Impact of a novel prioritization framework on clinician-led oncology drug submissions.
In Canada, requests for public reimbursement of cancer drugs are predominately initiated by pharmaceutical manufacturers. Clinician-led submissions provide a mechanism to initiate the drug funding process when industry does not submit a request for funding consideration. Although such requests are resource-intensive to produce, Cancer Care Ontario (cco) has the capacity to facilitate clinician-led submissions. In 2014, cco began developing a cancer drug prioritization framework that allocates resources to systematically address a growing number of clinician-identified funding gaps with clinician-led submissions. Cancer site-specific drug advisory committees established by cco consist of health care practitioners whose roles include identifying and prioritizing funding gaps. The committees submit their identified gaps to a cross-cancer-site prioritization exercise in which the requests are ranked based on a set of guiding principles derived from health technology assessment. The requests are then sequentially allocated the resources needed to meet submission requirements. Whether the funding gap is of provincial or pan-Canadian relevance determines where the submission is filed for assessment. Since its inception, the cco framework has identified 17 funding gaps in 9 cancer sites. In 4 prioritizations, the framework supported 6 submissions. As of June 2018, the framework had contributed to the eventual funding of more than 9 new drug-indication pairs, with more awaiting funding consideration. The cco prioritization framework has enabled clinicians to effectively and systematically identify, prioritize, and fill funding gaps not addressed by industry. Ultimately, the framework helps to ensure that patients can access evidence-informed and cost-effective therapies. The framework will continue to evolve as it encounters new challenges, including funding requests for rare indications.


Circular RNA AGFG1 motivates breast cancer cell proliferation, invasion, migration, and glycolysis by controlling microRNA-653-5p/14-3-3 protein epsilon.
A recent Pairwise meta-analysis confirmed that circular RNA AGFG1 (circAGFG1) is abnormally highly expressed in breast cancer (BC) and may be associated with death risk. The purpose of this study was to elucidate the biological role of circAGFG1 in BC and to explore its potential downstream molecular mechanisms. CircAGFG1, miR-653-5p and YWHAE expression in BC tissues and cells were analyzed by RT-qPCR or western blot. Gene expression was regulated by transfection of plasmids or oligonucleotides and the biological behaviors of BC cells were analyzed by a series of assays. The ring structure of circAGFG1 was analyzed by RNase R and actinomycin D treatment. Dual luciferase reporter assay and RNA-pull down were used to verify the targeting relationship of circAGFG1 and downstream factors. A nude mouse xenograft experiment was performed to verify the effect of circAGFG1 on cancer cells in vivo. The results showed that circAGFG1 and YWHAE were highly expressed in BC while miR-653-5p was lowly expressed. Both circAGFG1 and YWHAE had a targeting relationship with miR-653-5p. Knockdown of circAGFG1 inhibited BC cell proliferation, invasion, migration, and glycolysis. The inhibitory effect of circAGFG1 knockdown on BC was reversed by silencing miR-653-5p. The inhibitory effect of overexpression of miR-653-5p on malignant behaviors of BC cells was reversed by overexpression of YWHAE. Knockdown of circAGFG1 inhibited tumor growth in vivo. Taken together, these data suggest that circAGFG1 acts as a sponge for miR-653-5p to mediate YWHAE expression to promote the malignant behaviors of BC.


The role of aryl-topology in balancing between selective and dual 5-HT7R/5-HT1A actions of 3,5-substituted hydantoins.
In order to search for active and selective serotonin 5-HT7R antagonists among 3,5-disubstituted arylpiperazine-imidazolidine-2,4-diones, the role of the introduction/deletion and the mutual orientation of aromatic rings was analyzed. Chemical modifications of 2nd generation lead structure of 3-(3-(4-(diphenylmethyl)piperazin-1-yl)-2-hydroxypropyl)-5-(4-fluorophenyl)-5-methylimidazolidine-2,4-dione (2, KKB16) were performed. New derivatives (4-18) were designed and synthesized. X-ray crystallographic analysis of the representative compound 5-(4-fluorophenyl)-3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl]-5-methylimidazolidine-2,4-dione (3) was performed to support molecular modeling and SAR studies. The affinity for 5-HT7R, D2R and 5-HT1AR in radioligand binding assays for the entire series and ADME-Tox parameters in vitro for selected compounds (7, 10, and 13) were evaluated. Molecular docking and pharmacophore model assessment were performed. According to the obtained results, 5-methyl-5-naphthylhydantoin derivatives were found to be the new highly active 5-HT7R agents (Ki ≤ 5 nM) with significant selectivity over 5-HT1AR and D2R. On the contrary, the (1-naphthyl)piperazine moiety was gained with the potent dual 5-HT7R/5-HT1AR action (Ki: 11 nM/19 nM).


Collagen Mimetic Peptides Promote Repair of MMP-1-Damaged Collagen in the Rodent Sclera and Optic Nerve Head.
The structural and biomechanical properties of collagen-rich ocular tissues, such as the sclera, are integral to ocular function. The degradation of collagen in such tissues is associated with debilitating ophthalmic diseases such as glaucoma and myopia, which often lead to visual impairment. Collagen mimetic peptides (CMPs) have emerged as an effective treatment to repair damaged collagen in tissues of the optic projection, such as the retina and optic nerve. In this study, we used atomic force microscopy (AFM) to assess the potential of CMPs in restoring tissue stiffness in the optic nerve head (ONH), including the peripapillary sclera (PPS) and the glial lamina. Using rat ONH tissue sections, we induced collagen damage with MMP-1, followed by treatment with CMP-3 or vehicle. MMP-1 significantly reduced the Young's modulus of both the PPS and the glial lamina, indicating tissue softening. Subsequent CMP-3 treatment partially restored tissue stiffness in both the PPS and the glial lamina. Immunohistochemical analyses revealed reduced collagen fragmentation after MMP-1 digestion in CMP-3-treated tissues compared to vehicle controls. In summary, these results demonstrate the potential of CMPs to restore collagen stiffness and structure in ONH tissues following enzymatic damage. CMPs may offer a promising therapeutic avenue for preserving vision in ocular disorders involving collagen remodeling and degradation.


Biodemographic modeling of the links between fertility motivation and fertility outcomes in the NLSY79.
In spite of long-held beliefs that traits related to reproductive success tend to become fixed by evolution with little or no genetic variation, there is now considerable evidence that the natural variation of fertility within populations is genetically influenced and that a portion of that influence is related to the motivational precursors to fertility. We conduct a two-stage analysis to examine these inferences in a time-ordered multivariate context. First, using data from the National Longitudinal Survey of Youth, 1979, and LISREL analysis, we develop a structural equation model in which five hypothesized motivational precursors to fertility, measured in 1979-1982, predict both a child-timing and a child-number outcome, measured in 2002. Second, having chosen two time-ordered sequences of six variables from the SEM to represent our phenotypic models, we use Mx to conduct both univariate and multivariate behavioral genetic analyses with the selected variables. Our results indicate that one or more genes acting within a gene network have additive effects that operate through child-number desires to affect both the timing of the next child born and the final number of children born, that one or more genes acting through a separate network may have additive effects operating through gender role attitudes to produce downstream effects on the two fertility outcomes, and that no genetic variance is associated with either child-timing intentions or educational intentions.


The human LT system. XII. Purification and functional studies of LT and "TNF-like" LT forms from a continuous human T cell line.
A clone of the continuous human T cell line HUT-102, termed YM 1.2, can spontaneously release alpha-LT in vitro. However, when stimulated with phorbol myristic acetate, these cells release other LT forms. These LT forms were purified to homogeneity by DEAE chromatography, column isoelectric focusing, and polyacrylamide gel electrophoresis. One LT form, termed LT-2, is a 79,000 m.w. component in aqueous solution and composed of 21,000 m.w. subunits. This form is immunologically related to macrophage-derived TNF and has a lytic capacity in vitro on K-562, Molt-4F, and Raji cells similar to that described for cytotoxins derived from NK effector cells, termed NK-CF. A second LT form, termed LT-3, is a single 69,000 m.w. peptide which could not be reduced into the smaller subunits. This form expresses antigens in common with both alpha-LT and TNF, because both anti-LT and anti-TNF were required to completely neutralize cell lytic activity in vitro. Functional testing revealed that the LT-3 form is lytic on all continuous cells tested in vitro, including NK-resistant target cells. The LT-3 component appears similar by immunologic, biochemical, and functional criteria to the LT form derived from primary human cytolytic T cells in vitro. At the levels tested, none of these LT-TNF forms had measurable effects on primary fibroblasts in vitro.


Neuronal Activity in the Sciatic Nerve Is Accompanied by Immediate Cytoskeletal Changes.
Mechanical events and alterations in neuronal morphology that accompany neuronal activity have been observed for decades. However, no clear neurophysiological role, nor an agreed molecular mechanism relating these events to the electrochemical process, has been found. Here we hypothesized that intense, yet physiological, electrical activity in neurons triggers cytoskeletal depolymerization. We excited the sciatic nerve of anesthetized mice with repetitive electric pulses (5, 10, and 100 Hz) for 1 and 2 min and immediately fixed the excised nerves. We then scanned the excised nerves with high-resolution transmission electron microscopy, and quantified cytoskeletal changes in the resulting micrographs. We demonstrate that excitation with a stimulation frequency that is within the physiological regime is accompanied by a significant reduction in the density of cytoskeletal proteins relative to the baseline values recorded in control nerves. After 10 Hz stimulation with durations of 1 and 2 min, neurofilaments density dropped to 55.8 and 51.1% of the baseline median values, respectively. In the same experiments, microtubules density dropped to 23.7 and 38.5% of the baseline median values, respectively. These changes were also accompanied by a reduction in the cytoskeleton-to-cytoplasm contrast that we attribute to the presence of depolymerized electron-dense molecules in the lumen. Thus, we demonstrate with an in vivo model a link between electrical activity and immediate cytoskeleton rearrangement at the nano-scale. We suggest that this cytoskeletal plasticity reduces cellular stiffness and allows cellular homeostasis, maintenance of neuronal morphology and that it facilitates in later stages growth of the neuronal projections.


Geriatric bone lead metabolism in a female nonhuman primate population.
A geriatric rhesus monkey (Macaca mulatta) population, previously exposed to lead, was investigated using 109Cd K X-ray fluorescence (K XRF) to determine whether metabolism of lead in bone was similar to that in human populations. The accumulation rate of lead into the tibia in this group of monkeys was determined to be 0.10-0.13 micrograms Pb (g bone mineral)-1 (microgram dl-1 year)-1, which compares well with human data, where the rate has been found to be 0.05-0.10 microgram Pb (g bone mineral)-1 (microgram dl-1 year)-1. In addition, bone lead changes over a 10-month time period were investigated, but no statistically significant difference was found. A halflife for lead in "bone" was calculated by fitting a single exponential model to serial blood lead data; the mean half-life of lead in bone was found to be 3.0 +/- 1.0 years. Both endogenous and exogenous lead exposure were found to be low at the present time, 10 years after cessation of lead intake. It is concluded that rhesus monkeys are an extremely good animal model of human bone lead metabolism and, in addition, that further research is needed to provide a more complete understanding of lead metabolism in geriatric populations.


Exploiting the vicinal disubstituent effect on the diastereoselective synthesis of γ and δ lactones.
Trifluoroacetic acid catalysed lactonization of vicinal disubstituted γ-hydroxyesters was investigated in different solvents. The reaction kinetics, monitored by NMR spectroscopy, showed that: (i) the vic-disubstituent effect is stereoselective since the anti diastereoisomer ring closes substantially more rapidly than the syn isomer ring; (ii) the anti-vic effect is much stronger than the classical Thorpe-Ingold effect (known also as the gem-disubstituent effect), instead the syn diastereoisomers have rate constants comparable to that of the gem-disubstituted ester; (iii) the vic-effect can be enhanced by increasing the steric hindrance of one of the two substituents or carrying out the reaction in non-polar solvents. DFT computations of energy barriers (ΔG‡) were in good agreement with the experimental data. The distortion/interaction-activation strain model together with the Winstein-Holness kinetic scheme gave more insights into the origin of the vic-effect. An application of this effect consists of the diastereomeric resolution of disubstituted γ and δ lactones, among which are the naturally occurring Nicotiana t. lactone, the whisky and cognac oak lactones, and the Aerangis lactone. Both cis and trans diastereoisomers of these lactones were isolated in good yield and with high diastereomeric excess (de >92%). The selectivities of the diastereomeric resolution process, determined by NMR spectroscopy, are reported as well.


Apparent recombinants between virus-liKE (VL30) and murine leukemia virus-related sequences in mouse DNA.
VL30 elements are a dispersed multigene family that is ubiquitous in all murine cells. Despite not sharing nucleic acid sequence homology with natural retroviruses (exogenous or endogenous), VL30 elements are distinguished by several retrovirus-like features. By screening a mouse embryonic library, we have cloned DNA units that contain VL30 sequences linked to MuLV-related sequences. Using blot hybridization with the aid of specific subgenomic probes and heteroduplex analyses, we have established that the DNA element is composed of two VL30 long terminal repeat (LTR) units, a limited subset of VL30 information adjacent to both 5' and 3' LTRs, and an enclosure of MuLV-related information that shares homology primarily with MuLV gag and pol determinants (but lacks MuLV-related LTRs). This sequence arrangement is reciprocal in nature to the recombinations between MuLV and rat VL30 that generated the genomes of the Harvey and Kirsten strains of mouse sarcoma virus and most likely is the consequence of recombination between VL30 and MuLV-related elements and the subsequent deposition of the putative recombinant DNA in the mouse genome.


Alterations in carbohydrate metabolism as they apply to reproductive endocrinology.
This review has characterized the current state of knowledge of four clinical situations in which an interrelationship of gynecology, endocrinology and carbohydrate metabolism is recognized. The literature contains conflicting descriptions of changes in glucose homeostasis during the menstrual cycle and while using birth control pills. Physiologic changes in receptor number have been demonstrated in each of these situations, so failure to observe differences using glucose tolerance testing may reflect an in vivo homeostatic response to changes in these hormone levels. Thus, in vivo identification of alterations in carbohydrate metabolism induced by endogenous or exogenous steroids may require utilization of models that prevent these homeostatic mechanisms. The association between hyperandrogenism and hyperinsulinism has been better characterized, but the relationship is complicated by the frequent coexistence of obesity. The association may be due to insulin-stimulated ovarian androgen production, and insulin insensitivity may reflect a postreceptor defect. Insulin and its metabolic effects have also been implicated in ovulatory dysfunction in women with diabetes mellitus and identified as a factor affecting all levels of the hypothalamic-pituitary-ovarian axis. A clearer understanding of these relationships and their application to clinical management await further study.


Adherence to cardiovascular prevention strategies in patients with rheumatoid arthritis.
Patients with rheumatoid arthritis (RA) have a high risk of cardiovascular disease (CVD). Recent national and international guidelines suggest strict treatment of CVD risk factors in RA. The aim of this study was to evaluate the self-reported adherence to CV prevention strategies in patients with RA. RA patients visiting an outpatient clinic for strict CVD risk management received a validated questionnaire to evaluate adherence to CV prevention strategies. Strict treatment targets were defined and lifestyle recommendations were given following a prespecified protocol. CVD risk was assessed using the SCORE algorithm. In total, 111 questionnaires were returned (response rate of 82%). A high 10-year CVD risk (≥ 20%) was present in 53%, but only 3% thought they had an increased CVD risk. A total of 53% of patients reported that they 'follow the doctors' suggestions exactly' and 75% reported finding it 'easy to follow the suggestions'. Of the 69% of patients who were prescribed lipid- and/or blood pressure-lowering drugs, 90% reported taking all prescribed tablets. The advice to follow a diet was given to 42%, of whom 68% said they followed the advised diet. Physical exercise was advised to 67%, of whom 62% said they performed specific physical exercise on at least 3 days a week. The adherence to lifestyle recommendations was not significantly different across the CVD risk groups. RA patients tend to underestimate their CVD risk. The self-reported adherence of RA patients to CVD risk management was high concerning pharmaceutical interventions and moderate in the case of lifestyle interventions.


Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR.
Pregnane X receptor (PXR) which belongs to the nuclear hormone receptor superfamily plays vital roles in several biological functions, especially in the inflammatory procedure. Besides that, PXR is revealed by recent studies to have essential effects on bone tissue. As an agonist of PXR, meclizine is a piperazine-derived histamine H1 antagonist, and has been frequently used for prevention and treatment of vomiting and nausea. Because osteoclastogenesis is characterized by the activation of inflammation-related signaling pathways, we speculated that meclizine may affect formation and function of osteoclast. In the present study, we explored the effect of meclizine on RANKL-induced osteoclastogenesis both in vivo and in vitro. In primary bone marrow-derived macrophages (BMMs), meclizine reduced osteoclast formation and bone resorption in a dose-dependent manner, while knockdown of PXR with siRNA partially abrogated the osteoclastogenesis inhibition of meclizine. On the one hand, at the molecular level, meclizine attenuated RANKL-induced activation of c-Fos, NFATc1, nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPKs), including ERK and p38, but not JNK. Meanwhile, meclizine reduced the expression of osteoclast-specific genes, including TRAP, MMP9, Cathepsin K and NFATc1. On the other hand, meclizine decreased OVX-induced bone loss by repressing osteoclast activity. In conclusion, our results indicated that meclizine inhibits osteoclastogenesis via regulation of several RANKL signaling pathways and PXR was involved in the processes. Therefore, meclizine may be considered as a novel therapeutic candidate for osteoclast-related diseases.


Membrane-associated and secreted genes in breast cancer.
The identification of membrane-associated and secreted genes that are differentially expressed is a useful step in defining new targets for the diagnosis and treatment of cancer. Extracting information on the subcellular localization of genes represented on DNA microarrays is difficult and is limited by the incomplete sequence and annotation that is available in existing databases. Here we combine a biochemical and bioinformatic approach to identify membrane-associated and secreted genes expressed in the MCF-7 breast cancer cell line. Our approach is based on the analysis of differential hybridization levels of RNAs that have been physically separated by virtue of their association with polysomes on the endoplasmic reticulum. This approach is specifically applicable to oligonucleotide microarrays such as Affymetrix, which use single-color hybridization instead of dual-color competitive hybridizations. Assignment to membrane-associated and secreted class membership is based on both the differential hybridization levels and an expression threshold, which are calculated empirically from data collected on a reference set of known cytoplasmic and membrane proteins. This method enabled the identification of 755 membrane-associated and secreted probe sets expressed in MCF-7 cells for which this annotation did not previously exist. The data were used to filter a previously reported expression dataset to identify membrane-associated and secreted genes which are associated with poor prognosis in breast cancer and represent potential targets for diagnosis and treatment. The approach reported here should provide a useful tool for the analysis of gene expression patterns, identifying membrane-associated or secreted genes with biological relevance that have the potential for clinical applications in diagnosis or treatment.


Antenatal retinoic acid does not alter alveolization or postnatal lung function in preterm sheep.
Retinoic acid exposure has been shown to promote surfactant production in foetal rats and to promote alveolization in neonatal rats. It was hypothesized that antenatal retinoic acid treatment would promote alveolization and accelerate functional maturation in the lungs of late gestation preterm sheep. Foetuses received a single i.m. injection of all-trans retinoic acid (RA, 20 mg x kg(-1)) or vehicle control at 115 days gestation (term=150 days) and were delivered at 125 days gestation. To examine the longer term effects of RA on alveolization a second group of animals received RA or vehicle at 121 days gestation and were delivered at 146 days gestation. Liver retinol levels at time of delivery were 2-3-fold higher in both preterm and near-term RA treated animals, indicating a significant impact of RA treatment on retinol metabolism. Dynamic compliance, gas exchange, lung gas volume and saturated phosphatidylcholine pool size at 125 days were unaffected by antenatal RA treatment. Alveolar volume, wall thickness and number at 125 or 146 days were also unaffected by RA treatment. Retinoic acid, as administered in this study, does not appear to accelerate structural or functional maturation of the foetal sheep lung. Response to retinoic acid may be species dependent, highlighting a need for caution when interpreting results from animal based studies.


Comparison of apraxia in corticobasal degeneration and progressive supranuclear palsy.
To describe ideomotor apraxia in patients with corticobasal degeneration and those with progressive supranuclear palsy, two parkinsonian disorders that are often misdiagnosed due to the overlap in their clinical features, and to determine whether systematic apraxia testing is useful for differential diagnosis. Fourteen patients fulfilling National Institute of Neurological Disorders and Stroke-Society for Progressive Supranuclear Palsy clinical criteria for progressive supranuclear palsy, 13 patients fulfilling modified Lang criteria for corticobasal degeneration, and 12 normal healthy control subjects were given the Test of Oral and Limb Apraxia, which was scored according to the Florida Apraxia Battery for occurrence of various types of apraxic errors. Both patients with progressive supranuclear palsy and corticobasal degeneration committed a greater number of apraxic errors than normal healthy control subjects on both transitive and intransitive tasks (p < 0.001 in both cases), but apraxia was much more severe in patients with corticobasal degeneration than progressive supranuclear palsy (p < 0.001). The index of apraxia severity, in combination with the assessment of the two key features of progressive supranuclear palsy (falls and vertical gaze palsy), correctly classified all patients. Patients with corticobasal degeneration show more severe ideomotor apraxia than patients with progressive supranuclear palsy, and systematic assessment of ideomotor apraxia facilitates the differential diagnosis between patients with progressive supranuclear palsy and those with corticobasal degeneration.


Exploring the role of polymer hydrophobicity in polymer-metal binding thermodynamics.
Metal-chelating polymers play a key role in rare-earth element (REE) extraction and separation processes. Often, these processes occur in aqueous solution, but the interactions among water, polymer, and REE are largely under-investigated in these applications. To probe these interactions, we synthesized a series of poly(amino acid acrylamide)s with systematically varied hydrophobicity around a consistent chelating group (carboxylate). We then measured the ΔH of Eu3+ chelation as a function of temperature across the polymer series using isothermal titration calorimetry (ITC) to give the change in heat capacity (ΔCP). We observed an order of magnitude variation in ΔCP (39-471 J mol1 K-1) with changes in the hydrophobicity of the polymer. Atomistic simulations of the polymer-metal-water interactions revealed greater Eu3+ and polymer desolvation when binding to the more hydrophobic polymers. These combined experimental and computational results demonstrate that metal binding in aqueous solution can be modulated not only by directly modifying the chelating groups, but also by altering the molecular environment around the chelating site, thus suggesting a new design principle for developing increasingly effective metal-chelating materials.


A Social Constructionist Approach to Diversity and Social Relations Among Muslim Americans.
Social relations among Muslim elders in the U.S. were examined to investigate diversity within an ethnic group whose members share a common religious belief system. Data included a web-based survey (N = 264) and semi-structured interviews (N = 18). A social constructionist perspective was used recognizing that ethnicity is fluid, not static and culture was highlighted as a way of seeing as opposed to a way of being. Regression analysis was conducted using survey data to investigate diversity among Muslims elders concerning social contact and activities. Social contact was predominantly with older adults for both African American and European compared to South Asian Muslims. Concerning social activities, the U.S. born was less likely than immigrants to be satisfied with activities for elders. Grounded analysis of semi-structured data uncovered two themes: social connectedness and communication. Each theme provided in-depth understandings of how culture, as ways of seeing the world, shape social relations in diverse ways, leading to the proposition that though family may be necessary for well-being in old age, it is not sufficient. By focusing on one religious group that included both immigrants and those born in the U.S., with various ancestral origins, findings advance a systematic and critical approach to challenge essentialist assumptions in the study of ethnic aging.


The Monetary Valuation of Lifetime Health Improvement and Life Expectancy Gains in Turkey.
The main objective of this study is to estimate the monetary value of the gains of healthy days and life expectancy due to the ambient air quality standard that came into effect in 2014 by estimating the country-specific value of a life year (VOLY) and the value of the healthier and longer life (VHLL) for Turkey. Contingent valuation method is adopted to reveal individuals' willingness to pay for an improvement of health condition and the extension of their life expectancy by avoiding respiratory and lung related illnesses. VHLL is composed of two parts, WTP for an extension of one's life years (VOLY) and for an increase in the number of healthy days throughout one's life time (VHLL-VOLY). We found that close to 80% of WTP is allocated to the latter component of VHLL and only 20% is for VOLY mainly due to Islamic beliefs of the respondents. A total of 1314 observations are collected by face-to-face interviews from Afsin-Elbistan, Kutahya-Tavsanli and Ankara. The estimated VHLL and VOLY are [41,750 TL, 10,258 TL] with all the observations, [30,185 TL, 7132 TL] for Afsin-Elbistan, [31,718 TL, 7081 TL] for Kutahya-Tavsanli and [52,334 TL, 14,813 TL] for Ankara. The Inverse-U shaped relationship between Age and WTP is confirmed. The income elasticities of WTP is found to be close to 0.5 for all study areas while an Inverse-U shaped relationship between the household income and Income Elasticity of WTP is observed in the income group based analysis. Age and household income are the two prominent determinants of VHLL.


Adolescent Victims of Commercial Sexual Exploitation versus Sexually Abused Adolescents.
We have discovered in our clinical review that sexually abused girls have significantly better therapeutic outcomes than girls who have been victims of sex trafficking. Thus, we compared the mental health records of 25 adolescent female victims of commercial sexual exploitation with a group of 25 girls with a history of sexual abuse matched for age. Exclusion criteria included IQ <70, organicity, and psychosis. Victims of sexual exploitation were more likely to be in foster care; to have arrests, suspensions from school, and a history of running away; to abuse drugs; to be more impaired in social and school activities; to be withdrawn and depressed; to manifest social and thought problems and aggressive and rule-breaking behaviors; and to have a diagnosis of mood or conduct disorder or both. The results of this study suggest that the psychopathology of girl victims of sexual exploitation is markedly different from that of sexually abused girls.


Study of Biomolecular Interactions of Mitochondrial Proteins Related to Alzheimer's Disease: Toward Multi-Interaction Biomolecular Processes.
Progressive mitochondrial dysfunction due to the accumulation of amyloid beta (Aβ) peptide within the mitochondrial matrix represents one of the key characteristics of Alzheimer's disease (AD) and appears already in its early stages. Inside the mitochondria, Aβ interacts with a number of biomolecules, including cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), and affects their physiological functions. However, despite intensive ongoing research, the exact mechanisms through which Aβ impairs mitochondrial functions remain to be explained. In this work, we studied the interactions of Aβ with cypD and 17β-HSD10 in vitro using the surface plasmon resonance (SPR) method and determined the kinetic parameters (association and dissociation rates) of these interactions. This is the first work which determines all these parameters under the same conditions, thus, enabling direct comparison of relative affinities of Aβ to its mitochondrial binding partners. Moreover, we used the determined characteristics of the individual interactions to simulate the concurrent interactions of Aβ with cypD and 17β-HSD10 in different model situations associated with the progression of AD. This study not only advances the understanding of Aβ-induced processes in mitochondria during AD, but it also provides a new perspective on research into complex multi-interaction biomolecular processes in general.


Cerebral mucormycosis after liver transplantation: a case report.
A fatal case of cerebral mucormycosis occurring shortly after liver transplantation is described. The patient was a 32-yr-old male with advanced end-stage liver disease manifested by tense ascites, spontaneous bacterial peritonitis, deepening jaundice and anuria requiring hemodialysis. The 3rd day after successful liver transplantation the patient developed acute respiratory failure, then focal motor signs. Computed tomography showed fluid in the left maxillary sinus, partial opacification of the ethmoid and sphenoid sinuses, and diffuse low density lesions in both cerebral hemispheres. Despite treatment for cerebritis and cerebral edema, the patient's pupils became fixed and dilated, and brain death was declared. Autopsy revealed mucor sinusitis and cerebritis. Mucormycosis is an opportunistic fungal infection occurring in patients with diabetic ketoacidosis, malignancy, or immunodeficiency, and in those receiving wide-spectrum antibiotics, corticosteroids, or cytotoxic therapy. Mucor most frequently involves the face, rhinocerebral disease predominating. These infections are difficult to treat, but are curable with aggressive and frequent surgical debridement, discontinuation or reduction of immunosuppressive therapy and amphotericin. The diagnosis of mucormycosis is very difficult to make in cases such as the present one, in which the typical presentation and classical signs are not present. A high index of suspicion based on identified risk factors may assist in more rapid diagnosis of this life-threatening mycosis.


Down-regulated CK8 expression in human intervertebral disc degeneration.
As an intermediate filament protein, cytokeratin 8 (CK8) exerts multiple cellular functions. Moreover, it has been identified as a marker of notochord cells, which play essential roles in human nucleus pulposus (NP). However, the distribution of CK8 positive cells in human NP and their relationship with intervertebral disc degeneration (IDD) have not been clarified until now. Here, we found the percentage of CK8 positive cells in IDD (25.7±4.14%) was significantly lower than that in normal and scoliosis NP (51.9±9.73% and 47.8±5.51%, respectively, p<0.05). Western blotting and qRT-PCR results confirmed the down-regulation of CK8 expression in IDD on both of protein and mRNA levels. Furthermore, approximately 37.4% of cell clusters were CK8 positive in IDD. Taken together, this is the first study to show a down-regulated CK8 expression and the percentage of CK8 positive cell clusters in IDD based upon multiple lines of evidence. Consequently, CK8 positive cells might be considered as a potential option in the development of cellular treatment strategies for NP repair.


How should doctors disclose conflicts of interest to patients? A focus group investigation.
Disclosure is often proposed as a strategy for handling financial conflicts of interest in medicine. Yet there has been no guidance on how clinicians should disclose potential conflicts of interest to patients. To discern patients' attitudes toward conflicts of interest in medicine and their opinions about how physicians should disclose possible conflicts in the clinical setting, we conducted six focus groups with patients recruited from three clinics in the Twin Cities area. Investigators reviewed audio recordings of the focus group discussions independently and identified themes. Maintaining patient-doctor trust was critical to all study participants. Most wanted to know only about conflicts of interest that were directly relevant to their care. In addition, most participants said physicians and other health care providers should offer patients an easy-to-read document about any conflict of interest during clinic check-ins and bring up the subject when discussing specific treatment plans for which the conflict of interest is relevant. Our study offers the first insights into patient attitudes toward and opinions about disclosure practices in clinical settings. More research into the practical aspects of managing conflicts of interest is needed as ineffective disclosure may undermine patients' trust in their doctors.


Quantitative analysis of foot-and-mouth disease virus RNA loads in bovine tissues: implications for the site of viral persistence.
To understand better the pathogenesis of foot-and-mouth disease (FMD), the levels of viral RNA in various bovine tissues during the acute and persistent stages of FMD virus (FMDV) infection were investigated by using quantitative RT-PCR. The viral RNA levels in the tissues examined had peaked by day 1 post-infection (p.i.) and were markedly different among the tissues examined. The epithelium collected from sites of lesion development, i.e. the interdigital area and coronary band on the feet, and the tongue, contained the highest level of viral RNA, indicating the predominant tissue sites of viral infection and amplification during the acute stage of infection. Clearance of viral RNA from most of the tissues occurred relatively rapidly and the rate of clearance was largely independent of the level of viral RNA. The viral RNA load in most of the tissues declined slower than in serum, in which viral clearance is rapid. Beyond 28 days p.i., a proportion of pharyngeal region tissues (soft palate, pharynx, tonsil and mandibular lymph node) from infected animals still contained a detectable level of viral RNA, while viral RNA in non-pharyngeal region tissues was generally only detectable for variable periods ranging from 4 to 14 days p.i. The presence of viral RNA in dorsal soft palate tissue had a good correlation with the presence of infectious virus in oesophageal-pharyngeal fluid (OP-fluid) samples, a finding indicative of the specific tissue sites of FMDV persistence.


Dermal C4d Deposition and Neutrophil Alignment Along the Dermal-Epidermal Junction as a Diagnostic Adjunct for Hypocomplementemic Urticarial Vasculitis (Anti-C1q Vasculitis) and Underlying Systemic Disease.
Urticarial vasculitis (UV) is a clinicopathologic entity characterized by persistent urticarial lesions with biopsy features of vasculitis. Currently, only certain clinical features such as arthralgia and serum complement concentrations are used to identify UV patients at risk for an underlying systemic disease. Hypocomplementemic urticarial vasculitis (HUV) is in contrast to normocomplementemic urticarial vasculitis (NUV), strongly associated with underlying systemic disease, especially systemic lupus erythematosus (SLE). The aim of this study was to find specific histopathological features associated with HUV and underlying systemic disease in UV. In addition, the use of complement C4d deposition in skin biopsies was evaluated as a diagnostic adjunct for HUV- and UV-associated systemic disease. In this retrospective study, the clinical, histopathological, and immunohistological (C4d) features of 43 patients with UV were compared between HUV and NUV and analyzed for association with UV-associated systemic disease. Eight of 43 patients with UV (19%) had hypocomplementemia. Patients with HUV showed a significantly higher number of perivascular neutrophils and lower number of eosinophils compared to NUV. Of all histopathological features, alignment of neutrophils along the dermal-epidermal junction (DEJ) and dermal granular C4d deposition were found to be strongly associated with HUV and underlying SLE. This study shows that both the alignment of neutrophils along the DEJ and dermal C4d deposition are strongly associated with HUV and SLE. Therefore, these (immuno)histopathological features can be used as an easy diagnostic adjunct for early detection of underlying systemic disease in UV.


Hippocampal estrogens rescued the decline of synaptic plasticity after surgery and anesthesia by inhibiting microglia overactivation.
Elderly patients experience postoperative cognitive impairment frequently; therefore, effective interventions are urgently needed. Central nervous inflammation characterized by microglia may promote the progression of POCD by reducing synaptic plasticity. Notably, clinical studies revealed that the incidence of female patients was significantly lower than that of male patients. Besides, the brain estrogens have an anti-inflammatory effect and regulate the microglia at the same times. This study aimed to determine whether suppressing microglia overactivation by hippocampal estrogens can rescue the decrease of synaptic plasticity after surgery and anesthesia. Exploratory laparotomy was used to establish the POCD model in 15-month-old male or female C57BL/6J mice and animal behavioral tests were performed to test hippocampal-dependent memory capacity. Western blot and immunofluorescence were used to detect the microglial activation and plasticity related protein expressions. Elisa was used to detect the content of estrogens in the hippocampus. Estrogens and estrogen receptor inhibitor were used to replenish the estrogens in the brain and inhibit the effect of estrogens. Surgery and anesthesia did not cause POCD in female mice (P>0.05), while the cognitive function decreased significantly after estrogen receptor inhibitor was given(P<0.05). Male mice experienced cognitive dysfunction after surgery and anesthesia, and their cognitive function improved after estrogens supplementation (P<0.05). Given estrogens and estrogen receptor inhibitors at the same time, the cognitive function of male mice could not be saved (P<0.05). By correlation analysis, there was a negative correlation between the content of hippocampal estrogens and microglia (P<0.05). The number or degree of activation of microglia affected the synaptic plasticity, which ultimately regulated the cognitive function of mice. Hippocampal estrogens rescued the decline of synaptic plasticity after surgery and anesthesia by inhibiting microglia overactivation.


Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease.
Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.


US health policy related to hookah tobacco smoking.
Although US cigarette smoking is decreasing, hookah tobacco smoking (HTS) is an emerging trend associated with substantial toxicant exposure. We assessed how a representative sample of US tobacco control policies may apply to HTS. We examined municipal, county, and state legal texts applying to the 100 largest US cities. We developed a summary policy variable that distinguished among cities on the basis of how current tobacco control policies may apply to HTS and used multinomial logistic regression to determine associations between community-level sociodemographic variables and the policy outcome variable. Although 73 of the 100 largest US cities have laws that disallow cigarette smoking in bars, 69 of these cities have exemptions that allow HTS; 4 of the 69 have passed legislation specifically exempting HTS, and 65 may permit HTS via generic tobacco retail establishment exemptions. Cities in which HTS may be exempted had denser populations than cities without clean air legislation. Although three fourths of the largest US cities disallow cigarette smoking in bars, nearly 90% of these cities may permit HTS via exemptions. Closing this gap in clean air regulation may significantly reduce exposure to HTS.


Palladium-catalyzed intramolecular chloroamination of alkenes.
A mild and facile Pd-catalyzed intramolecular chloroamination of unactivated alkenes has been described. This reaction takes place at room temperature and is tolerant of synthetically useful acid-sensitive functional groups. Generally high exo-selectivities are observed in the formation of a variety of 5- and 6-membered rings. This system is unique in its ability to tolerate multidentate ligands on palladium, which opens up the possibility of controlling the absolute sense of induction using a chiral ligand.


Nanoalloys based on clays: intercalated semicrystalline blends of syndiotactic polystyrene with poly(2,6-dimethyl-p-phenylene oxide).
Nanoalloys of syndiotactic polystyrene with poly(2,6-dimethyl-p-phenylene oxide) clay were prepared by a solution intercalation technique using 1,1,2,2-tetrachloroethane. A mixed intercalated/exfoliated morphology in the nanoalloys containing organo-clays is evinced by transmission electron microscopy. Thermal stability is found to improve with 5% by weight of organo-clays, but a reverse trend is observed by increasing the concentration of clay. The influence of montmorillonite clays in isothermal melt-crystallization behavior of blends was thoroughly investigated by using differential scanning calorimetry and wide-angle X-ray diffraction. A considerable change in polymorphic behavior of syndiotactic polystyrene is observed by the incorporation of different clays into the blends, and the temperature window of isothermal crystallization for the formation of a-crystals of syndiotactic polystyrene is found to broaden in the presence of organo-clays. In contrast, the pristine clay is found to induce only the beta-crystal of syndiotactic polystyrene at all the crystallization temperatures studied in this work. The amorphous component poly(2,6-dimethyl-p-phenylene oxide) affects the crystallinity of syndiotactic polystyrene adversely and favors the beta-form of syndiotactic polystyrene in blends; a-crystals are observed in the nano-alloys containing 20 wt% of poly(2,6-dimethyl-p-phenylene oxide). The crystalline morphology, as characterized by polarized optical microscopy, clearly indicates rapid formation of the alpha-form induced by the nanoscale dispersion of organo-clays in spherulites of smaller dimension.


Arthroscopic Bankart repair for traumatic anterior shoulder instability with the use of suture anchors.
The arthroscopic method offers a less invasive technique of Bankart repair for traumatic anterior shoulder instability. The results continue to improve with the advancements made in instrumentation and technique. This study aims to evaluate the outcome of arthroscopic Bankart repair with the use of suture anchors for cases that were followed-up for at least two years from the date of surgery. This was a consecutive series of 40 shoulders in 37 patients who underwent arthroscopic Bankart repair with suture anchor. The mean age at the time of operation was 26.3 years. The patients were assessed with two different outcome measurement tools (the University of California at Los Angeles [UCLA] shoulder rating scale and simple shoulder test [SST] score). The mean duration of follow-up was 30.2 months. The recurrence rate, range of motion, and postoperative function were evaluated. The two shoulder scores significantly improved after surgery (p-value is less than 0.05). According to the UCLA scale, 37 shoulders (92.5 percent) had excellent or good scores, one shoulder (2.5 percent) had a fair score, and two (five percent) had poor scores. All 12 components of SST showed improvement, which was statistically significant. Overall, the rate of postoperative recurrence was 7.5 percent (three shoulders). All patients either maintained or demonstrated improvement of range of motion. There was no loss of external rotation range of motion postoperatively. Arthroscopic Bankart repair with the use of suture anchors is a reliable treatment method that can provide a good clinical outcome with excellent postoperative shoulder motion and low recurrence rate.


Clinical and biochemical responses after Gamma Knife surgery for a dopamine-secreting paraganglioma: case report.
The efficacy of Gamma Knife surgery (GKS) in local tumor control of non-secreting paragangliomas (PGLs) has been fully described by previous studies. However, with regard to secreting PGL, only one previous case report exists advocating its efficacy at a biological level. The aims of this study were: 1) to evaluate the safety/efficacy of GKS in a dopamine-secreting PGL; 2) to investigate whether the biological concentrations of free methoxytyramine could be used as a marker of treatment efficacy during the follow-up. We describe the case of a 62-year-old man diagnosed with left PGL. He initially underwent complete surgical excision. Thirty months after, he developed recurrent biological and neuroradiological disease; the most sensitive biomarker for monitoring the disease, concentration of plasma free methoxytyramine, started to increase. GKS was performed at a maximal marginal dose of 16 Gy. During the following 30 months, concentration of free methoxytyramine gradually decreased from 0.14 nmol/l (2*URL) before GKS to 0.09 nmol/l, 6 months after GKS and 0.07 nmol/l at the last follow-up after GKS (1.1*URL), confirming the efficacy of the treatment. Additionally, at 30 months there was approximately 36.6% shrinkage from the initial target volume. The GKS treatment was safe and effective, this being confirmed clinically, neuroradiologically and biologically. The case illustrates the importance of laboratory tests taking into account methoxytyramine when analyzing biological samples to assess the biochemical activity of a PGL. In addition, the identification of methoxytyramine as a unique positive biomarker could designate it for the monitoring of tumor relapse after treatments, including Gamma Knife surgery.


Causal link between lipid profile and bone mineral density: A Mendelian randomization study.
The level of serum lipids is associated with bone mineral density (BMD), an important skeletal trait. Yet the causality has not been determined. Here we performed a Mendelian randomization (MR) analysis to test potential causal links between BMD and lipid profile, i.e., low-density lipoprotein cholesterol (LDC-c), total cholesterol (TC), triglyceride (TG) and high-density lipoprotein cholesterol (HDL-c). We observed causal effect of LDL-c, TC and TG to BMD, and reversely the effect of BMD to HDL-c. We further explored the effect of body mass index (BMI) in these causalities and found that the effect of LDL-c, TC and TG to BMD is independent of BMI. Our findings provided useful information in the clinical relevance of blood lipids on BMD variation and osteoporosis risk.


Waterborne diseases classification and relationship with social-environmental factors in Florianópolis city - Southern Brazil.
This study aimed to investigate and classify the occurrence of waterborne diseases in Florianópolis city, Santa Catarina State, Southern Brazil and to correlate these diseases with the following social-environmental indicators of the local population: type of water supply, adequate collection and sewage treatment, areas of flooding and domestic water tank cleaning. Reports of outpatients were analyzed for surveillance of waterborne diseases during the period of 2002 to 2009. Waterborne diseases were classified into four groups: Group A: diarrheal diseases; Group B: parasitological diseases; Group C: skin diseases and Group D: eye diseases. The diarrheal, parasitological and skin diseases were the most frequently reported. Waterborne diseases belonging to Group A in all sites were correlated with other waterborne diseases groups, which can be an indicator of the circulation of other waterborne diseases. Regarding the social-environmental indicators assessed, the most correlated with waterborne diseases were the origin and quality of the water supply, followed by inadequate collection and treatment of sewage, frequent flooding, and finally the lack of cleanliness of the water reservoir. The results highlight the need for policies aiming for improvement of the sanitation service in the maintenance of human, animal and environmental health.


Endocarpic microorganisms of two types of windrow-dried peanut fruit (Arachis hypogaea L.).
The endocarpic microorganisms of peanut fruit dried in either a random windrow (plants left as they fell from the digger) or an inverted windrow (plants inverted to expose fruit to sunlight) were different from that of freshly dug fruit. Chaetomium, Penicillium, Trichoderma, Rhizoctonia, and Fusarium were the dominant fungi found associated with shells (pericarp) of freshly dug fruit. The dominant fungi of shells of windrowed fruit included Chaetomium, Rhizoctonia, Fusarium, Sclerotium, and Alternaria. Seeds of freshly dug fruit were dominated by Penicillium and Aspergillus. The only dominant species in seed of windrowed fruit was Penicillium. Microorganisms were isolated from shells and seed of freshly dug fruit at a frequency of 79% and 52%, respectively. The percentage of infestation was reduced by drying in the field. This was particularly true of the inverted windrow. The proportion of shells and seed infested with a microorganism was reduced 13% and 36%, respectively, after field drying for 5 to 7 days in random and inverted windrows. Microorganisms were isolated much more frequently from shell pieces (73%) than from seed (36%).


The potential energy landscape contribution to the dynamic heat capacity.
The dynamic heat capacity of a simple polymeric, model glassformer was computed using molecular dynamics simulations by sinusoidally driving the temperature and recording the resultant energy. The underlying potential energy landscape of the system was probed by taking a time series of particle positions and quenching them. The resulting dynamic heat capacity demonstrates that the long time relaxation is the direct result of dynamics resulting from the potential energy landscape. Moreover, the equilibrium (low frequency) portion of the potential energy landscape contribution to the heat capacity is found to increase rapidly at low temperatures and at high packing fractions. This increase in the heat capacity is explained by a statistical mechanical model based on the distribution of minima in the potential energy landscape.


Axenfeld's anomaly and related disorders.
Axenfeld's anomaly is a bilateral disorder characterized by a prominent, anteriorly displaced. Schwalbe's line (posterior embryotoxon) and peripheral iris strands which span the anterior chamber angle to attach to Schwalbe's line. Although this particular condition is benign, the two clinical features manifested are observed in other ocular disorders with potentially sight-threatening sequelae. An asymptomatic patient with Axenfeld's anomaly presented to our office for routine eye care. A case report, discussion of the condition and differential diagnoses are presented regarding this ocular anomaly and related disorders.


Repetitive levosimendan infusions for patients with advanced chronic heart failure in the vulnerable post-discharge period: The multinational randomized LeoDOR trial.
The LeoDOR trial explored the efficacy and safety of intermittent levosimendan therapy in the vulnerable phase following a hospitalization for acute heart failure (HF). In this prospective multicentre, double-blind, two-armed trial, patients with advanced HF were randomized 2:1 at the end of an index hospitalization for acute HF to intermittent levosimendan therapy or matching placebo for 12 weeks. All patients had left ventricular ejection fraction (LVEF) ≤30% during index hospitalization. Levosimendan was administered according to centre preference either as 6 h infusion at a rate of 0.2 μg/kg/min every 2 weeks, or as 24 h infusion at a rate of 0.1 μg/kg/min every 3 weeks. The primary efficacy assessment after 14 weeks was based on a global rank score consisting of three hierarchical groups. Secondary clinical endpoints included the composite risk of tiers 1 and 2 at 14 and 26 weeks, respectively. Due to the COVID-19 pandemic, the planned number of patients could not be recruited. The final modified intention-to-treat analysis included 145 patients (93 in the combined levosimendan arm, 52 in the placebo arm), which reduced the statistical power to detect a 20% risk reduction in the primary endpoint to 60%. Compared with placebo, intermittent levosimendan had no significant effect on the primary endpoint: the mean rank score was 72.55 for the levosimendan group versus 73.81 for the placebo group (p = 0.863). However, there was a signal towards a higher incidence of the individual clinical components of the primary endpoint in the levosimendan group versus the placebo group both after 14 weeks (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.12-7.68; p = 0.021) and 26 weeks (HR 1.64, 95% CI 0.87-3.11; p = 0.122). Among patients recently hospitalized with HF and reduced LVEF, intermittent levosimendan therapy did not improve post-hospitalization clinical stability.


Mechanics of a 'simple' ear: tympanal vibrations in noctuid moths.
Anatomically, the ears of moths are considered to be among the simplest ears found in animals. Microscanning laser vibrometry was used to examine the surface vibrations of the entire tympanal region of the ears of the noctuid moths Agrotis exclamationis, Noctua pronuba, Xestia c-nigrum and Xestia triangulum. During stimulation with ultrasound at intensities known to activate receptor neurones, the tympanum vibrates with maximum deflection amplitudes at the location where the receptor cells attach. In the reportedly heterogeneous tympana of noctuid moths, this attachment site is an opaque zone that is surrounded by a transparent, thinner cuticular region. In response to sound pressure, this region moves relatively little compared with the opaque zone. Thus, the deflections of the moth tympanic membrane are not those of a simple circular drum. The acoustic sensitivity of the ear of N. pronuba, as measured on the attachment site, is 100+/-14 nm Pa(-1) (N=10), corresponding to tympanal motion of a mere 200 pm at sound pressure levels near the neural threshold.


Neuroprotective Properties of Cardoon Leaves Extracts against Neurodevelopmental Deficits in an In Vitro Model of Rett Syndrome Depend on the Extraction Method and Harvest Time.
This study investigates the bioactive properties of different extracts of cardoon leaves in rescuing neuronal development arrest in an in vitro model of Rett syndrome (RTT). Samples were obtained from plants harvested at different maturity stages and extracted with two different methodologies, namely Naviglio® and supercritical carbon dioxide (scCO2). While scCO2 extracts more hydrophobic fractions, the Naviglio® method extracts phenolic compounds and less hydrophobic components. Only the scCO2 cardoon leaves extract obtained from plants harvested in spring induced a significant rescue of neuronal atrophy in RTT neurons, while the scCO2 extract from the autumn harvest stimulated dendrite outgrowth in Wild-Type (WT) neurons. The scCO2 extracts were the richest in squalene, 3ß-taraxerol and lupeol, with concentrations in autumn harvest doubling those in spring harvest. The Naviglio® extract was rich in cynaropicrin and exerted a toxic effect at 20 µM on both WT and RTT neurons. When cynaropicrin, squalene, lupeol and 3ß-taraxerol were tested individually, no positive effect was observed, whereas a significant neurotoxicity of cynaropicrin and lupeol was evident. In conclusion, cardoon leaves extracts with high content of hydrophobic bioactive molecules and low cynaropicrin and lupeol concentrations have pharmacological potential to stimulate neuronal development in RTT and WT neurons in vitro.


Innate immunity induced by fungal β-glucans via dectin-1 signaling pathway.
Mushrooms are a highly valuable source of substances that possess unique biological properties and medicinal efficacy. Medicinal mushrooms traditionally have been used to treat cancer, fungal infections, hypertension, diabetes, inflammation, and renal disorders. Medicinal mushrooms produce high-molecular-weight β-glucans, which have antitumor and antifungal activities that stimulate innate immunity. Innate immune cells express pattern recognition receptors (PRRs) such as dectin-1, Toll-like receptors, and mannose receptors on their cell surfaces. These PRRs recognize pathogens by binding to highly conserved pathogen-associated molecular patterns such as β-glucan, mannan, and lipopolysaccharide. The immunomodulating activities of innate immune cells are augmented by the binding of β-glucans to dectin-1 that is expressed by macrophages or dendritic cells. Upon binding β-glucan, innate immune cells activate adaptive immune cells such as B and T lymphocytes or natural killer cells by secreting various cytokines such as interleukins (IL-4, IL-6) and tumor necrosis factor-α. Water-insoluble β-glucans have stronger immunostimulating activities than their water-soluble counterparts. β-glucans have antifungal activity that is similar to their anticancer activities and is mediated by binding to dectin-1, albeit by an unknown mechanism. In this review we discuss recent progress in understanding the mechanisms responsible for the antitumor activities of fungal β-glucans that act through pathogen-associated molecular patterns and PRRs.


Cobalamin inactivation decreases purine and methionine synthesis in cultured lymphoblasts.
The megaloblastic anemia of cobalamin deficiency appears secondary to decreased methionine synthetase activity. Decreased activity of this enzyme should cause 5-methyltetrahydrofolate to accumulate intracellularly, and consequently, decrease purine and DNA synthesis; this is the basis of the "methylfolate trap" hypothesis of cobalamin deficiency. However, only some of the clinical and biochemical manifestations of cobalamin deficiency can be explained by the methylfolate trap. We investigated cobalamin deficiency by treating cultured human lymphoblasts with N2O since N2O inhibits methionine synthetase activity by inactivating cobalamin. We found that 4 h of N2O exposure reduced rates of methionine synthesis by 89%. Rates of purine synthesis were not significantly reduced by N2O when folate and methionine were present at 100 microM in the medium; however, at the physiologic methionine concentration of 10 microM, N2O decreased rates of purine synthesis by 33 and 57% in the presence of 100 microM folate and in the absence of folate, respectively. The dependency of rates of purine synthesis on methionine availability would be expected in cells with restricted methionine synthetic capacity because methionine is the immediate precursor of S-adenosylmethionine, a potent inhibitor of 5-methyltetrahydrofolate synthesis; methionine serves as a source of formate for purine synthesis; and rates of purine synthesis are dependent on the intracellular availability of essential amino acids. We conclude that cobalamin inactivation decreases purine synthesis by both methylfolate trapping and reduction of intracellular methionine synthesis.


Evaluation of highly accelerated real-time cardiac cine MRI in tachycardia.
Electrocardiogram (ECG)-gated breath-hold cine MRI is considered to be the gold standard test for the assessment of cardiac function. However, it may fail in patients with arrhythmia, impaired breath-hold capacity and poor ECG gating. Although ungated real-time cine MRI may mitigate these problems, commercially available real-time cine MRI pulse sequences using parallel imaging typically yield relatively poor spatiotemporal resolution because of their low image acquisition efficiency. As an extension of our previous work, the purpose of this study was to evaluate the diagnostic quality and accuracy of eight-fold-accelerated real-time cine MRI with compressed sensing (CS) for the quantification of cardiac function in tachycardia, where it is challenging for real-time cine MRI to provide sufficient spatiotemporal resolution. We evaluated the performances of eight-fold-accelerated cine MRI with CS, three-fold-accelerated real-time cine MRI with temporal generalized autocalibrating partially parallel acquisitions (TGRAPPA) and ECG-gated breath-hold cine MRI in 21 large animals with tachycardia (mean heart rate, 104 beats per minute) at 3T. For each cine MRI method, two expert readers evaluated the diagnostic quality in four categories (image quality, temporal fidelity of wall motion, artifacts and apparent noise) using a Likert scale (1-5, worst to best). One reader evaluated the left ventricular functional parameters. The diagnostic quality scores were significantly different between the three cine pulse sequences, except for the artifact level between CS and TGRAPPA real-time cine MRI. Both ECG-gated breath-hold cine MRI and eight-fold accelerated real-time cine MRI yielded all four scores of ≥ 3.0 (acceptable), whereas three-fold-accelerated real-time cine MRI yielded all scores below 3.0, except for artifact (3.0). The left ventricular ejection fraction (LVEF) measurements agreed better between ECG-gated cine MRI and eight-fold-accelerated real-time cine MRI (mean difference, -1.6%) than between ECG-gated cine MRI and three-fold-accelerated real-time cine MRI (mean difference, -5.7%). Eight-fold-accelerated real-time cine MRI with CS yields acceptable diagnostic quality and relatively accurate LVEF measurements in the challenging setting of tachycardia.


Stem cell-based therapy in gastroenterology and hepatology.
Protagonists of a new scientific era, stem cells are promising tools on which regenerative medicine relies for the treatment of human pathologies. Stem cells can be obtained from various sources, including embryos, fetal tissues, umbilical cord blood, and also terminally differentiated organs. Once forced to expand and differentiate into functional progenies, stem cells may become suitable for cell replacement and tissue engineering. The manipulation and/or stimulation of adult stem cells seems to be particularly promising, as it could improve the endogenous regenerative potential without risks of rejection and overcome the ethical and political issues related to embryonic stem cell research. Stem cells are already leaving the bench and reaching the bedside, despite an incomplete knowledge of the genetic control program driving their fate and plasticity. In gastroenterology and hepatology, the first attempts to translate stem cell basic research into novel therapeutic strategies have been made for the treatment of several disorders, such as inflammatory bowel diseases, diabetes mellitus, celiachy and acute or chronic hepatopaties. Nonetheless, critical aspects need to be further addressed, including the long-term safety, tolerability and efficacy of cell-based treatments, as well as their carcinogenic potential. Aim of this review is to summarize the state-of-the-arts on gastrointestinal and hepatic stem cells and on stem cell-based therapies in gastroenterology and hepatology, highlighting both the benefits and the potential risks of these new tools for the treatment and prevention of human diseases.


Medical Students' Reactions to Uncertainty During Clinical Rotations.
Family physicians routinely manage uncertainty in their clinical practice. During their first year of clinical rotations, medical students learn communication and patient care skills that will influence the care they provide as future physicians. However, little is known about how their reactions to uncertainty change during this formative year, and medical education often fails to teach students how to manage uncertainty effectively. This study employs a repeated measures analysis of students' reactions to uncertainty over the course of their third year. We surveyed 273 medical students at four time points during their third year and employed hierarchical linear modeling to analyze a series of models in which phase and intolerance of uncertainty were entered as covariates. We modeled age and gender as control variables. Analyses revealed that students' affective reactions to uncertainty did not significantly change during the third year, but reluctance to disclose uncertainty to physicians and patients significantly decreased across phases. Analyses also showed that general intolerance of uncertainty predicted affective reactions to medical-specific uncertainty. These findings confirm that students experience negative reactions to uncertainty during clinical rotations. Students would benefit from curriculum designed to mitigate consequences of negative affective reactions to uncertainty, particularly those students characteristically higher in intolerance of uncertainty. Given that students demonstrated more willingness to communicate about their uncertainty over time, medical school should equip students with the communication skills needed to discuss their uncertainty effectively with patients and preceptors.


Review of national AIDS councils in Africa: findings from five countries.
National AIDS councils (NACs) were established in many African countries to co-ordinate the multi-sectoral response to HIV/ AIDS. Their main mandate is to provide strategic leadership and co-ordinate activities geared to fight against HIV/AIDS. This study sought to understand the extent to which NACs have achieved their goals and the challenges they face. Best practices were identified and shared among countries involved, so as to enhance their efforts. This review is crucial given that the fight against HIV/AIDS is far from being won. Data for this study were collected from five countries: Ghana, Tanzania, Kenya, Zimbabwe and Lesotho. A qualitative study approach was employed by conducting individual in-depth interviews with senior staff members of NACs. We also collected important NAC documents that are used in achieving their mandates. The NAC documentation seemed to be in order in all countries visited, and there was a good understanding of the NACs' mandate and their functioning. There were numerous constraints and challenges that need to be addressed in order to make NACs perform their activities better. NACs need to operate independently of the usual government bureaucracy. Additional work is still needed by governments in making NACs responsible for the multi-sectoral response in sub-Saharan Africa.


[Avoidable "fever of unknown origin" due to Ralstonia pickettii bacteremia].
Ralstonia pickettii bacteraemia from the atrial part of a ventriculo-atrial shunt was diagnosed as the cause of recurring febrile episodes with systemic toxicity in a 38-year old female. A prior neurosurgical resection of intracerebral cavernoma was complicated by postoperative recurrent meningitis with this non-fermenting gram-negative rod, due to an intra-operative contamination of a in situ shunt, from which only the intracerebral part of the ventriculo-atriostomy had been removed, following the episodes of meningitis. Ralstonia pickettii is a rare isolate and is seldom identified as a human pathogen. It formerly belonged to the genera Pseudomonas and Burkholderia. There are some casuistic reports of nosocomial bacteraemias, associated with the use of contaminated IV products or aerosols. There was an important diagnostic delay due to (1) insufficient communication between the different medical doctors in several hospitals, in different episodes of the clinical follow-up and (2) a misinterpretation of a positive blood culture with R. pickettii, which was interpreted as contamination. This misinterpretation and insufficient data transfer caused a considerable delay in the diagnostic process.


Healthcare workers' compliance with the catheter associated urinary tract infection prevention guidelines: an observational study in Yemen.
Catheter-associated urinary tract infection is a global problem but it can be prevented with the appropriate implementation of evidence-based guidelines. This study was conducted to assess the level of compliance of healthcare workers with the catheter-associated urinary tract infection prevention guidelines during the insertion of a urinary catheter. An observational study using a descriptive cross-sectional design was conducted at Sana'a City hospitals, Yemen. All the nurses and physicians from the governmental, teaching, and private hospitals were eligible to participate in the study. The data collection was performed through convenience sampling from March 2020 to December 2020, using a structured observational checklist prepared specifically for this study. The majority of the urinary catheter insertions were performed by nurses. There were no written policy or procedures for an urinary catheter insertion and no in-service education or training departments in the majority of the hospitals. The overall mean score of compliance was 7.31 of 10. About 71% of the healthcare workers had a high or acceptable level of compliance and 29% had an unsafe level of compliance. Compliance was low for maintaining aseptic technique throughout the insertion procedure, using a single use packet of lubricant jelly, performing hand hygiene immediately before insertion, and securing the urinary catheter once inserted. Factors affecting the healthcare workers compliance were gender, the working ward/unit of the healthcare workers, the availability of a written policy/procedure and a department or unit for in-service education. Yemeni healthcare workers' overall compliance was acceptable but it was unsafe in several critical measures. There is an urgent need for developing, implementing, and monitoring national guidelines and institutional policy and procedures for catheter-associated urinary tract infection prevention. Periodical in-service education and training programs and adequate access to the necessary materials and supplies are paramount.


Improvement of foaming property of egg white protein by phosphorylation through dry-heating in the presence of pyrophosphate.
Egg white protein (EWP) was phosphorylated by dry-heating in the presence of pyrophosphate at pH 4 and 85 degrees C for 1 d, and the foaming properties of phosphorylated EWP (PP-EWP) were investigated. The phosphorus content of EWP increased to 0.71% as a result of phosphorylation. To estimate the foaming properties of EWP, the foams were prepared by 2 methods: bubbling of the 0.1% (w/v) protein solution and whipping of the 10% (w/w) protein solution with an electric mixer. The foaming power, which was defined as an initial conductivity of foam from 0.1% (w/v) protein solution, was a little higher in PP-EWP than in native EWP (N-EWP), and the foaming stability of PP-EWP was much higher than that of dry-heated EWP (DH-EWP) and N-EWP. The microscopic observation of foams from the 10% (w/w) solution showed that the foams of PP-EWP were finer and more uniform than those of N- and DH-EWP. Although there were no significant differences in the specific gravity and overrun of the foams between PP- and DH-EWP (P < 0.05), the specific gravity and overrun of the foams from PP-EWP were smaller and higher, respectively, than that of the foams from N-EWP. The drainage volume was smaller in the foams from PP-EWP than in those from N- and DH-EWP. These results demonstrated that phosphorylation of EWP by dry-heating in the presence of pyrophosphate improved the foaming properties, and that it was more effective for the foam stability than for the foam formation.


Relationship between empathic family attitude and relapse in schizophrenia: a 2-year followup prospective study.
Empathy plays a central role in social relationships, and lack of empathy has been suggested as part of expressed emotion in the relatives of patients with schizophrenia. The aim of this research is to measure empathy in the relatives of schizophrenia patients and to establish the relationship between lack of empathy and relapse. Eighty schizophrenia patients were followed up in a 2-year prospective cohort study. Relatives' empathy, defined as the ability to perceive the patient's mood state, was measured at the beginning of the study with a questionnaire given after a 10-minute interaction between the patient and his or her relative. Several other attitudinal, clinical, and social variables were also measured. A significant relationship was found between poor empathic attitude and relapse. Lack of treatment compliance, negative symptoms, unemployment, and poor premorbid adjustment were also associated with relapse. In a multivariate analysis, the association between poor empathic attitude and relapse was maintained. Statistical control of the relatives' critical attitude showed that each kind of attitude predicts relapse independently.


Early and late pulmonary complications of botulism.
Pulmonary complications of botulism were studied in an outbreak of 34 cases of type A botulism in New Mexico in 1978. Hospital record review, standardized questionnaires, and pulmonary function tests were used to define pulmonary complications during the acute illness and the patient's status one year later. Pulmonary involvement was documented in 81% of patients. Ventilatory failure occurred in 11, aspiration pneumonia in nine, and death in two patients. Difficulties in the diagnosis of ventilatory insufficiency were identified. At one year, most patients had residual symptoms, including easy fatigability in 68% and exertional dyspnea in 46%. However, only minor pulmonary function abnormalities were present. This study confirms the generally favorable prognosis of botulism and provides clinical guidance for the diagnosis and management of pulmonary complications in botulism.


Modeling the environmental suitability of anthrax in Ghana and estimating populations at risk: Implications for vaccination and control.
Anthrax is hyper-endemic in West Africa. Despite the effectiveness of livestock vaccines in controlling anthrax, underreporting, logistics, and limited resources makes implementing vaccination campaigns difficult. To better understand the geographic limits of anthrax, elucidate environmental factors related to its occurrence, and identify human and livestock populations at risk, we developed predictive models of the environmental suitability of anthrax in Ghana. We obtained data on the location and date of livestock anthrax from veterinary and outbreak response records in Ghana during 2005-2016, as well as livestock vaccination registers and population estimates of characteristically high-risk groups. To predict the environmental suitability of anthrax, we used an ensemble of random forest (RF) models built using a combination of climatic and environmental factors. From 2005 through the first six months of 2016, there were 67 anthrax outbreaks (851 cases) in livestock; outbreaks showed a seasonal peak during February through April and primarily involved cattle. There was a median of 19,709 vaccine doses [range: 0-175 thousand] administered annually. Results from the RF model suggest a marked ecological divide separating the broad areas of environmental suitability in northern Ghana from the southern part of the country. Increasing alkaline soil pH was associated with a higher probability of anthrax occurrence. We estimated 2.2 (95% CI: 2.0, 2.5) million livestock and 805 (95% CI: 519, 890) thousand low income rural livestock keepers were located in anthrax risk areas. Based on our estimates, the current anthrax vaccination efforts in Ghana cover a fraction of the livestock potentially at risk, thus control efforts should be focused on improving vaccine coverage among high risk groups.


Unique and highly selective anticytomegalovirus activities of artemisinin-derived dimer diphenyl phosphate stem from combination of dimer unit and a diphenyl phosphate moiety.
We report that the artemisinin-derived dimer diphenyl phosphate (DPP; dimer 838) is the most selective inhibitor of human cytomegalovirus (CMV) replication among a series of artemisinin-derived monomers and dimers. Dimer 838 was also unique in being an irreversible CMV inhibitor. The peroxide unit within artemisinins' chemical structures is critical to their activities, and its absence results in loss of anti-CMV activities. Surprisingly, the deoxy dimer of 838 retained modest anti-CMV activity, suggesting that the DPP moiety of dimer 838 contributes to its anti-CMV activities. DPP alone did not inhibit CMV replication, but triphenyl phosphate (TPP) had modest CMV inhibition, although its selectivity index was low. Artemisinin DPP derivatives dimer 838 and monomer diphenyl phosphate (compound 558) showed stronger CMV inhibition and a higher selectivity index than their analogs lacking the DPP unit. An add-on and removal assay revealed that removing DPP derivatives (compounds 558 and 838) but not the non-DPP backbones (artesunate and compound 606) at 24 h postinfection (hpi) already resulted in dominant CMV inhibition. CMV inhibition was fully irreversible with 838 and partially irreversible with 558, while non-DPP artemisinins were reversible inhibitors. While all artemisinin derivatives and TPP reduced the expression of the CMV immediate early 2 (IE2), UL44, and pp65 proteins at or after 48 hpi, only TPP inhibited the expression of both IE1 and IE2. Combination of a non-DPP dimer (compound 606) with TPP was synergistic in CMV inhibition, while ganciclovir and TPP were additive. Although TPP shared structural similarity with monomer DPP (compound 558) and dimer DPP (compound 838), its pattern of CMV inhibition was significantly different from the patterns of the artemisinins. These findings demonstrate that the DPP group contributes to the unique activities of compound 838.


All twist and no bend makes raft edges splay: Spontaneous curvature of domain edges in colloidal membranes.
Using theory and experiments, we study the interface between two immiscible domains in a colloidal membrane composed of rigid rods of different lengths. Geometric considerations of rigid rod packing imply that a domain of sufficiently short rods in a background membrane of long rods is more susceptible to twist than the inverse structure, a long-rod domain in a short-rod membrane. The midplane tilt at the interdomain edge forces splay, which, in turn, manifests as spontaneous edge curvature with energetics controlled by the length asymmetry of constituent rods. A thermodynamic model of such tilt-curvature coupling at interdomain edges explains a number of experimental observations, including annularly shaped long-rod domains, and a nonmonotonic dependence of edge twist on domain radius. Our work shows how coupling between orientational and compositional degrees of freedom in two-dimensional fluids gives rise to complex shapes of fluid domains, analogous to shape transitions in 3D fluid vesicles.


Changes in the clinical picture of schizophrenia.
Records of all patients admitted to inpatient facilities of a state department of mental health from 1948 to 1952 and from 1965 to 1969 and diagnosed schizophrenic were reviewed to determine diagnostic trends, if any. The percentage of diagnoses of the catatonic subtype showed a general decline, the hebephrenic subtype showed a marked decline, the paranoid subtype a general increase, and the nonclassical subtypes a marked increase. Analysis of the symptoms for the subtypes and comparison between subtypes did not reveal any particular symptoms to be totally characteristic of a specific subtype. Many symptoms occurred with approximately equal frequency in all subtypes. Comparison of patients' symptoms for the two periods did not reveal wide qualitative variation between periods. However, there were large quantitative variations. We conclude that the apparent change in schizophrenia is but a moderation of primary symptoms.


The adhesion molecule on glia (AMOG) is a homologue of the beta subunit of the Na,K-ATPase.
AMOG (adhesion molecule on glia) is a Ca2(+)-independent adhesion molecule which mediates selective neuron-astrocyte interaction in vitro (Antonicek, H., E. Persohn, and M. Schachner. 1987. J. Cell Biol. 104:1587-1595). Here we report the structure of AMOG and its association with the Na,K-ATPase. The complete cDNA sequence of mouse AMOG revealed 40% amino acid identity with the previously cloned beta subunit of rat brain Na,K-ATPase. Immunoaffinity-purified AMOG and the beta subunit of detergent-purified brain Na,K-ATPase had identical apparent molecular weights, and were immunologically cross-reactive. Immunoaffinity-purified AMOG was associated with a protein of 100,000 Mr. Monoclonal antibodies revealed that this associated protein comprised the alpha 2 (and possibly alpha 3) isoforms of the Na,K-ATPase catalytic subunit, but not alpha 1. The monoclonal AMOG antibody that blocks adhesion was shown to interact with Na,K-ATPase in intact cultured astrocytes by its ability to increase ouabain-inhibitable 86Rb+ uptake. AMOG-mediated adhesion occurred, however, both at 4 degrees C and in the presence of ouabain, an inhibitor of the Na,K-ATPase. Both AMOG and the beta subunit are predicted to be extracellularly exposed glycoproteins with single transmembrane segments, quite different in structure from the Na,K-ATPase alpha subunit or any other ion pump. We hypothesize that AMOG or variants of the beta subunit of the Na,K-ATPase, tightly associated with an alpha subunit, are recognition elements for adhesion that subsequently link cell adhesion with ion transport.


[The immunosuppressive action of different fractions of Salmonella typhimurium lipopolysaccharide].
The suppressing activity of lipopolysaccharide (LPS) of the filtrates of genetically related S. typhimurium 415 and 415/307 cultures with respect to delayed hypersensitivity to nonbacterial antigen in mice was studied. In LPS of the virulent strain two immunosuppressing fractions differing in their molecular weight were detected by the method of gel filtration. One of them was detected in LPS of the genetically related nonplasmid clone of S. typhimurium 415/307. The possibility of the chemical inactivation and reactivation of the immunosuppressing properties of LPS was shown.


Acquired Cystic Disease-Associated Renal Cell Carcinoma: Review of Pathogenesis, Morphology, Ancillary Tests, and Clinical Features.
Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is a recently described subtype of RCC found in individuals with ACD of the kidney. Because of underrecognition, information regarding this lesion is sparse but continues to accumulate with each new report. Herein, a thorough literature review amassing the current understanding of this unique neoplasm is presented. Discussion focuses on clinical features, pathogenesis, disease outcome, and relation to the duration of dialysis. The macroscopic and characteristic microscopic features are described with illustrations. Compared with previous opinion, compiled immunohistochemical data may now allow for recognition of a unique immunophenotypic pattern of ACD-RCC. Distinction of ACD-RCC from clear cell and papillary RCCs based on molecular genetic information is deliberated, including a summary of the most frequently detected cytogenetic abnormalities. The key morphologic and immunophenotypic patterns used to distinguish this entity from a comprehensive differential diagnosis are provided.


Human behavior in Prisoner's Dilemma experiments suppresses network reciprocity.
During the last few years, much research has been devoted to strategic interactions on complex networks. In this context, the Prisoner's Dilemma has become a paradigmatic model, and it has been established that imitative evolutionary dynamics lead to very different outcomes depending on the details of the network. We here report that when one takes into account the real behavior of people observed in the experiments, both at the mean-field level and on utterly different networks, the observed level of cooperation is the same. We thus show that when human subjects interact in a heterogeneous mix including cooperators, defectors and moody conditional cooperators, the structure of the population does not promote or inhibit cooperation with respect to a well mixed population.


Successful treatment of canine necrolytic migratory erythema (superficial necrolytic dermatitis) due to metastatic glucagonoma with octreotide.
Necrolytic migratory erythema (NME; also known as superficial necrolytic dermatitis) is a syndrome most often associated with certain chronic liver diseases or pancreatic glucagonomas. In humans with glucagonoma-associated NME, skin lesions usually respond to octreotide, a somatostatin analogue that inhibits glucagon release. In this report an 11-year-old golden retriever dog with pancreatic glucagonoma and metastasis to the regional lymph nodes, spleen and liver was diagnosed with NME. The dog exhibited erosions, ulcers and crusts on the paws, pressure points, muzzle, periocular area and prepuce. The dog was also anorexic and had difficulty walking. Because metastasis precluded surgery, treatment was initiated with subcutaneous octreotide (2 μg/kg twice daily). Skin lesions and systemic clinical signs improved markedly within 5 days. The dosage was increased to nearly 3 μg/kg twice daily and signs almost completely resolved within 10 days. Anorexia was the major adverse effect observed. During the following month, both dosage (1-3.7 μg/kg) and frequency (two to four times daily) of the octreotide injections were adjusted to permit control of clinical signs while maintaining adequate appetite. Temporary cessation of octreotide administration resulted in the rapid recurrence of skin lesions. Resuming injections led to improvement of clinical signs within 48 h. The dog was later euthanized because of progressive metastatic disease. In conclusion, subcutaneous octreotide injections were beneficial in this dog with glucagonoma-associated NME. This somatostatin analogue could be a valuable option to treat canine patients with non-resectable or relapsing pancreatic glucagonoma-associated NME.


Food habits and nutritional status of elderly people living in a Spanish Mediterranean city.
The aim of this study was to assess the food habits and nutritional status of free-living, non-institutionalised, elderly people of Torrevieja, a Spanish city located in the Mediterranean coast. Anthropometric and dietary survey (two 24 hour recalls) were assessed in 200 (83 men and 117 women) free-living elderly people (average age 72.3±6.6 years). Just married women accomplished the recommended energy intake. The contribution of macronutrients to the total energy intake was different from the Recommended Intake for the elderly, since it was too derived from proteins, fats, SFA and sugars, but in only small amounts was derived from complex carbohydrates. High percentages of elderly persons showed inadequate intake of calcium, zinc, magnesium, potassium, copper, iodine, folic acid, vitamin A, vitamin D, vitamin E, and riboflavin. Men showed lower micronutrient intake than women. An increase in dietary complex carbohydrate, and a decrease in protein and fats, especially SFA, is recommended. It would be desirable to increase the consumption of fruits, vegetables, whole cereals, fish and skimmed dairy products.


STATISTICALLY ASSISTED FLUID IMAGE REGISTRATION ALGORITHM - SAFIRA.
In this paper, we develop and validate a new Statistically Assisted Fluid Registration Algorithm (SAFIRA) for brain images. A non-statistical version of this algorithm was first implemented in [2] and re-formulated using Lagrangian mechanics in [3]. Here we extend this algorithm to 3D: given 3D brain images from a population, vector fields and their corresponding deformation matrices are computed in a first round of registrations using the non-statistical implementation. Covariance matrices for both the deformation matrices and the vector fields are then obtained and incorporated (separately or jointly) in the regularizing (i.e., the non-conservative Lagrangian) terms, creating four versions of the algorithm. We evaluated the accuracy of each algorithm variant using the manually labeled LPBA40 dataset, which provides us with ground truth anatomical segmentations. We also compared the power of the different algorithms using tensor-based morphometry -a technique to analyze local volumetric differences in brain structure-applied to 46 3D brain scans from healthy monozygotic twins.


Recognition and management of Lyme disease.
Lyme disease, the most common tick-borne illness in the United States, has an annual incidence of 0.5 percent in endemic areas. It most commonly occurs in the Northeast and upper Midwest, in areas that encourage and harbor the deer tick. The tick transmits an infection of the spirochete Borrelia burgdorferi that typically manifests as a localized skin lesion, erythema migrans. Rarely, Lyme disease manifests as localized arthritis, heart block or disease of the nervous system. Lyme disease is a clinical diagnosis, and laboratory tests should only be used to clarify diagnostic issues. The current standard for laboratory diagnosis includes a two-step approach using an initial immunoassay with a confirmatory Western blot. Treatment includes 10 to 21 days of oral doxycycline in nonpregnant adults or a similar course of amoxicillin in children or pregnant women. Overdiagnosis and overtreatment of Lyme disease have become common.


Efficacy and safety of dutasteride, tamsulosin and their combination in a subpopulation of the CombAT study: 2-year results in Asian men with moderate-to-severe BPH.
Although ethnicity-based differences in prostate size and physiology have been reported, results of benign prostatic hyperplasia (BPH) treatment trials in predominantly Caucasian patients are assumed to be applicable to non-Caucasian populations. This post hoc analysis investigated whether an Asian subpopulation of men with moderate-to-severe BPH in the CombAT study achieves treatment responses in line with those of the overall study population. In this double-blind, randomized, parallel-group trial, 325 Asian men were assigned to treatment with 0.5 mg dutasteride once daily, 0.4 mg tamsulosin once daily or the combination. Decrease in international prostate symptom score (IPSS) at month 24 from baseline (the primary endpoint) was significantly greater with combination treatment compared with tamsulosin (P<0.05), and numerically, but not statistically significantly, greater compared with dutasteride. Mean IPSS was reduced from baseline by 7.5 (+/-0.84) in the combination group, by 6.3 (+/-0.86) in the dutasteride group and by 4.5 (+/-0.78) in the tamsulosin group, resulting in respective mean IPSS at months 24 of 11.4 (+/-0.60), 12.7 (+/-0.70) and 14.3 (+/-0.74). The adverse event profile was similar to that observed in the overall CombAT population, and drug-related adverse events were more common with combination therapy (26%) than with tamsulosin (15%) or dutasteride (9%). No unexpected adverse events emerged. In conclusion, in Asian men with moderate-to-severe lower urinary tract symptoms and an enlarged prostate, combination therapy achieved significantly greater improvements from baseline BPH symptoms, flow rate, quality of life, reduced prostate volume and improved treatment satisfaction compared with tamsulosin monotherapy.


The effectiveness of cabergoline for the prevention of ovarian hyperstimulation syndrome.
Type 2 receptors for vascular endothelial growth factor are believed to be involved in the pathophysiology of ovarian hyperstimulation syndrome (OHSS). The objective of this study was to examine the preventive effects of cabergoline on OHSS and its complications. The study is a non randomized clinical trial conducted in 2006-2008 on 75 patients, which were at risk of OHSS and underwent assisted reproductive techniques. The diagnosis and severity of OHSS were determined using standard criteria. The study included an intervention and a control group. The intervention group comprised of 50 women at risk of OHSS, who were treated with cabergoline (1 mg every other day for 8 days) commencing from the day of ovum pick up. The control group comprised of 25 historical cases, which were similar to the case group. The latter group did not receive cabergoline, and their OHSS, if occurred, were managed conservatively after hospital admission. The rates of OHSS, baseline characteristics, ovarian stimulation parameters, and pregnancy occurrence were compared. There was no significant difference between baseline characteristics or ovarian stimulation parameters form the two groups. The incidence of OHSS in the cabergoline-treated group, was significantly (P=0.01) lower than that in the control group (12% vs 36%). Embryo freezing was significantly (P=0.001) lower in the control group, but cycle cancellation was significantly (0.03) lower in the cabergoline group. The findings of the study indicate that cabergoline reduces the incidence of OHSS, and is not associated with adverse effects on pregnancy.