity, and reverted after treatment. Besides, we revealed distinct features of T cells in synovial fluid (SF) that the expression of Tfh/Tph-related genes and pro-inflammatory cytokines and chemokines, including CXCL13, were significantly enriched, whereas these phenotype were Th1-like. Finally, we identified specific pathways, such as mTORC1, IL-2-stat5, E2F, cell cycle and interferon-related genes, that were significantly enriched in SF, in particular, as well as PB of untreated patients with RA, and notably, these features reverted after treatment. Our multi-dimensional investigation identified disease relevant T-cell subsets and gene signatures deeply involved in pathogenesis of RA. These findings could aid in our understanding of essential roles of T cells in RA and will facilitate to development better diagnostic and therapeutic interventions.


Information technology and knowledge exchange in health-care organizations.
Despite the increasing global interest in information technology among health care institutions, little has been discussed about its importance for the effectiveness of knowledge management. In this study, economic theories are used to analyze and describe a theoretical framework for the use of information technology in the exchange of knowledge. The analyses show that health care institutions would benefit from developing global problem-solving collaboration, which allows practitioners to exchange knowledge unrestricted by time and geographical barriers. The use of information technology for vertical integration of health-care institutions would reduce knowledge transaction costs, i.e. decrease costs for negotiating and creating communication channels, and facilitating the determination of what, when, and how to produce knowledge. A global network would allow organizations to increase existing knowledge, and thus total productivity, while also supporting an environment where the generation of new ideas is unrestricted. Using all the intellectual potential of market actors and thereby releasing economic resources can reduce today's global budget conflicts in the public sector, i.e. the necessity to choose between health care services and, for instance, schools and support for the elderly. In conclusion, global collaboration and coordination would reduce the transaction costs inherent in knowledge administration and allow a more effective total use of scarce health-care resources.


Blue protein with red fluorescence.
The walleye (Sander vitreus) is a golden yellow fish that inhabits the Northern American lakes. The recent sightings of the blue walleye and the correlation of its sighting to possible increased UV radiation have been proposed earlier. The underlying molecular basis of its adaptation to increased UV radiation is the presence of a protein (Sandercyanin)-ligand complex in the mucus of walleyes. Degradation of heme by UV radiation results in the formation of Biliverdin IXα (BLA), the chromophore bound to Sandercyanin. We show that Sandercyanin is a monomeric protein that forms stable homotetramers on addition of BLA to the protein. A structure of the Sandercyanin-BLA complex, purified from the fish mucus, reveals a glycosylated protein with a lipocalin fold. This protein-ligand complex absorbs light in the UV region (λmax of 375 nm) and upon excitation at this wavelength emits in the red region (λmax of 675 nm). Unlike all other known biliverdin-bound fluorescent proteins, the chromophore is noncovalently bound to the protein. We provide here a molecular rationale for the observed spectral properties of Sandercyanin.


Adult life expectancy trends in the era of antiretroviral treatment in rural Uganda (1991-2012).
To estimate the impact of antiretroviral therapy (ART) on population-wide adult life expectancy. A population-based open cohort study with repeated HIV status measurements and registration of vital events in Southwestern Uganda (1991-2012). Nonparametric survival analysis techniques are used for estimating trends in the adult life expectancy of the general population (aged 15 and above), the adult life expectancy by HIV status, and the adult life expectancy deficit. The life expectancy deficit is estimated as the difference between overall life expectancy and life expectancy of the HIV-negative population. All estimates are disaggregated by sex. Between 1991-1993 and 2009-2012, population-wide adult life expectancy increased from 39.3 [95% confidence interval (CI): 35.9-42.8] to 56.1 years (95% CI: 54.0-58.5) in women, and from 38.6 (95% CI: 35.4-42.1) to 51.4 years (95% CI: 49.2-53.7) in men. Most of the adult life expectancy gains coincide with the introduction of ART in 2004; as evidenced by an increase in the adult life expectancy of people living with HIV between 2000-2002 and 2009-2012 of 22.9 and 20.0 years for women and men, respectively. Over the whole period of observation, the adult life expectancy deficit associated with HIV decreased from 16.1 (95% CI: 12.7-19.8) to 6.0 years (95% CI: 4.1-7.8) among women, and from 16.0 (95% CI: 12.1-19.9) to 2.8 years (95% CI: 1.2-4.6) among men. Population-wide life expectancy increased substantially, largely driven by reductions in HIV-related mortality. Women have gained more adult life years than men since the introduction of ART, but the burden of HIV in terms of the life years lost is still larger for women than it is for men.


Semiochemicals of the Scarabaeinae VIII. Identification of active constituents of the abdominal sex-attracting secretion of the male dung beetle, Kheper bonellii, using gas chromatography with flame ionization and electroantennographic detection in parallel.
Using gas chromatography with flame ionization detection and electroantennographic detection in parallel (GC-FID/EAD), the active constituents of the sex attractant of male dung beetles of Kheper bonellii were located in the gas chromatogram of an extract of the secretion. These constituents were identified as propanoic acid, butanoic acid, indole, 3-methylindole (skatole) and methyl cis-cascarillate (methyl cis-2-2'-hexylcyclopropylacetate) by, inter alia, GC-MS, (1)H and (13)C NMR analysis, and synthesis. These compounds elicited EAD responses in male as well as female antennae. Racemic methyl cis-cascarillate was synthesized for comparison with the natural methyl ester. Enantioselective GC-FID/EAD using a capillary column coated with OV-1701-OH containing 10% heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-beta-cyclodextrin showed that the natural compound co-eluted with the first-eluting enantiomer of the racemic methyl cis-cascarillate, which was the only enantiomer that elicited EAD responses in the antennae of male and female K. bonellii. The absolute configuration of this enantiomer was established by a stereoselective synthesis, which gave methyl (R,R)-cascarillate [methyl (1'R,2'R)-2-2'-hexylcyclopropylacetate] in an enantiomeric excess of 69%.


Laparoscopic versus open colectomy for colon cancer in an older population: a cohort study.
Laparoscopic colectomy for colon cancer has been compared with open colectomy in randomized controlled trials, but these studies may not be generalizable because of strict enrollment and exclusion criteria which may explicitly or inadvertently exclude older individuals due to associated comorbidities. Previous studies of older patients undergoing laparoscopic colectomy have generally focused on short-term outcomes. The goals of this cohort study were to identify predictors of laparoscopic colectomy in an older population in the United States and to compare short-term and long-term outcomes. Patients aged 65 years or older with incident colorectal cancer diagnosed 1996-2002 who underwent colectomy within 6 months of cancer diagnosis were identified from the linked Surveillance, Epidemiology, and End Results-Medicare database. Laparoscopic and open colectomy patients were compared with respect to length of stay, blood transfusion requirements, intensive care unit monitoring, complications, 30-day mortality, and long-term survival. We adjusted for potential selection bias in surgical approach with propensity score matching. Laparoscopic colectomy cases were associated with left-sided tumors; areas with higher population density, income, and education level; areas in the western United States; and National Cancer Institute-designated cancer centers. Laparoscopic colectomy cases had shorter length of stay and less intensive care unit monitoring. Although laparoscopic colectomy patients (n = 424) had fewer complications (21.5% versus 26.3%), lower 30-day mortality (3.3% versus 5.8%), and longer median survival (6.6 versus 4.8 years) compared with open colectomy patients (n = 27,012), after propensity score matching these differences disappeared. In this older population, laparoscopic colectomy practice patterns were associated with factors which likely correlate with tertiary referral centers. Although short-term and long-term survival are comparable, laparoscopic colectomy offers shorter hospitalizations and less intensive care.


Impact of time-to-treatment on overall survival of non-small cell lung cancer patients-an analysis of the national cancer database.
The association between time-to-treatment and outcomes for lung cancer has not been conclusively established. In this study, we evaluated the effect of time-to-treatment on the overall 5-year survival of patients with non-small cell lung cancer (NSCLC) with cancer stage at diagnosis. We analyzed data in the National Cancer Data Base for adult patients newly diagnosed with NSCLC in 2003-2011 (N=693,554). Extended Cox regression with counting process was used to model the effect of time-to-treatment on survival, adjusted for demographic and clinical factors. Multivariable analyses were performed separately for the groups with different stages at diagnosis. Time-to-treatment was defined as the interval between diagnosis and treatment initiation, with the categories of (I) 0 day, (II) 1 day-4 weeks, (III) 4.1-6.0 weeks, and (IV) >6 weeks (the 1 day-4 weeks group was considered the reference group). Compared to treatment initiated between 1 day and 4 weeks after diagnosis, time-to-treatment at 4.1-6.0 weeks was associated with a lower risk of death for patients with early-stage cancer [adjusted HR (aHR), 0.84 (95% CI, 0.82-0.85)], with locally advanced cancer [aHR, 0.82 (95% CI, 0.80-0.83)], and with metastatic cancer [aHR, 0.75 (95% CI, 0.74-0.76)]. Similarly, a lower risk of death was associated with time-to-treatment longer than 6 weeks for patients with any cancer stage at diagnosis. However, a subset analysis for early-stage patients who received surgery only showed that extended time-to-surgery was associated a higher risk of death [aHR 4.1-6.0 weeks, 1.06 (95% CI, 1.03-1.09); aHR>6 weeks 1.17 (95% CI, 1.14-1.20)]. The findings show that, although time-to-treatment should not be compromised, it is imperative to ensure that patients receive optimal pre-treatment assessments rather than rushing the treatment. Future research should focus on examining clinical characteristics to determine an optimal time-to-treatment to achieve the best possible survival for NSCLC patients.


Distribution of calcium absorption in middle-aged women.
Distribution of true fractional absorption of calcium in estrogen-deprived, nonosteoporotic, middle-aged women was examined in 273 person-studies, using a double-tracer method. Fractional absorption averaged 0.266 (+/- 0.096). Calcium intake averaged 0.802 g/day (+/- 0.419) and urine calcium, 0.144 g/day (+/- 0.062). Fractional absorption was inversely correlated with intake. Using parameters of the regression equation for the two variables, each absorption value was adjusted to the mean intake of the group so that absorption could be evaluated apart from the effect of intake. The distribution of such diet-adjusted values revealed that 55% of these estrogen-deprived women had insufficient absorption to maintain calcium balance at an intake equal to the 1980 RDA. Nearly one-fourth would still be in negative balance at an intake of 1.5 g/day. Since urine calcium was positively correlated with absorbed calcium (r = 0.521), we conclude that defective absorption and not bone breakdown is the basis for low absorptive performance in these women.


Vascular-targeting agents and radiation therapy in lung cancer: where do we stand in 2005?
With recent Food and Drug Administration approval of the anti-vascular endothelial growth factor (VEGF) antibody for the treatment of colon cancer, it may be possible to achieve similar progress in the treatment of locally advanced lung cancer. Antiangiogenic therapies in the clinic are a reality, and it is important to demonstrate that they can be used safely with conventional modalities, including radiation therapy (RT). Strategies under scrutiny in preclinical and clinical studies include the use of endogenous inhibitors of angiogenesis, use of agents that target VEGF and VEGF receptor signaling, targeting endothelial-related integrins during angiogenesis, and targeting the preexisting immature vessels growing within tumors (ie, vascular targeting). Regardless of the approach, it is necessary to address whether angiogenesis is a consistent phenomenon within the lung parenchyma around a cancer and a relevant target and whether inhibiting angiogenesis will improve current lung cancer therapies without increasing toxicity. Vascular-targeting agents (VTAs) are an interesting class of agents that have the potential to enhance RT, but their clinical promise has yet to be realized. In preclinical models, these agents selectively destroy the tumor vasculature, initiating a rapid centralized necrosis within established tumors. Characteristically, after treatment with VTAs, a rim of viable tumor cells remains at the periphery of the tumor, which remains well perfused and should therefore be relatively sensitive to radiation-induced cytotoxicity. This review will focus on VTAs in the treatment of lung cancer and includes a discussion of combination studies with RT in the laboratory and some of the hurdles in the clinical application of these agents.


3D bio-etching of a complex composite-like embryonic tissue.
Morphogenesis involves a complex series of cell signaling, migration and differentiation events that are coordinated as tissues self-assemble during embryonic development. Collective cell movements such as those that occur during morphogenesis have typically been studied in 2D with single layers of cultured cells adhering to rigid substrates such as glass or plastic. In vivo, the intricacies of the 3D microenvironment and complex 3D responses are pivotal in the formation of functional tissues. To study such processes as collective cell movements within 3D multilayered tissues, we developed a microfluidic technique capable of producing complex 3D laminar multicellular structures. We call this technique "3D tissue-etching" because it is analogous to techniques used in the microelectromechanics (MEMS) field where complex 3D structures are built by successively removing material from a monolithic solid through subtractive manufacturing. We use a custom-designed microfluidic control system to deliver a range of tissue etching reagents (detergents, chelators, proteases, etc.) to specific regions of multilayered tissues. These tissues were previously isolated by microsurgical excision from embryos of the African claw-toed frog, Xenopus laevis. The ability to shape the 3D form of multicellular tissues and to control 3D stimulation will have a high impact on tissue engineering and regeneration applications in bioengineering and medicine as well as provide significant improvements in the synthesis of highly complex 3D integrated multicellular biosystems.


Caring for critically ill patients with ebola virus disease. Perspectives from West Africa.
The largest ever Ebola virus disease outbreak is ravaging West Africa. The constellation of little public health infrastructure, low levels of health literacy, limited acute care and infection prevention and control resources, densely populated areas, and a highly transmissible and lethal viral infection have led to thousands of confirmed, probable, or suspected cases thus far. Ebola virus disease is characterized by a febrile severe illness with profound gastrointestinal manifestations and is complicated by intravascular volume depletion, shock, profound electrolyte abnormalities, and organ dysfunction. Despite no proven Ebola virus-specific medical therapies, the potential effect of supportive care is great for a condition with high baseline mortality and one usually occurring in resource-constrained settings. With more personnel, basic monitoring, and supportive treatment, many of the sickest patients with Ebola virus disease do not need to die. Ebola virus disease represents an illness ready for a paradigm shift in care delivery and outcomes, and the profession of critical care medicine can and should be instrumental in helping this happen.


Molecular adaptation during a rapid adaptive radiation.
"Explosive" adaptive radiations on islands remain one of the most puzzling evolutionary phenomena and the evolutionary genetic processes behind such radiations remain unclear. Rapid morphological and ecological evolution during island radiations suggests that many genes may be under fairly strong selection, although this remains untested. Here, we report that during a rapid recent diversification in the Hawaiian endemic plant genus Schiedea (Caryophyllaceae), 5 in 36 studied genes evolved under positive selection. Positively selected genes are involved in defence mechanisms, photosynthesis, and reproduction. Comparison with eight mainland plant groups demonstrates both the relaxation of purifying selection and more widespread positive selection in Hawaiian Schiedea. This provides compelling evidence that adaptive evolution of protein-coding genes may play a significant role during island adaptive radiations.


Perinatal outcome of triplet gestation: does prophylactic cerclage make a difference?
To compare the perinatal outcome of triplet gestations with and without prophylactic cerclage. A retrospective chart review of all triplet gestations delivered between January 1988 and June 1997 was performed. Only women initiating prenatal care before 15 weeks gestation were included. The cerclage group was compared to the no-cerclage group for maternal and perinatal outcome variables. Student t-test, Chi-square, and Fisher's exact test were used for analysis. Twenty of the 59 (33.8%) sets of triplet gestations had prophylactic cerclage. There were no differences between groups when compared for maternal age, parity, preterm labor rate, gestational diabetes, anemia, antenatal steroid use, histologic chorioamnionitis, and postoperative endometritis. In addition, there were no differences in mean birth weight, Apgar scores, respiratory distress syndrome (RDS), intraventricular hemorrhage/periventricular leucomalacia (IVH/PVL), and neonatal mortality. Although the mean gestational age at delivery for the cerclage group (32.8+/-2.4 weeks) was not different from the no-cerclage group (31.5+/-3.6 weeks), the proportion of pregnancies delivered at 31 weeks or more, and at 32 weeks or more, was significantly higher in the cerclage group (90 vs. 62%, P = .02; 80 vs. 54%, P = .05), respectively. In addition, the incidence of extremely low birth weight (LBW) was significantly decreased in the cerclage compared with the no-cerclage group (1.7 vs. 15.4%, P = .005). Prophylactic cerclage decreased significantly the incidence of extremely LBW neonates in triplet pregnancies. The proportion of neonates delivered at 31 weeks or more, and at 32 weeks or more was higher in the cerclage group.


Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model.
Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5'-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors.


Non-comedogenic and non-acnegenic claim substantiation.
There are currently two methods to evaluate comedogenecity. One is the inexpensive human model developed by Mills and Kligman and modified by others. The second is the more costly human clinical trial, which is the gold standard for comedogenesis and to which the human model is compared. The qualification of each method to support the comedogenecity claim is evaluated and contrasted.


The Effects of Dracocephalum Heterophyllum Benth Flavonoid on Hypertrophic Cardiomyocytes Induced by Angiotensin II in Rats.
BACKGROUND Dracocephalum heterophyllum Benth flavonoid (DHBF) is a Tibetan and Uighur traditional medicine used to treat various disorders such as hypertension, lung heat, cough, and bronchitis; it has good antioxidant activity. Previous studies have shown that DHBF can reduce blood pressure in renovascular hypertensive rats, improve left ventricular systolic and diastolic function, and improve myocardial contractility. Therefore, we aimed to study the effect of DHBF on cardiomyocyte hypertrophy in cultured cells. MATERIAL AND METHODS Neonatal rat cardiomyocytes were cultured, and hypertrophy was induced by angiotensin II (Ang II), with or without varying concentrations of the DHBF extract. Cell Counting Kit-8 assay was used to assess cell viability, RT-qPCR was used to determine mRNA levels, confocal laser scanning microscopy was used to measure cell surface area and intracellular Ca2+ concentrations ([Ca2+]i), and colorimetric assays were used to assess nitric oxide (NO) levels and nitric oxide synthase (NOS) activity. RESULTS Ang II treatment of cardiomyocytes reduced cell viability to ~75% that of controls. Ang II treatment also increased cell surface area; increased mRNA expression of c-jun, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC); increased [Ca2+]i; and reduced NOS activity and NO production. DHBF treatment could reverse these effects in a concentration-dependent manner. CONCLUSIONS These results showed that DHBF can ameliorate cardiomyocyte hypertrophy induced by Ang II, as indicated by the downregulation of cardiac hypertrophy genes (ANP, BNP, and β-MHC) and reduction in cell surface area. The mechanism may be related to NO release and [Ca2+]I regulation.


Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial.
Cytisine is more effective than placebo and nicotine replacement therapy for smoking cessation. However, cytisine has not been tested against the most effective smoking cessation medication, varenicline, which is associated with adverse events known to lead to discontinuation of therapy. To examine whether standard cytisine treatment (25 days) was at least as effective as standard varenicline treatment (84 days) for smoking cessation. This noninferiority, open-label randomized clinical trial with allocation concealment and blinded outcome assessment was undertaken in Australia from November 2017 through May 2019; follow-up was completed in January 2020. A total of 1452 Australian adult daily smokers willing to make a quit attempt were included. Data collection was conducted primarily by computer-assisted telephone interview, but there was an in-person visit to validate the primary outcome. Treatments were provided in accordance with the manufacturers' recommended dosage: cytisine (n = 725), 1.5-mg capsules taken 6 times daily initially then gradually reduced over the 25-day course; varenicline (n = 727), 0.5-mg tablets titrated to 1 mg twice daily for 84 days (12 weeks). All participants were offered referral to standard telephone behavioral support. The primary outcome was 6-month continuous abstinence verified using a carbon monoxide breath test at 7-month follow-up. The noninferiority margin was set at 5% and the 1-sided significance threshold was set at .025. Among 1452 participants who were randomized (mean [SD] age, 42.9 [12.7] years; 742 [51.1%] women), 1108 (76.3%) completed the trial. Verified 6-month continuous abstinence rates were 11.7% for the cytisine group and 13.3% for the varenicline group (risk difference, -1.62% [1-sided 97.5% CI, -5.02% to ∞]; P = .03 for noninferiority). Self-reported adverse events occurred less frequently in the cytisine group (997 events among 482 participants) compared with the varenicline group (1206 events among 510 participants) and the incident rate ratio was 0.88 (95% CI, 0.81 to 0.95; P = .002). Among daily smokers willing to quit, cytisine treatment for 25 days, compared with varenicline treatment for 84 days, failed to demonstrate noninferiority regarding smoking cessation. anzctr.org.au Identifier: ACTRN12616001654448.


Impact of the Introduction of a Package of Diagnostic Tools, Diagnostic Algorithm, and Training and Communication on Outpatient Acute Fever Case Management at 3 Diverse Sites in Uganda: Results of a Randomized Controlled Trial.
Increasing trends of antimicrobial resistance are observed around the world, driven in part by excessive use of antimicrobials. Limited access to diagnostics, particularly in low- and middle-income countries, contributes to diagnostic uncertainty, which may promote unnecessary antibiotic use. We investigated whether introducing a package of diagnostic tools, clinical algorithm, and training-and-communication messages could safely reduce antibiotic prescribing compared with current standard-of-care for febrile patients presenting to outpatient clinics in Uganda. This was an open-label, multicenter, 2-arm randomized controlled trial conducted at 3 public health facilities (Aduku, Nagongera, and Kihihi health center IVs) comparing the proportions of antibiotic prescriptions and clinical outcomes for febrile outpatients aged ≥1 year. The intervention arm included a package of point-of-care tests, a diagnostic and treatment algorithm, and training-and-communication messages. Standard-of-care was provided to patients in the control arm. A total of 2400 patients were enrolled, with 49.5% in the intervention arm. Overall, there was no significant difference in antibiotic prescriptions between the study arms (relative risk [RR]: 1.03; 95% CI: .96-1.11). In the intervention arm, patients with positive malaria test results (313/500 [62.6%] vs 170/473 [35.9%]) had a higher RR of being prescribed antibiotics (1.74; 1.52-2.00), while those with negative malaria results (348/688 [50.6%] vs 376/508 [74.0%]) had a lower RR (.68; .63-.75). There was no significant difference in clinical outcomes. This study found that a diagnostic intervention for management of febrile outpatients did not achieve the desired impact on antibiotic prescribing at 3 diverse and representative health facility sites in Uganda.


Climate extremes promote fatal co-infections during canine distemper epidemics in African lions.
Extreme climatic conditions may alter historic host-pathogen relationships and synchronize the temporal and spatial convergence of multiple infectious agents, triggering epidemics with far greater mortality than those due to single pathogens. Here we present the first data to clearly illustrate how climate extremes can promote a complex interplay between epidemic and endemic pathogens that are normally tolerated in isolation, but with co-infection, result in catastrophic mortality. A 1994 canine distemper virus (CDV) epidemic in Serengeti lions (Panthera leo) coincided with the death of a third of the population, and a second high-mortality CDV epidemic struck the nearby Ngorongoro Crater lion population in 2001. The extent of adult mortalities was unusual for CDV and prompted an investigation into contributing factors. Serological analyses indicated that at least five "silent" CDV epidemics swept through the same two lion populations between 1976 and 2006 without clinical signs or measurable mortality, indicating that CDV was not necessarily fatal. Clinical and pathology findings suggested that hemoparsitism was a major contributing factor during fatal epidemics. Using quantitative real-time PCR, we measured the magnitude of hemoparasite infections in these populations over 22 years and demonstrated significantly higher levels of Babesia during the 1994 and 2001 epidemics. Babesia levels correlated with mortalities and extent of CDV exposure within prides. The common event preceding the two high mortality CDV outbreaks was extreme drought conditions with wide-spread herbivore die-offs, most notably of Cape buffalo (Syncerus caffer). As a consequence of high tick numbers after the resumption of rains and heavy tick infestations of starving buffalo, the lions were infected by unusually high numbers of Babesia, infections that were magnified by the immunosuppressive effects of coincident CDV, leading to unprecedented mortality. Such mass mortality events may become increasingly common if climate extremes disrupt historic stable relationships between co-existing pathogens and their susceptible hosts.


Rethinking the family in the context of care for adolescents living with HIV in Swaziland.
Drawing from 18 months of ethnographic fieldwork in one urban and one rural setting in Swaziland, involving 13 case studies of adolescents living with HIV, in this article we explore the meaning of the family as it applies to Swazi adolescents' everyday life. Our findings suggest that the meaning of the family is constantly evolving and transforming based on changing needs of, and expectations by, adolescents in different contexts and moments of the care continuum. Central to the meaning of the family is a strong desire for belonging - that is, being accepted, welcomed and appreciated. Traditional institutions that used to regulate where children belong still shape adolescents' perceptions, hopes and desires, but may also prevent their realisation. Support groups are important but do not substitute for the familial belongings adolescents living with HIV have lost, and long for. Policymakers, programme managers and health providers working with adolescents living with HIV need to embrace the complexity and dynamism of the meaning of family and base their policies, programmes, standards and guidelines not only on the factual care arrangements that adolescents find themselves in, nor on legal definitions of rights and responsibilities, but also on what adolescents want.


Using targeted enrichment of nuclear genes to increase phylogenetic resolution in the neotropical rain forest genus Inga (Leguminosae: Mimosoideae).
Evolutionary radiations are prominent and pervasive across many plant lineages in diverse geographical and ecological settings; in neotropical rainforests there is growing evidence suggesting that a significant fraction of species richness is the result of recent radiations. Understanding the evolutionary trajectories and mechanisms underlying these radiations demands much greater phylogenetic resolution than is currently available for these groups. The neotropical tree genus Inga (Leguminosae) is a good example, with ~300 extant species and a crown age of 2-10 MY, yet over 6 kb of plastid and nuclear DNA sequence data gives only poor phylogenetic resolution among species. Here we explore the use of larger-scale nuclear gene data obtained though targeted enrichment to increase phylogenetic resolution within Inga. Transcriptome data from three Inga species were used to select 264 nuclear loci for targeted enrichment and sequencing. Following quality control to remove probable paralogs from these sequence data, the final dataset comprised 259,313 bases from 194 loci for 24 accessions representing 22 Inga species and an outgroup (Zygia). Bayesian phylogenies reconstructed using either all loci concatenated or a gene-tree/species-tree approach yielded highly resolved phylogenies. We used coalescent approaches to show that the same targeted enrichment data also have significant power to discriminate among alternative within-species population histories within the widespread species I. umbellifera. In either application, targeted enrichment simplifies the informatics challenge of identifying orthologous loci associated with de novo genome sequencing. We conclude that targeted enrichment provides the large volumes of phylogenetically-informative sequence data required to resolve relationships within recent plant species radiations, both at the species level and for within-species phylogeographic studies.


Hydrated xenogeneic decellularized tracheal matrix as a scaffold for tracheal reconstruction.
Tracheal injury is a rare but complex problem. Primary tracheal reconstructions are commonly performed, but complications such as tension and inadequate vascular supply limit the length of surgical resection. The objective of the present study was to determine whether a hydrated, decellularized porcine tracheal extracellular matrix showed the potential to serve as a functional tracheal replacement graft. Porcine tracheas were decellularized and evaluated to characterize their biochemical composition and biomechanical behavior. Hydrated decellularized tracheal matrix (HDTM) grafts (>5 cm) were implanted heterotopically beneath the strap muscle and wrapped in the omentum in a canine model for 2 and 8 weeks followed by histologic and mechanical analysis. HDTM patches (2 x 3 cm) were also used in a patch tracheoplasty model. The repair site was evaluated bronchoscopically and radiographically, and the grafts were analyzed by histologic methods to evaluate epithelialization and persistence of the cartilage rings. The present study showed that HDTM maintains mechanical characteristics necessary for function under physiologic loading conditions even after 8 weeks of heterotopic implantation. After orthotopic implantation, the grafts were shown to support development of a columnar, pseudostratified, ciliated epithelium, but the cartilage structures showed histologic evidence of degradation and limited new cartilage formation. The results of the study showed tracheal ECM scaffolds support the formation of site-specific epithelium and provide sufficient mechanical integrity withstand physiologic pressures in the short-term. However, for long-term success, it appears that pre-implantation to allow vascularization or preseeding of the graft with chondrocytes will be necessary.


Intra-SA-nodal pacemaker shifts induced by autonomic nerve stimulation in the dog.
Pacemaker shifts in the canine heart were inferred during stimulation of thoracic cardiac nerves and following norepinephrine from changes in the initial site of activation of bipolar electrodes sutured over the rostral, middle, and caudal regions of the sinus node, over the internodal pathways, and His bundle. During control periods, pacemaker activity was localized within the sinoatrial (SA) node 87% of the time, with the middle electrode most frequently showing initial activation. Stimulation of the right-sympathetic nerves enhanced sinus node pacemaker dominance, shifting it rostrally within the node. Right-vagal stimulation shifted the pacemaker caudally within the SA node, to nonnodal sites, and to the lower atrioventricular node and His bundle. Left-sympathetic stimulation shifted the pacemaker caudally within the sinus node and enhanced pacemaker activity in the vicinity of the internodal pathway electrodes and His bundle. Dispersion of pacemaker activity was particularly apparent during stimulation of the ventrolateral cervical cardiac nerve. Stimulation of the left-vagal nerves produced effects similar to those of the left-sympathetic nerves. Norepinephrine enhanced pacemaker activity particularly in the rostral region of the sinus node. Slight shifts in pacemaker activity within the sinus node produced changes in pattern of atrial excitation.